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68dcc601157f79f4e30776c854c2fd66fdcc6825 | wikidoc | Doxofylline | Doxofylline
# Overview
Doxofylline (INN), (also known as doxophylline) is a xanthine derivative drug used in the treatment of asthma.
It has antitussive and bronchodilator effects, and acts as a phosphodiesterase inhibitor.
In animal and human studies, it has shown similar efficacy to theophylline but with significantly fewer side effects.
Unlike other xanthines, doxofylline lacks any significant affinity for adenosine receptors and does not produce stimulant effects. This suggests that its antiasthmatic effects are mediated by another mechanism, perhaps its actions on phosphodiesterase. | Doxofylline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Doxofylline (INN), (also known as doxophylline) is a xanthine derivative drug used in the treatment of asthma.[1]
It has antitussive[citation needed] and bronchodilator[2] effects, and acts as a phosphodiesterase inhibitor.[3]
In animal and human studies, it has shown similar efficacy to theophylline but with significantly fewer side effects.[4]
Unlike other xanthines, doxofylline lacks any significant affinity for adenosine receptors and does not produce stimulant effects. This suggests that its antiasthmatic effects are mediated by another mechanism, perhaps its actions on phosphodiesterase.[1] | https://www.wikidoc.org/index.php/Doxofylline | |
4fd94e534e4c4ad466d19989a792055e32aca9ad | wikidoc | Dried fruit | Dried fruit
# Overview
Dried fruit is fruit that has been dried, either naturally or through use of a machine, such as a dehydrator. Raisins, prunes and dates are examples of popular dried fruits. Other fruits that may be dried include apples, apricots, bananas, cranberries, figs, kiwi, mangoes, pawpaw, peaches, pears, persimmons, pineapples, strawberries and tomatoes.
Dried fruit has a long shelf life and therefore can provide a good alternate to fresh fruit, allowing out of season fruits to be available. Drying is a good way to preserve fruit in the absence of refrigeration. Dried fruit is often added to baking mixes and breakfast cereals.
Dried fruits are rich in vitamins (A, B1, B2, B3, B6, pantothenic acid) and dietary minerals (calcium, iron, magnesium, phosphorus, potassium, sodium, copper, manganese). They contain approximately 250 calories and 1 - 5g of protein per 100g. .
Due to the water loss experienced during dehydration, which may be as high as 7 parts out of eight, dried fruit has a stronger, more intense flavour. However the drying process also destroys most of the Vitamin C in the food, so that the dried version of the fruit has only a fraction of the levels of Vitamin C that would exist in the fruit if it were fresh.
Commercially prepared dried fruit may contain added sulfur dioxide which can trigger asthma in sensitive individuals, though dried fruit without sulfur dioxide is also available, particularly in health stores. The sulphur is added to "fix" the color of the product. "Organic" dried fruit is produced without sulphur which results in dark fruit and the flavour is much more characteristic of the fresh fruit. The color of some fruits can also be "fixed" to some extent, with minimal impact on flavour, by treating the freshly cut fruit with a preparation rich in Vitamin C (e.g., a mixture of water and lemon juice) for a few minutes prior to drying.
In addition to dried whole fruits, fruit purée can be dried to make fruit leather. | Dried fruit
# Overview
Dried fruit is fruit that has been dried, either naturally or through use of a machine, such as a dehydrator. Raisins, prunes and dates are examples of popular dried fruits. Other fruits that may be dried include apples, apricots, bananas, cranberries, figs, kiwi, mangoes, pawpaw, peaches, pears, persimmons, pineapples, strawberries and tomatoes.
Dried fruit has a long shelf life and therefore can provide a good alternate to fresh fruit, allowing out of season fruits to be available. Drying is a good way to preserve fruit in the absence of refrigeration. Dried fruit is often added to baking mixes and breakfast cereals.
Dried fruits are rich in vitamins (A, B1, B2, B3, B6, pantothenic acid) and dietary minerals (calcium, iron, magnesium, phosphorus, potassium, sodium, copper, manganese). They contain approximately 250 calories and 1 - 5g of protein per 100g. [1][2].
Due to the water loss experienced during dehydration, which may be as high as 7 parts out of eight, dried fruit has a stronger, more intense flavour. However the drying process also destroys most of the Vitamin C in the food, so that the dried version of the fruit has only a fraction of the levels of Vitamin C that would exist in the fruit if it were fresh.
Commercially prepared dried fruit may contain added sulfur dioxide which can trigger asthma in sensitive individuals, though dried fruit without sulfur dioxide is also available, particularly in health stores. The sulphur is added to "fix" the color of the product. "Organic" dried fruit is produced without sulphur which results in dark fruit and the flavour is much more characteristic of the fresh fruit. The color of some fruits can also be "fixed" to some extent, with minimal impact on flavour, by treating the freshly cut fruit with a preparation rich in Vitamin C (e.g., a mixture of water and lemon juice) for a few minutes prior to drying.
In addition to dried whole fruits, fruit purée can be dried to make fruit leather. | https://www.wikidoc.org/index.php/Dried_fruit | |
5c7f87bc9f65e0106fbedf9520043ac92ef18e38 | wikidoc | Dromotropic | Dromotropic
A dromotropic agent is one which affects the conduction velocity of the AV node, and subsequently the rate of electrical impulses in the heart.
Agents that are dromotropic are often (but not always) inotropic and chronotropic. For example, parasympathetic stimulation is usually negatively dromotropic, inotropic, and chronotropic.
Non-dihydropyridine calcium channel blockers such as verapamil block the slow inward calcium current in cardiac tissues thereby having a negatively dromotropic, chronotropic and inotropic effect. This (and other) pharmacological effect makes these drugs useful in the treatment of angina pectoris. Conversely, they can lead to
symptomatic disturbances in cardiac conduction and bradyarrhythmias, and may aggravate left ventricular failure. | Dromotropic
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A dromotropic agent is one which affects the conduction velocity of the AV node, and subsequently the rate of electrical impulses in the heart.[1][2]
Agents that are dromotropic are often (but not always) inotropic and chronotropic. For example, parasympathetic stimulation is usually negatively dromotropic, inotropic, and chronotropic.
Non-dihydropyridine calcium channel blockers such as verapamil block the slow inward calcium current in cardiac tissues thereby having a negatively dromotropic, chronotropic and inotropic effect[3]. This (and other) pharmacological effect makes these drugs useful in the treatment of angina pectoris. Conversely, they can lead to
symptomatic disturbances in cardiac conduction and bradyarrhythmias, and may aggravate left ventricular failure[4]. | https://www.wikidoc.org/index.php/Dromotropic | |
e54642f0f7574141cd097160eb1101c75a4d3901 | wikidoc | Dronedarone | Dronedarone
- Dosing Information
- 400 mg PO bid ( taken as one tablet with the morning meal and one tablet with the evening meal)
- Treatment with Class I or III antiarrhythmics (e.g., amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (e.g., ketoconazole) must be stopped before starting MULTAQ.
# Maintain the Sinus Rhythm
- Developed by: American College of Cardiology (ACC) and American Heart Association (AHA)
- Class of Recommendation: Class IIa
- Level of Evidence: Level B
- Dosing information
- Not Applicable
- Dosing information
- 400 mg/day PO
- Permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored).
- Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms
- Second- or third-degree atrioventricular (AV) block, or sick sinus syndrome (except when used in conjunction with a functioning pacemaker).
- Bradycardia <50 bpm
- Concomitant use of strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir
- Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics
- Liver or lung toxicity related to the previous use of amiodarone
- QTc Bazett interval ≥500 ms or PR interval >280 ms
- Severe hepatic impairment
- Pregnancy (Category X): MULTAQ may cause fetal harm when administered to a pregnant woman. MULTAQ is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- Nursing mothers
- Hypersensitivity to the active substance or to any of the excipients
- MULTAQ is contraindicated in patients with NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization because it doubles the risk of death.
- Cardiovascular Death and heart failure in Permanent AF
- MULTAQ doubles the risk of cardiovascular death (largely arrhythmic) and heart failure events in patients with permanent AF. Patients treated with dronedarone should undergo monitoring of cardiac rhythm no less often than every 3 months. Cardiovert patients who are in atrial fibrillation (if clinically indicated) or discontinue MULTAQ. MULTAQ offers no benefit in subjects in permanent AF.
- Increased Risk of Stroke in Permanent AF
- In a placebo-controlled study in patients with permanent atrial fibrillation, dronedarone was associated with an increased risk of stroke, particularly in the first two weeks of therapy. MULTAQ should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy.
- New Onset or Worsening heart failure
- New onset or worsening of heart failure has been reported during treatment with MULTAQ in the postmarketing setting. In a placebo controlled study in patients with permanent AF increased rates of heart failure were observed in patients with normal left ventricular function and no history of symptomatic heart failure, as well as those with a history of heart failure or left ventricular dysfunction.
- Advise patients to consult a physician if they develop signs or symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath. If heart failure develops or worsens and requires hospitalization, discontinue MULTAQ.
- Liver Injury
- Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the postmarketing setting. Advise patients treated with MULTAQ to report immediately symptoms suggesting hepatic injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching). Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment, but it is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury. If hepatic injury is suspected, promptly discontinue MULTAQ and test serum enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase, as well as serum bilirubin, to establish whether there is liver injury. If liver injury is found, institute appropriate treatment and investigate the probable cause. Do not restart MULTAQ in patients without another explanation for the observed liver injury.
- Pulmonary Toxicity
- Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in patients treated with MULTAQ in the post-marketing setting. Onset of dyspnea or non-productive cough may be related to pulmonary toxicity and patients should be carefully evaluated clinically. If pulmonary toxicity is confirmed, MULTAQ should be discontinued.
- Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics
- Hypokalemia or hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be within the normal range prior to administration of MULTAQ and maintained in the normal range during administration of MULTAQ.
- QT Interval Prolongation
- Dronedarone induces a moderate (average of about 10 ms but much greater effects have been observed) QTc (Bazett) prolongation and . If the QTc Bazett interval is ≥500 ms, discontinue MULTAQ.
- Renal Impairment and Failure
- Marked increase in serum creatinine, pre-renal azotemia and acute renal failure, often in the setting of heart failure or hypovolemia, have been reported in patients taking MULTAQ. In most cases, these effects appear to be reversible upon drug discontinuation and with appropriate medical treatment. Monitor renal function periodically.
- Small increases in creatinine levels (about 0.1 mg/dL) following dronedarone treatment initiation have been shown to be a result of inhibition of creatinine's tubular secretion.
- The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation.
- Women of Childbearing Potential
- Premenopausal women who have not undergone a hysterectomy or oophorectomy must use effective contraception while using MULTAQ. Dronedarone caused fetal harm in animal studies at doses equivalent to recommended human doses. Counsel women of childbearing potential regarding appropriate contraceptive choices.
- In clinical trials, premature discontinuation because of adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% of the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2 % versus 1.8% in the placebo group) and QT prolongation (1.5% versus 0.5% in the placebo group).
- The most frequent adverse reactions observed with MULTAQ 400 mg twice daily in the 5 studies were diarrhea, nausea, abdominal pain, vomiting, and asthenia.
- Table 1 displays adverse reactions more common with dronedarone 400 mg twice daily than with placebo in AF or AFL patients, presented by system organ class and by decreasing order of frequency. Adverse laboratory and ECG effects are presented separately in Table 2.
- Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ.
- The following laboratory data/ECG parameters were reported with MULTAQ 400 mg twice daily.
- Assessment of demographic factors such as gender or age on the incidence of treatment-emergent adverse events did not suggest an excess of adverse events in any particular sub-group.
Cardiac: New or worsening heart failure,atrial flutter with 1:1 atrioventricular conduction has been reported very rarely.
Hepatic: Liver Injury
Respiratory: Interstitial lung disease including pneumonitis and pulmonary fibrosis
Immune: Anaphylactic reactions including angioedema
Vascular: Vasculitis, including leukocytoclastic vasculitis
- Drugs prolonging the QT interval (inducing Torsade de Pointes)
- Co-administration of drugs prolonging the QT interval (such as certain phenothiazines, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated because of the potential risk of Torsade de Pointes-type ventricular tachycardia.
- Digoxin
- In the ANDROMEDA (patients with recently decompensated heart failure) and PALLAS (patients with permanent AF) trials baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in dronedarone-treated patients compared to placebo. In patients not taking digoxin, no difference in risk of sudden death was observed in the dronedarone vs. placebo groups.
- Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). Dronedarone increases exposure to digoxin.
- Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.
- Calcium channel blockers
- Calcium channel blockers with depressant effects on the sinus and AV nodes could potentiate dronedarone's effects on conduction.
- Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.
- Beta-blockers
- In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers.
- Give a low dose of beta-blockers initially, and increase only after ECG verification of good tolerability.
- Ketoconazole and other potent CYP 3A inhibitors
- Concomitant use of ketoconazole as well as other potent CYP 3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated because exposure to dronedarone is significantly increased .
- Grapefruit juice
- Patients should avoid grapefruit juice beverages while taking MULTAQ because exposure to dronedarone is significantly increased.
- Rifampin and other CYP 3A inducers
- Avoid rifampin or other CYP 3A inducers such as phenobarbital, carbamazepine, phenytoin, and St John's wort because they decrease exposure to dronedarone significantly.
- Calcium channel blockers
- Verapamil and diltiazem are moderate CYP 3A inhibitors and increase dronedarone exposure. Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.
- Simvastatin
- Dronedarone increased simvastatin/simvastatin acid exposure. Avoid doses greater than 10 mg once daily of simvastatin.
- Other statins
- Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP 3A and P-gp inhibitors such as dronedarone.
- Calcium channel blockers
- Dronedarone increased the exposure of calcium channel blockers (verapamil, diltiazem or nifedipine). Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.
- Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range
- Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3A substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately.
- Beta-blockers and other CYP 2D6 substrates
- Dronedarone increased the exposure of propranolol and metoprolol. Give low doses of beta-blockers initially, and increase only after ECG verification of good tolerability. Other CYP 2D6 substrates, including other beta-blockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have increased exposure upon co-administration with dronedarone.
- P-glycoprotein substrates
- Digoxin
- Dronedarone increased digoxin exposure by inhibiting the P-gp transporter. Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.
- Dabigatran
- Exposure to dabigatran is higher when it is administered with dronedarone than when it is administered alone.
- Other P-gp substrates are expected to have increased exposure when co-administered with dronedarone.
- Warfarin
- When co-administered with dronedarone exposure to S-warfarin was slightly higher than when warfarin was administered alone. There were no clinically significant increases in INR.
- More patients experienced clinically significant INR elevations (≥ 5) usually within 1 week after starting dronedarone vs. placebo in patients taking oral anticoagulants in ATHENA. However, no excess risk of bleeding was observed in the dronedarone group.
- Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated on dronedarone. Monitor INR after initiating dronedarone in patients taking warfarin.
- When pregnant rats received dronedarone at oral doses greater than or equal to the MRHD (on a mg/m2 basis), fetuses had increased rates of external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior vena cava, brachydactyly, ectrodactylia, syndactylia, and anterior and/or posterior club feet). When pregnant rabbits received dronedarone, at a dose approximately half the MRHD (on a mg/m2 basis), fetuses had an increased rate of skeletal abnormalities (anomalous ribcage and vertebrae, pelvic asymmetry) at doses ≥20 mg/kg (the lowest dose tested and approximately half the MRHD on a mg/m2 basis).
Actual animal doses: rat (≥80 mg/kg/day); rabbit (≥20 mg/kg)
- Treatment with Class I or III antiarrhythmics (e.g., amiodarone, - flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (e.g., ketoconazole) must be stopped before starting MULTAQ.
- Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment, but it is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury
- In most cases, these effects appear to be reversible upon drug discontinuation and with appropriate medical treatment. Monitor renal function periodically.
- If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.
- Monitor plasma concentrations and adjust dosage appropriately.
- Monitor INR after initiating dronedarone in patients taking warfarin.
- In the event of overdosage, monitor the patient's cardiac rhythm and blood pressure.
It is not known whether dronedarone or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis or hemofiltration).
- There is no specific antidote available.
- N-{2-butyl-3-benzofuran-5-yl} methanesulfonamide, hydrochloride.
- Dronedarone HCl is a white fine powder that is practically insoluble in water and freely soluble in methylene chloride and methanol.
- Its empirical formula is C31H44N2O5 S, HCl with a relative molecular mass of 593.2. Its structural formula is:
- MULTAQ is provided as tablets for oral administration.
- Each tablet of MULTAQ contains 400 mg of dronedarone (expressed as base).
The inactive ingredients are:
- Core of the tablets- hypromellose, starch, crospovidone, poloxamer 407, lactose monohydrate, colloidal silicon dioxide, magnesium stearate.
- Coating / polishing of the tablets- hypromellose, polyethylene glycol 6000, titanium dioxide, carnauba wax.
- Dronedarone exhibits properties of all four Vaughn-Williams antiarrhythmic classes, although it is unclear which of these are important in producing dronedarone's clinical effects. The effect of dronedarone on 12-lead ECG parameters (heart rate, PR, and QTc) was investigated in healthy subjects following repeated oral doses up to 1600 mg once daily or 800 mg twice daily for 14 days and 1600 mg twice daily for 10 days. In the dronedarone 400 mg twice daily group, there was no apparent effect on heart rate; a moderate heart rate lowering effect (about 4 bpm) was noted at 800 mg twice daily. There was a clear dose-dependent effect on PR-interval with an increase of +5 ms at 400 mg twice daily and up to +50 ms at 1600 mg twice daily. There was a moderate dose related effect on the QTc-interval with an increase of +10 ms at 400 mg twice daily and up to +25 ms with 1600 mg twice daily.
- DAFNE was a dose-response study in patients with recurrent AF, evaluating the effect of dronedarone in comparison with placebo in maintaining sinus rhythm. The doses of dronedarone in this study were 400, 600, and 800 mg twice a day. In this small study, doses above 400 mg were not more effective and were less well tolerated.
- Absorption
- Because of presystemic first pass metabolism the absolute bioavailability of dronedarone without food is low, about 4%. It increases to approximately 15% when dronedarone is administered with a high fat meal. After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours. After repeated administration of 400 mg twice daily, steady state is reached within 4 to 8 days of treatment and the mean accumulation ratio for dronedarone ranges from 2.6 to 4.5. The steady state Cmax and exposure of the main N-debutyl metabolite is similar to that of the parent compound. The pharmacokinetics of dronedarone and its N-debutyl metabolite both deviate moderately from dose proportionality: a 2-fold increase in dose results in an approximate 2.5- to 3.0- fold increase with respect to Cmax and AUC.
- Distribution
- The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is >98 % and not saturable. Both compounds bind mainly to albumin. After intravenous (IV) administration the volume of distribution at steady state is about 1400 L.
- Metabolism
- Dronedarone is extensively metabolized, mainly by CYP 3A. The initial metabolic pathway includes N-debutylation to form the active N-debutyl metabolite, oxidative deamination to form the inactive propanoic acid metabolite, and direct oxidation. The metabolites undergo further metabolism to yield over 30 uncharacterized metabolites. The N-debutyl metabolite exhibits pharmacodynamic activity but is 1/10 to 1/3 as potent as dronedarone.
- Excretion/Elimination
- In a mass balance study with orally administered dronedarone (14C-labeled) approximately 6% of the labeled dose was excreted in urine, mainly as metabolites (no unchanged compound excreted in urine), and 84% was excreted in feces, mainly as metabolites. Dronedarone and its N-debutyl active metabolite accounted for less than 15% of the resultant radioactivity in the plasma.
- After IV administration the plasma clearance of dronedarone ranges from 130 to 150 L/h. The elimination half-life of dronedarone ranges from 13 to 19 hours.
- Dronedarone did not demonstrate genotoxic potential in the in vivo mouse micronucleus test, the Ames bacterial mutation assay, the unscheduled DNA synthesis assay, or an in vitro chromosomal aberration assay in human lymphocytes. S-9 processed dronedarone, however, was positive in a V79 transfected Chinese hamster V79 assay.
- In fertility studies conducted with female rats, dronedarone given prior to breeding and implantation caused an increase in irregular estrus cycles and cessation of cycling at doses ≥10mg/kg (equivalent to 0.12× the MRHD on a mg/m2 basis).
Corpora lutea, implantations and live fetuses were decreased at 100 mg/kg (equivalent to 1.2× the MRHD on a mg/m2 basis). There were no reported effects on mating behavior or fertility of male rats at doses of up to 100 mg/kg/day.
- ATHENA was a multicenter, multinational, double blind, and randomized placebo-controlled study of dronedarone in 4628 patients with a recent history of AF/AFL who were in sinus rhythmor who were to be converted to sinus rhythm. The objective of the study was to determine whether dronedarone could delay death from any cause or hospitalization for cardiovascular reasons.
- Initially patients were to be ≥70 years old, or <70 years old with at least one risk factor (including hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or LVEF<0.40). The inclusion criteria were later changed such that patients were to be ≥75 years old, or ≥70 years old with at least one risk factor. Patients had to have both AF/AFL and sinus rhythm documented within the previous 6 months. Patients could have been in AF/AFL or in sinus rhythm at the time of randomization, but patients not in sinus rhythm were expected to be either electrically or chemically converted to normal sinus rhythm after anticoagulation.
- Subjects were randomized and treated for up to 30 months (median follow-up: 22 months) with either MULTAQ 400 mg twice daily (2301 patients) or placebo (2327 patients), in addition to conventional therapy for cardiovascular diseases that included beta-blockers (71%), ACE inhibitors or angiotensin II receptor blockers (ARBs) (69%), digoxin (14%), calcium antagonists (14%), statins (39%), oral anticoagulants (60%), aspirin (44%), other chronic antiplatelet therapy (6%) and diuretics (54%).
- The primary endpoint of the study was the time to first hospitalization for cardiovascular reasons or death from any cause. Time to death from any cause, time to first hospitalization for cardiovascular reasons, and time to cardiovascular death and time to all causes of death were also explored.
- Patients ranged in age from 23 to 97 years; 42% were 75 years old or older. Forty-seven percent (47%) of patients were female and a majority was Caucasian (89%). Approximately seventy percent (71%) of those enrolled had no history of heart failure. The median ejection fraction was 60%. Twenty-nine percent (29%) of patients had heart failure, mostly NYHA class II (17%). The majority had hypertension (86%) and structural heart disease (60%).
- Results are shown in Table 3. MULTAQ reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2% when compared to placebo. This difference was entirely attributable to its effect on cardiovascular hospitalization, principally hospitalization related to AF.
- Other endpoints, death from any cause and first hospitalization for cardiovascular reasons, are shown in Table 3. Secondary endpoints count all first events of a particular type, whether or not they were preceded by a different type of event.
- The Kaplan-Meier cumulative incidence curves showing the time to first event are displayed in Figure 3. The event curves separated early and continued to diverge over the 30 month follow-up period.
- Figure 3: Kaplan-Meier Cumulative Incidence Curves from Randomization to First Cardiovascular Hospitalization or Death from any Cause
- Reasons for hospitalization included major bleeding (1% in both groups), syncope (1% in both groups), and ventricular arrhythmia (<1% in both groups).
The reduction in cardiovascular hospitalization or death from any cause was generally consistent in all subgroups based on baseline characteristics or medications (ACE inhibitors or ARBs; beta-blockers, digoxin, statins, calcium channel blockers, diuretics) (see Figure 4).
- Figure 4: Relative Risk (MULTAQ versus placebo) Estimates with 95% Confidence Intervals According to Selected Baseline Characteristics: First Cardiovascular Hospitalization or Death from any Cause.
a Determined from Cox regression model
b P-value of interaction between baseline characteristics and treatment based on Cox regression model
c Calcium antagonists with heart rate lowering effects restricted to diltiazem, verapamil and bepridil
- In EURIDIS and ADONIS, a total of 1237 patients in sinus rhythm with a prior episode of AF or AFL were randomized in an outpatient setting and treated with either MULTAQ 400 mg twice daily (n=828) or placebo (n=409) on top of conventional therapies (including oral anticoagulants, beta-blockers, ACE inhibitors or ARBs, chronic antiplatelet agents, diuretics, statins, digoxin, and calcium channel blockers). Patients had at least one ECG-documented AF/AFL episode during the 3 months prior to study entry but were in sinus rhythm for at least one hour. Patients ranged in age from 20 to 88 years, with the majority being Caucasian (97%), male (70%) patients. The most common co-morbidities were hypertension (56.8%) and structural heart disease (41.5%), including coronary heart disease (21.8%). Patients were followed for 12 months.
- In the pooled data from EURIDIS and ADONIS as well as in the individual trials, dronedarone delayed the time to first recurrence of AF/AFL (primary endpoint), lowering the risk of first AF/AFL recurrence during the 12-month study period by about 25%,with an absolute difference in recurrence rate of about 11% at 12 months.
- Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction (wall motion index ≤1.2) were randomized to either MULTAQ 400 mg twice daily or matching placebo, with a primary composite end point of all-cause mortality or hospitalization for heart failure. Patients enrolled in ANDROMEDA were predominantly NYHA Class II (40%) and III (57%), and only 25% had AF at randomization. After enrollment of 627 patients and a median follow-up of 63 days, the trial was terminated because of excess mortality in the dronedarone group. Twenty-five (25) patients in the dronedarone group died versus 12 patients in the placebo group (hazard ratio 2.13; 95% CI: 1.07 to 4.25). The main reason for death was worsening heart failure. Baseline digoxin therapy was reported in 6/16 dronedarone patients vs. 1/16 placebo patients who died of arrhythmia. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone vs. placebo groups.
- There were also excess hospitalizations for cardiovascular reasons in the dronedarone group (71 versus 51 for placebo).
- Patients with permanent AF (AF documented in 2 weeks prior to randomization and at least 6 months prior to randomization in whom cardioversion had failed or was not planned) and additional risk factors for thromboembolism (coronary artery disease, prior stroke or TIA, symptomatic heart failure, LVEF 75 with hypertension and diabetes) were randomized to dronedarone 400 mg twice daily or placebo.
- After enrollment of 3236 patients (placebo=1617 and dronedarone=1619) and a median follow up of 3.7 months for placebo and 3.9 for dronedarone, the study was terminated because of a significant increase in
- Mortality: 25 dronedarone vs. 13 placebo (HR, 1.94; CI, 0.99 to 3.79). The majority of deaths in the dronedarone group were classified as arrhythmic/sudden deaths (HR, 3.26; CI: 1.06 to 10.0). Baseline digoxin therapy was reported in 11/13 dronedarone patients who died of arrhythmia. None of the arrhythmic deaths on placebo (4) reported use of digoxin. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone vs. placebo groups.
- Stroke: 23 dronedarone vs. 10 placebo (HR, 2.32; CI: 1.11 to 4.88). The increased risk of stroke observed with dronedarone was observed in the first two weeks of therapy (10 dronedarone vs. 1 placebo), most of the subjects treated with dronedarone did not have an INR of 2.0 to 3.0.
- Hospitalizations for heart failure in the dronedarone group: 43 dronedarone vs. 24 placebo (HR, 1.81; CI: 1.10 to 2.99).
- Bottles of 60 tablets, NDC 0024-4142-60
- Bottles of 180 tablets, NDC 0024-4142-18
- Bottles of 500 tablets NDC 0024-4142-50
- Box of 10 blisters (10 tablets per blister) NDC 0024-4142-10
- MULTAQ should be administered with a meal. Warn patients not to take MULTAQ with grapefruit juice.
- If a dose is missed, patients should take the next dose at the regularly scheduled time and should not double the dose.
- Advise patients to consult a physician before stopping treatment with MULTAQ.
- Advise patients to consult a physician if they develop signs or symptoms of heart failure such as acute weight gain, dependent edema, or increasing shortness of breath.
- Advise patients to immediately report any symptoms of potential liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, jaundice, dark urine or itching) to their physician.
- Advise patients to inform their physician of any history of heart failure, rhythm disturbance other than atrial fibrillation or flutter or predisposing conditions such as uncorrected hypokalemia.
- MULTAQ may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.
- ↑ Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C et al. (2009) Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 360 (7):668-78. DOI:10.1056/NEJMoa0803778 PMID: 19213680
- ↑ Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A et al. (2007) Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 357 (10):987-99. DOI:10.1056/NEJMoa054686 PMID: 17804843 | Dronedarone
- Dosing Information
- 400 mg PO bid ( taken as one tablet with the morning meal and one tablet with the evening meal)
- Treatment with Class I or III antiarrhythmics (e.g., amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (e.g., ketoconazole) must be stopped before starting MULTAQ.
### Maintain the Sinus Rhythm
- Developed by: American College of Cardiology (ACC) and American Heart Association (AHA)
- Class of Recommendation: Class IIa
- Level of Evidence: Level B
- Dosing information
- Not Applicable
- Dosing information
- 400 mg/day PO [1][2]
- Permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored).
- Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms
- Second- or third-degree atrioventricular (AV) block, or sick sinus syndrome (except when used in conjunction with a functioning pacemaker).
- Bradycardia <50 bpm
- Concomitant use of strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir
- Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics
- Liver or lung toxicity related to the previous use of amiodarone
- QTc Bazett interval ≥500 ms or PR interval >280 ms
- Severe hepatic impairment
- Pregnancy (Category X): MULTAQ may cause fetal harm when administered to a pregnant woman. MULTAQ is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- Nursing mothers
- Hypersensitivity to the active substance or to any of the excipients
- MULTAQ is contraindicated in patients with NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization because it doubles the risk of death.
- Cardiovascular Death and heart failure in Permanent AF
- MULTAQ doubles the risk of cardiovascular death (largely arrhythmic) and heart failure events in patients with permanent AF. Patients treated with dronedarone should undergo monitoring of cardiac rhythm no less often than every 3 months. Cardiovert patients who are in atrial fibrillation (if clinically indicated) or discontinue MULTAQ. MULTAQ offers no benefit in subjects in permanent AF.
- Increased Risk of Stroke in Permanent AF
- In a placebo-controlled study in patients with permanent atrial fibrillation, dronedarone was associated with an increased risk of stroke, particularly in the first two weeks of therapy. MULTAQ should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy.
- New Onset or Worsening heart failure
- New onset or worsening of heart failure has been reported during treatment with MULTAQ in the postmarketing setting. In a placebo controlled study in patients with permanent AF increased rates of heart failure were observed in patients with normal left ventricular function and no history of symptomatic heart failure, as well as those with a history of heart failure or left ventricular dysfunction.
- Advise patients to consult a physician if they develop signs or symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath. If heart failure develops or worsens and requires hospitalization, discontinue MULTAQ.
- Liver Injury
- Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the postmarketing setting. Advise patients treated with MULTAQ to report immediately symptoms suggesting hepatic injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching). Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment, but it is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury. If hepatic injury is suspected, promptly discontinue MULTAQ and test serum enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase, as well as serum bilirubin, to establish whether there is liver injury. If liver injury is found, institute appropriate treatment and investigate the probable cause. Do not restart MULTAQ in patients without another explanation for the observed liver injury.
- Pulmonary Toxicity
- Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in patients treated with MULTAQ in the post-marketing setting. Onset of dyspnea or non-productive cough may be related to pulmonary toxicity and patients should be carefully evaluated clinically. If pulmonary toxicity is confirmed, MULTAQ should be discontinued.
- Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics
- Hypokalemia or hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be within the normal range prior to administration of MULTAQ and maintained in the normal range during administration of MULTAQ.
- QT Interval Prolongation
- Dronedarone induces a moderate (average of about 10 ms but much greater effects have been observed) QTc (Bazett) prolongation and . If the QTc Bazett interval is ≥500 ms, discontinue MULTAQ.
- Renal Impairment and Failure
- Marked increase in serum creatinine, pre-renal azotemia and acute renal failure, often in the setting of heart failure or hypovolemia, have been reported in patients taking MULTAQ. In most cases, these effects appear to be reversible upon drug discontinuation and with appropriate medical treatment. Monitor renal function periodically.
- Small increases in creatinine levels (about 0.1 mg/dL) following dronedarone treatment initiation have been shown to be a result of inhibition of creatinine's tubular secretion.
- The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation.
- Women of Childbearing Potential
- Premenopausal women who have not undergone a hysterectomy or oophorectomy must use effective contraception while using MULTAQ. Dronedarone caused fetal harm in animal studies at doses equivalent to recommended human doses. Counsel women of childbearing potential regarding appropriate contraceptive choices.
- In clinical trials, premature discontinuation because of adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% of the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2 % versus 1.8% in the placebo group) and QT prolongation (1.5% versus 0.5% in the placebo group).
- The most frequent adverse reactions observed with MULTAQ 400 mg twice daily in the 5 studies were diarrhea, nausea, abdominal pain, vomiting, and asthenia.
- Table 1 displays adverse reactions more common with dronedarone 400 mg twice daily than with placebo in AF or AFL patients, presented by system organ class and by decreasing order of frequency. Adverse laboratory and ECG effects are presented separately in Table 2.
- Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ.
- The following laboratory data/ECG parameters were reported with MULTAQ 400 mg twice daily.
- Assessment of demographic factors such as gender or age on the incidence of treatment-emergent adverse events did not suggest an excess of adverse events in any particular sub-group.
Cardiac: New or worsening heart failure,atrial flutter with 1:1 atrioventricular conduction has been reported very rarely.
Hepatic: Liver Injury
Respiratory: Interstitial lung disease including pneumonitis and pulmonary fibrosis
Immune: Anaphylactic reactions including angioedema
Vascular: Vasculitis, including leukocytoclastic vasculitis
- Drugs prolonging the QT interval (inducing Torsade de Pointes)
- Co-administration of drugs prolonging the QT interval (such as certain phenothiazines, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated because of the potential risk of Torsade de Pointes-type ventricular tachycardia.
- Digoxin
- In the ANDROMEDA (patients with recently decompensated heart failure) and PALLAS (patients with permanent AF) trials baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in dronedarone-treated patients compared to placebo. In patients not taking digoxin, no difference in risk of sudden death was observed in the dronedarone vs. placebo groups.
- Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). Dronedarone increases exposure to digoxin.
- Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.
- Calcium channel blockers
- Calcium channel blockers with depressant effects on the sinus and AV nodes could potentiate dronedarone's effects on conduction.
- Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.
- Beta-blockers
- In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers.
- Give a low dose of beta-blockers initially, and increase only after ECG verification of good tolerability.
- Ketoconazole and other potent CYP 3A inhibitors
- Concomitant use of ketoconazole as well as other potent CYP 3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated because exposure to dronedarone is significantly increased .
- Grapefruit juice
- Patients should avoid grapefruit juice beverages while taking MULTAQ because exposure to dronedarone is significantly increased.
- Rifampin and other CYP 3A inducers
- Avoid rifampin or other CYP 3A inducers such as phenobarbital, carbamazepine, phenytoin, and St John's wort because they decrease exposure to dronedarone significantly.
- Calcium channel blockers
- Verapamil and diltiazem are moderate CYP 3A inhibitors and increase dronedarone exposure. Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.
- Simvastatin
- Dronedarone increased simvastatin/simvastatin acid exposure. Avoid doses greater than 10 mg once daily of simvastatin.
- Other statins
- Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP 3A and P-gp inhibitors such as dronedarone.
- Calcium channel blockers
- Dronedarone increased the exposure of calcium channel blockers (verapamil, diltiazem or nifedipine). Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.
- Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range
- Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3A substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately.
- Beta-blockers and other CYP 2D6 substrates
- Dronedarone increased the exposure of propranolol and metoprolol. Give low doses of beta-blockers initially, and increase only after ECG verification of good tolerability. Other CYP 2D6 substrates, including other beta-blockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have increased exposure upon co-administration with dronedarone.
- P-glycoprotein substrates
- Digoxin
- Dronedarone increased digoxin exposure by inhibiting the P-gp transporter. Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.
- Dabigatran
- Exposure to dabigatran is higher when it is administered with dronedarone than when it is administered alone.
- Other P-gp substrates are expected to have increased exposure when co-administered with dronedarone.
- Warfarin
- When co-administered with dronedarone exposure to S-warfarin was slightly higher than when warfarin was administered alone. There were no clinically significant increases in INR.
- More patients experienced clinically significant INR elevations (≥ 5) usually within 1 week after starting dronedarone vs. placebo in patients taking oral anticoagulants in ATHENA. However, no excess risk of bleeding was observed in the dronedarone group.
- Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated on dronedarone. Monitor INR after initiating dronedarone in patients taking warfarin.
- When pregnant rats received dronedarone at oral doses greater than or equal to the MRHD (on a mg/m2 basis), fetuses had increased rates of external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior vena cava, brachydactyly, ectrodactylia, syndactylia, and anterior and/or posterior club feet). When pregnant rabbits received dronedarone, at a dose approximately half the MRHD (on a mg/m2 basis), fetuses had an increased rate of skeletal abnormalities (anomalous ribcage and vertebrae, pelvic asymmetry) at doses ≥20 mg/kg (the lowest dose tested and approximately half the MRHD on a mg/m2 basis).
Actual animal doses: rat (≥80 mg/kg/day); rabbit (≥20 mg/kg)
- Treatment with Class I or III antiarrhythmics (e.g., amiodarone, * flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (e.g., ketoconazole) must be stopped before starting MULTAQ.
- Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment, but it is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury
- In most cases, these effects appear to be reversible upon drug discontinuation and with appropriate medical treatment. Monitor renal function periodically.
- If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.
- Monitor plasma concentrations and adjust dosage appropriately.
- Monitor INR after initiating dronedarone in patients taking warfarin.
- In the event of overdosage, monitor the patient's cardiac rhythm and blood pressure.
It is not known whether dronedarone or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis or hemofiltration).
- There is no specific antidote available.
- N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide, hydrochloride.
- Dronedarone HCl is a white fine powder that is practically insoluble in water and freely soluble in methylene chloride and methanol.
- Its empirical formula is C31H44N2O5 S, HCl with a relative molecular mass of 593.2. Its structural formula is:
- MULTAQ is provided as tablets for oral administration.
- Each tablet of MULTAQ contains 400 mg of dronedarone (expressed as base).
The inactive ingredients are:
- Core of the tablets- hypromellose, starch, crospovidone, poloxamer 407, lactose monohydrate, colloidal silicon dioxide, magnesium stearate.
- Coating / polishing of the tablets- hypromellose, polyethylene glycol 6000, titanium dioxide, carnauba wax.
- Dronedarone exhibits properties of all four Vaughn-Williams antiarrhythmic classes, although it is unclear which of these are important in producing dronedarone's clinical effects. The effect of dronedarone on 12-lead ECG parameters (heart rate, PR, and QTc) was investigated in healthy subjects following repeated oral doses up to 1600 mg once daily or 800 mg twice daily for 14 days and 1600 mg twice daily for 10 days. In the dronedarone 400 mg twice daily group, there was no apparent effect on heart rate; a moderate heart rate lowering effect (about 4 bpm) was noted at 800 mg twice daily. There was a clear dose-dependent effect on PR-interval with an increase of +5 ms at 400 mg twice daily and up to +50 ms at 1600 mg twice daily. There was a moderate dose related effect on the QTc-interval with an increase of +10 ms at 400 mg twice daily and up to +25 ms with 1600 mg twice daily.
- DAFNE was a dose-response study in patients with recurrent AF, evaluating the effect of dronedarone in comparison with placebo in maintaining sinus rhythm. The doses of dronedarone in this study were 400, 600, and 800 mg twice a day. In this small study, doses above 400 mg were not more effective and were less well tolerated.
- Absorption
- Because of presystemic first pass metabolism the absolute bioavailability of dronedarone without food is low, about 4%. It increases to approximately 15% when dronedarone is administered with a high fat meal. After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours. After repeated administration of 400 mg twice daily, steady state is reached within 4 to 8 days of treatment and the mean accumulation ratio for dronedarone ranges from 2.6 to 4.5. The steady state Cmax and exposure of the main N-debutyl metabolite is similar to that of the parent compound. The pharmacokinetics of dronedarone and its N-debutyl metabolite both deviate moderately from dose proportionality: a 2-fold increase in dose results in an approximate 2.5- to 3.0- fold increase with respect to Cmax and AUC.
- Distribution
- The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is >98 % and not saturable. Both compounds bind mainly to albumin. After intravenous (IV) administration the volume of distribution at steady state is about 1400 L.
- Metabolism
- Dronedarone is extensively metabolized, mainly by CYP 3A. The initial metabolic pathway includes N-debutylation to form the active N-debutyl metabolite, oxidative deamination to form the inactive propanoic acid metabolite, and direct oxidation. The metabolites undergo further metabolism to yield over 30 uncharacterized metabolites. The N-debutyl metabolite exhibits pharmacodynamic activity but is 1/10 to 1/3 as potent as dronedarone.
- Excretion/Elimination
- In a mass balance study with orally administered dronedarone (14C-labeled) approximately 6% of the labeled dose was excreted in urine, mainly as metabolites (no unchanged compound excreted in urine), and 84% was excreted in feces, mainly as metabolites. Dronedarone and its N-debutyl active metabolite accounted for less than 15% of the resultant radioactivity in the plasma.
- After IV administration the plasma clearance of dronedarone ranges from 130 to 150 L/h. The elimination half-life of dronedarone ranges from 13 to 19 hours.
- Dronedarone did not demonstrate genotoxic potential in the in vivo mouse micronucleus test, the Ames bacterial mutation assay, the unscheduled DNA synthesis assay, or an in vitro chromosomal aberration assay in human lymphocytes. S-9 processed dronedarone, however, was positive in a V79 transfected Chinese hamster V79 assay.
- In fertility studies conducted with female rats, dronedarone given prior to breeding and implantation caused an increase in irregular estrus cycles and cessation of cycling at doses ≥10mg/kg (equivalent to 0.12× the MRHD on a mg/m2 basis).
Corpora lutea, implantations and live fetuses were decreased at 100 mg/kg (equivalent to 1.2× the MRHD on a mg/m2 basis). There were no reported effects on mating behavior or fertility of male rats at doses of up to 100 mg/kg/day.
- ATHENA was a multicenter, multinational, double blind, and randomized placebo-controlled study of dronedarone in 4628 patients with a recent history of AF/AFL who were in sinus rhythmor who were to be converted to sinus rhythm. The objective of the study was to determine whether dronedarone could delay death from any cause or hospitalization for cardiovascular reasons.
- Initially patients were to be ≥70 years old, or <70 years old with at least one risk factor (including hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or LVEF<0.40). The inclusion criteria were later changed such that patients were to be ≥75 years old, or ≥70 years old with at least one risk factor. Patients had to have both AF/AFL and sinus rhythm documented within the previous 6 months. Patients could have been in AF/AFL or in sinus rhythm at the time of randomization, but patients not in sinus rhythm were expected to be either electrically or chemically converted to normal sinus rhythm after anticoagulation.
- Subjects were randomized and treated for up to 30 months (median follow-up: 22 months) with either MULTAQ 400 mg twice daily (2301 patients) or placebo (2327 patients), in addition to conventional therapy for cardiovascular diseases that included beta-blockers (71%), ACE inhibitors or angiotensin II receptor blockers (ARBs) (69%), digoxin (14%), calcium antagonists (14%), statins (39%), oral anticoagulants (60%), aspirin (44%), other chronic antiplatelet therapy (6%) and diuretics (54%).
- The primary endpoint of the study was the time to first hospitalization for cardiovascular reasons or death from any cause. Time to death from any cause, time to first hospitalization for cardiovascular reasons, and time to cardiovascular death and time to all causes of death were also explored.
- Patients ranged in age from 23 to 97 years; 42% were 75 years old or older. Forty-seven percent (47%) of patients were female and a majority was Caucasian (89%). Approximately seventy percent (71%) of those enrolled had no history of heart failure. The median ejection fraction was 60%. Twenty-nine percent (29%) of patients had heart failure, mostly NYHA class II (17%). The majority had hypertension (86%) and structural heart disease (60%).
- Results are shown in Table 3. MULTAQ reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2% when compared to placebo. This difference was entirely attributable to its effect on cardiovascular hospitalization, principally hospitalization related to AF.
- Other endpoints, death from any cause and first hospitalization for cardiovascular reasons, are shown in Table 3. Secondary endpoints count all first events of a particular type, whether or not they were preceded by a different type of event.
- The Kaplan-Meier cumulative incidence curves showing the time to first event are displayed in Figure 3. The event curves separated early and continued to diverge over the 30 month follow-up period.
- Figure 3: Kaplan-Meier Cumulative Incidence Curves from Randomization to First Cardiovascular Hospitalization or Death from any Cause
- Reasons for hospitalization included major bleeding (1% in both groups), syncope (1% in both groups), and ventricular arrhythmia (<1% in both groups).
The reduction in cardiovascular hospitalization or death from any cause was generally consistent in all subgroups based on baseline characteristics or medications (ACE inhibitors or ARBs; beta-blockers, digoxin, statins, calcium channel blockers, diuretics) (see Figure 4).
- Figure 4: Relative Risk (MULTAQ versus placebo) Estimates with 95% Confidence Intervals According to Selected Baseline Characteristics: First Cardiovascular Hospitalization or Death from any Cause.
a Determined from Cox regression model
b P-value of interaction between baseline characteristics and treatment based on Cox regression model
c Calcium antagonists with heart rate lowering effects restricted to diltiazem, verapamil and bepridil
- In EURIDIS and ADONIS, a total of 1237 patients in sinus rhythm with a prior episode of AF or AFL were randomized in an outpatient setting and treated with either MULTAQ 400 mg twice daily (n=828) or placebo (n=409) on top of conventional therapies (including oral anticoagulants, beta-blockers, ACE inhibitors or ARBs, chronic antiplatelet agents, diuretics, statins, digoxin, and calcium channel blockers). Patients had at least one ECG-documented AF/AFL episode during the 3 months prior to study entry but were in sinus rhythm for at least one hour. Patients ranged in age from 20 to 88 years, with the majority being Caucasian (97%), male (70%) patients. The most common co-morbidities were hypertension (56.8%) and structural heart disease (41.5%), including coronary heart disease (21.8%). Patients were followed for 12 months.
- In the pooled data from EURIDIS and ADONIS as well as in the individual trials, dronedarone delayed the time to first recurrence of AF/AFL (primary endpoint), lowering the risk of first AF/AFL recurrence during the 12-month study period by about 25%,with an absolute difference in recurrence rate of about 11% at 12 months.
- Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction (wall motion index ≤1.2) were randomized to either MULTAQ 400 mg twice daily or matching placebo, with a primary composite end point of all-cause mortality or hospitalization for heart failure. Patients enrolled in ANDROMEDA were predominantly NYHA Class II (40%) and III (57%), and only 25% had AF at randomization. After enrollment of 627 patients and a median follow-up of 63 days, the trial was terminated because of excess mortality in the dronedarone group. Twenty-five (25) patients in the dronedarone group died versus 12 patients in the placebo group (hazard ratio 2.13; 95% CI: 1.07 to 4.25). The main reason for death was worsening heart failure. Baseline digoxin therapy was reported in 6/16 dronedarone patients vs. 1/16 placebo patients who died of arrhythmia. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone vs. placebo groups.
- There were also excess hospitalizations for cardiovascular reasons in the dronedarone group (71 versus 51 for placebo).
- Patients with permanent AF (AF documented in 2 weeks prior to randomization and at least 6 months prior to randomization in whom cardioversion had failed or was not planned) and additional risk factors for thromboembolism (coronary artery disease, prior stroke or TIA, symptomatic heart failure, LVEF <40%, peripheral arterial occlusive disease, or age >75 with hypertension and diabetes) were randomized to dronedarone 400 mg twice daily or placebo.
- After enrollment of 3236 patients (placebo=1617 and dronedarone=1619) and a median follow up of 3.7 months for placebo and 3.9 for dronedarone, the study was terminated because of a significant increase in
- Mortality: 25 dronedarone vs. 13 placebo (HR, 1.94; CI, 0.99 to 3.79). The majority of deaths in the dronedarone group were classified as arrhythmic/sudden deaths (HR, 3.26; CI: 1.06 to 10.0). Baseline digoxin therapy was reported in 11/13 dronedarone patients who died of arrhythmia. None of the arrhythmic deaths on placebo (4) reported use of digoxin. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone vs. placebo groups.
- Stroke: 23 dronedarone vs. 10 placebo (HR, 2.32; CI: 1.11 to 4.88). The increased risk of stroke observed with dronedarone was observed in the first two weeks of therapy (10 dronedarone vs. 1 placebo), most of the subjects treated with dronedarone did not have an INR of 2.0 to 3.0.
- Hospitalizations for heart failure in the dronedarone group: 43 dronedarone vs. 24 placebo (HR, 1.81; CI: 1.10 to 2.99).
- Bottles of 60 tablets, NDC 0024-4142-60
- Bottles of 180 tablets, NDC 0024-4142-18
- Bottles of 500 tablets NDC 0024-4142-50
- Box of 10 blisters (10 tablets per blister) NDC 0024-4142-10
- MULTAQ should be administered with a meal. Warn patients not to take MULTAQ with grapefruit juice.
- If a dose is missed, patients should take the next dose at the regularly scheduled time and should not double the dose.
- Advise patients to consult a physician before stopping treatment with MULTAQ.
- Advise patients to consult a physician if they develop signs or symptoms of heart failure such as acute weight gain, dependent edema, or increasing shortness of breath.
- Advise patients to immediately report any symptoms of potential liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, jaundice, dark urine or itching) to their physician.
- Advise patients to inform their physician of any history of heart failure, rhythm disturbance other than atrial fibrillation or flutter or predisposing conditions such as uncorrected hypokalemia.
- MULTAQ may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.
- ↑ Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C et al. (2009) Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 360 (7):668-78. DOI:10.1056/NEJMoa0803778 PMID: 19213680
- ↑ Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A et al. (2007) Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 357 (10):987-99. DOI:10.1056/NEJMoa054686 PMID: 17804843 | https://www.wikidoc.org/index.php/Dronedarone | |
68297d75446086f4861509ac1e01f9b65c82ae0a | wikidoc | Drop attack | Drop attack
# Overview
Drop attacks are sudden spontaneous falls while standing or walking, followed by a very swift recovery, within seconds or minutes.
Drop attacks are typically seen in elderly patients, and the most common cause is carotid sinus hypersensitivity, resulting in either short periods of reversible asystole, or in marked drop in blood pressure in response to carotid sinus stimulation. Drop attacks are differnetiated from vaso-vagal and other causes of syncope due to the characteristic feature of drop attack that is a sudden feeling of being pulled or pushed towards the ground without any loss of consciousness.
# Causes
Causes of drop attacks include:
- Vascular - transient ischemic attack, cerebrovascular accident, dissection, occlusion and hemorrhage
Intracranial hemorrhage
Posterior circulation infarction, emboli and vasospasm
Bilateral anterior circulation occlusion
Migraine - develops over 1 hour, with associated paresthesia, Hypertonia arterialis
Basilar artery insufficiency - older patient with no loss of consciousness, transient loss of lower extremity tone
- Intracranial hemorrhage
- Posterior circulation infarction, emboli and vasospasm
- Bilateral anterior circulation occlusion
- Migraine - develops over 1 hour, with associated paresthesia, Hypertonia arterialis
- Basilar artery insufficiency - older patient with no loss of consciousness, transient loss of lower extremity tone
- Epilepsy/paroxysmal:
Neurally mediated syncope - 75% of all causes
Myoclonic seizure
Myoclonic-astatic seizure
Petit mal syndrome
Lennox-Gastaut syndrome - atonic seizure, myoclonic seizure and generalized tonic-clonic seizure typically occurring in neurologically abnormal patients
Juvenile Myoclonic Epilepsy - fall with myoclonus
Laugh or cough triggered epilepsy
Cataplexy associated with narcolepsy
Periodic paralysis
Complex partial seizure
Breath-holding spells - associated pallor/cyanosis, emotion related
Pure autonomic failure (Riley-Day Syndrome, long standing diabetes mellitus)
Episodic ataxia
Panayiotopoulos syndrome
- Neurally mediated syncope - 75% of all causes
- Myoclonic seizure
- Myoclonic-astatic seizure
- Petit mal syndrome
- Lennox-Gastaut syndrome - atonic seizure, myoclonic seizure and generalized tonic-clonic seizure typically occurring in neurologically abnormal patients
- Juvenile Myoclonic Epilepsy - fall with myoclonus
- Laugh or cough triggered epilepsy
- Cataplexy associated with narcolepsy
- Periodic paralysis
- Complex partial seizure
- Breath-holding spells - associated pallor/cyanosis, emotion related
- Pure autonomic failure (Riley-Day Syndrome, long standing diabetes mellitus)
- Episodic ataxia
- Panayiotopoulos syndrome
- Degenerative disease:
Postural instability with Parkinsons
- Postural instability with Parkinsons
- Structural:
Chronic odontoid instability
Spinal cord trauma with transient paraplegia
Brainstem mass
- Chronic odontoid instability
- Spinal cord trauma with transient paraplegia
- Brainstem mass
- Metabolic:
Hypoglycemia
Hypocalcemia
Hypomagnesemia
Toxins, drugs - cocaine, sedatives, antihistamine and tricyclic antidepressants
- Hypoglycemia
- Hypocalcemia
- Hypomagnesemia
- Toxins, drugs - cocaine, sedatives, antihistamine and tricyclic antidepressants
- Cardiac:
Prolonged QT
Tachycardia
Bradycardia
Sick sinus syndrome
arhythmia
Hypertrophic cardiomyopathy
Aortic stenosis
Hypovolemia
- Prolonged QT
- Tachycardia
- Bradycardia
- Sick sinus syndrome
- arhythmia
- Hypertrophic cardiomyopathy
- Aortic stenosis
- Hypovolemia
- Psychologic:
Malingering
Conversion disorder
Panic attack
Anxiety
- Malingering
- Conversion disorder
- Panic attack
- Anxiety
# Common Causes
- Seizure
- Transient ischemic attack
- Cerebrovascular accident
- Basilar artery insufficiency
- Hypoglycemia
- Hypotension
- Cataplexy associated with narcolepsy
- Cardiac arrhythmia
- Sick sinus syndrome
- Migraine
- Aortic stenosis
- Conversion disorder
# Causes by Organ System
# Causes in alphabetical order
# Diagnosis
- Important in the presence of an inciting event (Neuroleptic malignant syndrome, breatholding, postural), any loss of consciousness and presence of post-ictal period
- Initial tests:
- Glucose
- EKG
- Pregnancy test
- Urine toxicology test
- CT head
- Electrolytes
- Later consider: EEG, Echocardiogram, MRI and Tilt test | Drop attack
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farman Khan, MD, MRCP [2]
# Overview
Drop attacks are sudden spontaneous falls while standing or walking, followed by a very swift recovery, within seconds or minutes.
Drop attacks are typically seen in elderly patients, and the most common cause is carotid sinus hypersensitivity, resulting in either short periods of reversible asystole, or in marked drop in blood pressure in response to carotid sinus stimulation. Drop attacks are differnetiated from vaso-vagal and other causes of syncope due to the characteristic feature of drop attack that is a sudden feeling of being pulled or pushed towards the ground without any loss of consciousness.
# Causes
Causes of drop attacks include:
- Vascular - transient ischemic attack, cerebrovascular accident, dissection, occlusion and hemorrhage
Intracranial hemorrhage
Posterior circulation infarction, emboli and vasospasm
Bilateral anterior circulation occlusion
Migraine - develops over 1 hour, with associated paresthesia, Hypertonia arterialis
Basilar artery insufficiency - older patient with no loss of consciousness, transient loss of lower extremity tone
- Intracranial hemorrhage
- Posterior circulation infarction, emboli and vasospasm
- Bilateral anterior circulation occlusion
- Migraine - develops over 1 hour, with associated paresthesia, Hypertonia arterialis
- Basilar artery insufficiency - older patient with no loss of consciousness, transient loss of lower extremity tone
- Epilepsy/paroxysmal:
Neurally mediated syncope - 75% of all causes
Myoclonic seizure
Myoclonic-astatic seizure
Petit mal syndrome
Lennox-Gastaut syndrome - atonic seizure, myoclonic seizure and generalized tonic-clonic seizure typically occurring in neurologically abnormal patients
Juvenile Myoclonic Epilepsy - fall with myoclonus
Laugh or cough triggered epilepsy
Cataplexy associated with narcolepsy
Periodic paralysis
Complex partial seizure
Breath-holding spells - associated pallor/cyanosis, emotion related
Pure autonomic failure (Riley-Day Syndrome, long standing diabetes mellitus)
Episodic ataxia
Panayiotopoulos syndrome
- Neurally mediated syncope - 75% of all causes
- Myoclonic seizure
- Myoclonic-astatic seizure
- Petit mal syndrome
- Lennox-Gastaut syndrome - atonic seizure, myoclonic seizure and generalized tonic-clonic seizure typically occurring in neurologically abnormal patients
- Juvenile Myoclonic Epilepsy - fall with myoclonus
- Laugh or cough triggered epilepsy
- Cataplexy associated with narcolepsy
- Periodic paralysis
- Complex partial seizure
- Breath-holding spells - associated pallor/cyanosis, emotion related
- Pure autonomic failure (Riley-Day Syndrome, long standing diabetes mellitus)
- Episodic ataxia
- Panayiotopoulos syndrome
- Degenerative disease:
Postural instability with Parkinsons
- Postural instability with Parkinsons
- Structural:
Chronic odontoid instability
Spinal cord trauma with transient paraplegia
Brainstem mass
- Chronic odontoid instability
- Spinal cord trauma with transient paraplegia
- Brainstem mass
- Metabolic:
Hypoglycemia
Hypocalcemia
Hypomagnesemia
Toxins, drugs - cocaine, sedatives, antihistamine and tricyclic antidepressants
- Hypoglycemia
- Hypocalcemia
- Hypomagnesemia
- Toxins, drugs - cocaine, sedatives, antihistamine and tricyclic antidepressants
- Cardiac:
Prolonged QT
Tachycardia
Bradycardia
Sick sinus syndrome
arhythmia
Hypertrophic cardiomyopathy
Aortic stenosis
Hypovolemia
- Prolonged QT
- Tachycardia
- Bradycardia
- Sick sinus syndrome
- arhythmia
- Hypertrophic cardiomyopathy
- Aortic stenosis
- Hypovolemia
- Psychologic:
Malingering
Conversion disorder
Panic attack
Anxiety
- Malingering
- Conversion disorder
- Panic attack
- Anxiety
# Common Causes
- Seizure
- Transient ischemic attack
- Cerebrovascular accident
- Basilar artery insufficiency
- Hypoglycemia
- Hypotension
- Cataplexy associated with narcolepsy
- Cardiac arrhythmia
- Sick sinus syndrome
- Migraine
- Aortic stenosis
- Conversion disorder
# Causes by Organ System
# Causes in alphabetical order
# Diagnosis
- Important in the presence of an inciting event (Neuroleptic malignant syndrome, breatholding, postural), any loss of consciousness and presence of post-ictal period
- Initial tests:
- Glucose
- EKG
- Pregnancy test
- Urine toxicology test
- CT head
- Electrolytes
- Later consider: EEG, Echocardiogram, MRI and Tilt test
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Drop_attack | |
791225bb49c33cc3aa97a99ea38823d6f839bf0c | wikidoc | Drospirnone | Drospirnone
# Overview
Drospirenone (INN, USAN), also known as 1,2-dihydrospirorenone, is synthetic, steroidal progestin with additional antimineralocorticoid and weak antiandrogen properties which is used as a hormonal contraceptive.
It is sold under the brand names Yasmin, Yasminelle, Yaz, Beyaz, Ocella, Zarah, and Angeliq, all of which are combination products of drospirenone with an estrogen such as ethinylestradiol.
# Medical uses
Drospirenone is part of some birth control pills and hormone replacement therapy. In combination with ethinyl estradiol it is used as contraception, to treat moderate acne, and for premenstrual dysphoric disorder. In combination with estradiol it is used to treat menopausal symptoms and premenstrual dysphoric disorder.
# Adverse effects
Women who take contraceptive pills containing drospirenone have a six- to sevenfold risk of developing thromboembolism compared to women who do not take any contraceptive pill, and twice the risk of women who take a contraceptive pill containing levonorgestrel.
Drospirenone can potentially cause hyperkalemia in high-risk patients, and is comparable to a 25 mg dose of spironolactone.
The medication is contraindicated in people with hepatic dysfunction, renal insufficiency, adrenal insufficiency, or in whom the use of oral contraceptives is contraindicated, such as smokers and patients with a history of DVT, stroke, or other blood clots. Because of the anti-mineralocorticoid effects care needs to be exercised when other drugs that may increase potassium levels are taken. Such medications include ACE inhibitors, angiotensin-II receptor agonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs.
Although there have been concerns raised regarding the safety of drospirenone containing oral contraceptives, the data is conflicting and it is unclear whether the increased risk of venous thrombembolic events seen in recent studies represents a true increase in this risk or whether flaws in the design of these studies are resulting in a false safety signal. Further study in this regard appears to be warranted. However, the FDA recently updated the label for contraceptives containing drospirenone to include warnings for stopping use prior to and after surgery; moreover, the FDA acknowledges that contraceptives with drospirenone may be associated with a higher risk of venous thromboembolism.
# Pharmacology
## Pharmacodynamics
Drospirenone differs from other synthetic progestins in that its pharmacological profile in preclinical studies shows it to be closer to the natural progesterone. As such it has potent antimineralocorticoid properties, counteracts the estrogen-stimulated activity of the renin-angiotensin-aldosterone system, and has also been shown to possess mild antiandrogen activity.
The antimineralocorticoid properties exhibited by drospirenone promote sodium excretion and prevent water retention.
## Pharmacokinetics
Drospirenone is taken orally with about 76% bioavailability. It is bound not by sex hormone-binding globulin or corticosteroid binding globulin, but by other serum proteins. Metabolites have not been shown to be biologically active, show up in urine and feces, and are essentially completely excreted within 10 days.
# Chemistry
It is an analog to spironolactone, with a molecular weight of 366.5 and the molecular formula C24H30O3.
# Formulations
The compound is part of certain newer oral contraceptive formulations:
- Yasmin contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet. It is indicated for the prevention of pregnancy in women who elect an oral contraceptive.
- Yasminelle contains 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is used for contraception.
- Yaz and Beyaz contain 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is given for 24/4 days with the same indications.
- Ocella contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet and is taken daily.
It has also been formulated in medication to manage menopausal symptoms using 0.5 mg drsp and 1 mg estradiol per day by oral application. This medication was introduced in the United States in 2007 as Angeliq.
# Litigation
In 2008, a series of television commercials prompted the FDA to cite Bayer for overstating the approved uses of Yaz while failing to adequately address the risks of the drug. Bayer was required to dispel the inaccurate information contained in those ads by creating new ads that clarified the drug's approved uses.
On October 8, 2009, Bayer disclosed that 129 lawsuits had been brought against them over the side effects and marketing of Yaz and Yasmin. The allegations include (but are not limited to):
- Glossing over risks associated with the products and overstating their approved uses in an effort to mislead users of Yaz and Yasmin into believing that the drugs were safe.
- Failure to properly research the medication.
- Failing to recall the drug after post-marketing reports demonstrated that the risk of potentially life-threatening side effects of Yasmin and Yaz outweighed potential benefits that could be achieved via other available oral contraceptives.
In September 2009, the FDA cited Bayer for sending out potentially low-quality batches of drosperinone. Bayer justified the shipments by explaining that they monitor the "average" quality of all shipments, not the quality of each individual batch.
In October 2011 the CBC TV program Marketplace ran a segment discussing issues involved with the usage of Yaz/Yasmin | Drospirnone
Template:Drospirnone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]
# Overview
Drospirenone (INN, USAN), also known as 1,2-dihydrospirorenone, is synthetic, steroidal progestin with additional antimineralocorticoid and weak antiandrogen properties which is used as a hormonal contraceptive.[1]
It is sold under the brand names Yasmin, Yasminelle, Yaz, Beyaz, Ocella, Zarah, and Angeliq, all of which are combination products of drospirenone with an estrogen such as ethinylestradiol.
# Medical uses
Drospirenone is part of some birth control pills and hormone replacement therapy. In combination with ethinyl estradiol it is used as contraception, to treat moderate acne, and for premenstrual dysphoric disorder.[2] In combination with estradiol it is used to treat menopausal symptoms and premenstrual dysphoric disorder.[3]
# Adverse effects
Women who take contraceptive pills containing drospirenone have a six- to sevenfold risk of developing thromboembolism compared to women who do not take any contraceptive pill, and twice the risk of women who take a contraceptive pill containing levonorgestrel.[4]
Drospirenone can potentially cause hyperkalemia in high-risk patients, and is comparable to a 25 mg dose of spironolactone.
The medication is contraindicated in people with hepatic dysfunction, renal insufficiency, adrenal insufficiency, or in whom the use of oral contraceptives is contraindicated, such as smokers and patients with a history of DVT, stroke, or other blood clots. Because of the anti-mineralocorticoid effects care needs to be exercised when other drugs that may increase potassium levels are taken. Such medications include ACE inhibitors, angiotensin-II receptor agonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs.
Although there have been concerns raised regarding the safety of drospirenone containing oral contraceptives, the data is conflicting and it is unclear whether the increased risk of venous thrombembolic events seen in recent studies represents a true increase in this risk or whether flaws in the design of these studies are resulting in a false safety signal. Further study in this regard appears to be warranted.[5] However, the FDA recently updated the label for contraceptives containing drospirenone to include warnings for stopping use prior to and after surgery; moreover, the FDA acknowledges that contraceptives with drospirenone may be associated with a higher risk of venous thromboembolism.[6]
# Pharmacology
## Pharmacodynamics
Drospirenone differs from other synthetic progestins in that its pharmacological profile in preclinical studies shows it to be closer to the natural progesterone. As such it has potent antimineralocorticoid properties, counteracts the estrogen-stimulated activity of the renin-angiotensin-aldosterone system, and has also been shown to possess mild antiandrogen activity.
The antimineralocorticoid properties exhibited by drospirenone promote sodium excretion and prevent water retention.[7]
## Pharmacokinetics
Drospirenone is taken orally with about 76% bioavailability. It is bound not by sex hormone-binding globulin or corticosteroid binding globulin, but by other serum proteins. Metabolites have not been shown to be biologically active, show up in urine and feces, and are essentially completely excreted within 10 days.
# Chemistry
It is an analog to spironolactone, with a molecular weight of 366.5 and the molecular formula C24H30O3.
# Formulations
The compound is part of certain newer oral contraceptive formulations:
- Yasmin contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet. It is indicated for the prevention of pregnancy in women who elect an oral contraceptive.
- Yasminelle contains 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is used for contraception.
- Yaz and Beyaz contain 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is given for 24/4 days with the same indications.
- Ocella contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet and is taken daily.
It has also been formulated in medication to manage menopausal symptoms using 0.5 mg drsp and 1 mg estradiol per day by oral application. This medication was introduced in the United States in 2007 as Angeliq.
# Litigation
In 2008, a series of television commercials prompted the FDA to cite Bayer for overstating the approved uses of Yaz while failing to adequately address the risks of the drug. Bayer was required to dispel the inaccurate information contained in those ads by creating new ads that clarified the drug's approved uses.[8]
On October 8, 2009, Bayer disclosed that 129 lawsuits had been brought against them over the side effects and marketing of Yaz and Yasmin. The allegations include (but are not limited to):
- Glossing over risks associated with the products and overstating their approved uses in an effort to mislead users of Yaz and Yasmin into believing that the drugs were safe.[8][9]
- Failure to properly research the medication.
- Failing to recall the drug after post-marketing reports demonstrated that the risk of potentially life-threatening side effects of Yasmin and Yaz outweighed potential benefits that could be achieved via other available oral contraceptives.
In September 2009, the FDA cited Bayer for sending out potentially low-quality batches of drosperinone. Bayer justified the shipments by explaining that they monitor the "average" quality of all shipments, not the quality of each individual batch.
In October 2011 the CBC TV program Marketplace ran a segment discussing issues involved with the usage of Yaz/Yasmin
[10] | https://www.wikidoc.org/index.php/Drospirnone | |
d9c9b3992998e7344fb0a5911ad1fb18c3718c5c | wikidoc | Drug design | Drug design
# Overview
Drug design also sometimes referred to as rational drug design is the inventive] process of finding new medications based on the knowledge of the biological target. The drug is most commonly a organic small molecule which activates or inhibits the function of a biomolecule such as a protein which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves design of small molecules that are complementary in shape and charge to the biomolecular target to which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques. This type of modeling often referred to as computer-aided drug design.
The phrase '"drug design" is to some extent a misnomer. What is really meant by drug design is ligand design. Modeling techniques for prediction of binding affinity are reasonably successful. However there are many other properties such as bioavailability, metabolic half life, lack of side effects, etc. that first must be optimized before a ligand can becomes a safe and efficacious drug. These other characteristics are often difficult to optimize using rational drug design techniques.
# Types
There are two major types of drug design. The first is referred to as structure-based drug design and the second, ligand-based drug design.
## Structure based
Structure-based drug design (or direct drug design) relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy. Using the structure of the biological target, candidate drugs that are predicted to bind with high affinity and selectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist. Alternatively various automated computational procedures may be used to suggest new drug candidates.
## Ligand based
Ligand-based drug design (or indirect drug design) relies on knowledge of other molecules that bind to the biological target of interest. These other molecules may be used to derive a pharmacophore which defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target. In other words, a model of the biological target may be built based on the knowledge of what binds to it and this model in turn may be used to design new molecular entities that interact with the target.
# Background
Typically a drug target is a key molecule involved in a particular metabolic or signaling pathway that is specific to a disease condition or pathology, or to the infectivity or survival of a microbial pathogen. Some approaches attempt to inhibit the functioning of the pathway in the diseased state by causing a key molecule to stop functioning. Drugs may be designed that bind to the active region and inhibit this key molecule. Another approach may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state. In addition, these drugs should also be designed in such a way as not to affect any other important "off-target" molecules that may be similar in appearance to the target molecule since drug interactions with off-target molecules may lead to undesirable side effects. Sequence homology is often used to identify such risks.
Most commonly, drugs are organic small molecules but protein based drugs (also known as biologics) are becoming increasing more common. In addition mRNA based gene silencing technologies may have therapeutic applications.
# Rational drug discovery
In contrast to traditional methods of drug discovery which rely on trial-and-error testing of chemical substances on cultured cells or animals, and matching the apparent effects to treatments, rational drug design begins with a hypothesis that modulation of a specific biological target may have therapeutic value. In order for a biomolecule to be selected as a drug target, two essential pieces of information are required. The first is evidence that modulation of the target will have therapeutic value. This knowledge may come from, for example, disease linkage studies that show an association between mutations in the biological target and certain disease states. The second is that the target is "drugable". This means that it is capable of binding to a small molecule and that its activity can be modulated by the small molecule.
Once a suitable target has been identified, the target is normally cloned and expressed. The expressed target is then used to establish a screening assay. In addition, the three-dimensional structure of the target may be determined.
The search for small molecules that bind to the target is begun by screening libraries of potential drug compounds. This may be done by using the screening assay (a "wet screen"). In addition, if the structure of the target is available, a virtual screen may be preformed of candidate drugs. Ideally the candidate drug compounds should be "drug-like", that is they should possess properties that are predicted to lead to oral bioavailability, adequate chemical and metabolic stability, and minimal toxic effects. One way of estimating druglikeness is Lipinski's Rule of Five. Several methods for predicting drug metabolism have been proposed in the scientific literature, and a recent example is SPORCalc. Due to the complexity of the drug design process, two terms of interest are still serendipity and bounded rationality. Those challenges are caused by the large chemical space describing potential new drugs without side-effects.
# Computer-assisted drug design
Computer-assisted drug design uses computational chemistry to discover, enhance, or study drugs and related biologically active molecules. The most fundamental goal is to predict whether a given molecule will bind to a target and if so how strongly. Molecular mechanics or molecular dynamics are most often used to predict the conformation of the small molecule and to model conformational changes in the biological target that may occur when the small molecule binds to it. Semi-empirical, ab initio quantum chemistry methods, or density functional theory are often used to provide optimized parameters for the molecular mechanics calculations and also provide an estimate of the electronic properties (electrostatic potential, polarizability, etc.) of the drug candidate which will influence binding affinity.
Molecular mechanics methods may also be used to provide semi-quantitative prediction of the binding affinity. Alternatively knowledge based scoring function may be used to provide binding affinity estimates. These methods use linear regression, machine learning, neural nets or other statistical techniques to derive predictive binding affinity equations by fitting experimental affinities to computationally derived interaction energies between the small molecule and the target.
Ideally the computational method should be able to predict affinity before a compound is synthesized and hence in theory only one compound needs to be synthesized. The reality however is that present computational methods provide at best only qualitative accurate estimates of affinity. Therefore in practice it still takes several iterations of design, synthesis, and testing before an optimal molecule is discovered. On the other hand, computational methods have accelerated discovery by reducing the number of iterations required and in addition have often provided more novel small molecule structures.
Drug design with the help of computers may be used at any of the following stages of drug discovery:
- hit identification using virtual screening (structure- or ligand-based design)
- hit-to-lead optimization of affinity and selectivity (structure-based design, QSAR, etc.)
- lead optimization optimization of other pharmaceutical properties while maintaining affinity
# Examples
A particular example of rational drug design involves the use of three-dimensional information about biomolecules obtained from such techniques as x-ray crystallography and NMR spectroscopy. This approach to drug discovery is sometimes referred to as structure-based drug design. The first unequivocal example of the application of structure-based drug design leading to an approved drug is the carbonic anhydrase inhibitor dorzolamide which was approved in 1995.
Another important case study in rational drug design is imatinib, a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein that is characteristic for Philadelphia chromosome-positive leukemias (chronic myelogenous leukemia and occasionally acute lymphocytic leukemia). Imatinib is substantially different from previous drugs for cancer, as most agents of chemotherapy simply target rapidly dividing cells, not differentiating between cancer cells and other tissues.
Additional examples include:
- Cimetidine, the prototypical H2-receptor antagonist from which the later members of the class were developed
- dorzolamide, a carbonic anhydrase inhibitor used to treat glaucoma
- Many of the atypical antipsychotics
- Selective COX-2 inhibitor NSAIDs
- SSRIs (selective serotonin reuptake inhibitors), a class of antidepressants
- Zanamivir, an antiviral drug
- Enfuvirtide, a peptide HIV entry inhibitor
- Probenecid
- nonbenzodiazepines like Zolpidem and Zopiclone | Drug design
# Overview
Drug design also sometimes referred to as rational drug design is the inventive] process of finding new medications based on the knowledge of the biological target.[1] The drug is most commonly a organic small molecule which activates or inhibits the function of a biomolecule such as a protein which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves design of small molecules that are complementary in shape and charge to the biomolecular target to which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques.[2] This type of modeling often referred to as computer-aided drug design.
The phrase '"drug design" is to some extent a misnomer. What is really meant by drug design is ligand design. Modeling techniques for prediction of binding affinity are reasonably successful. However there are many other properties such as bioavailability, metabolic half life, lack of side effects, etc. that first must be optimized before a ligand can becomes a safe and efficacious drug. These other characteristics are often difficult to optimize using rational drug design techniques.
# Types
There are two major types of drug design. The first is referred to as structure-based drug design and the second, ligand-based drug design.
## Structure based
Structure-based drug design (or direct drug design) relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy.[3] Using the structure of the biological target, candidate drugs that are predicted to bind with high affinity and selectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist. Alternatively various automated computational procedures may be used to suggest new drug candidates.
## Ligand based
Ligand-based drug design (or indirect drug design) relies on knowledge of other molecules that bind to the biological target of interest. These other molecules may be used to derive a pharmacophore which defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target.[4] In other words, a model of the biological target may be built based on the knowledge of what binds to it and this model in turn may be used to design new molecular entities that interact with the target.
# Background
Typically a drug target is a key molecule involved in a particular metabolic or signaling pathway that is specific to a disease condition or pathology, or to the infectivity or survival of a microbial pathogen. Some approaches attempt to inhibit the functioning of the pathway in the diseased state by causing a key molecule to stop functioning. Drugs may be designed that bind to the active region and inhibit this key molecule. Another approach may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state. In addition, these drugs should also be designed in such a way as not to affect any other important "off-target" molecules that may be similar in appearance to the target molecule since drug interactions with off-target molecules may lead to undesirable side effects. Sequence homology is often used to identify such risks.
Most commonly, drugs are organic small molecules but protein based drugs (also known as biologics) are becoming increasing more common. In addition mRNA based gene silencing technologies may have therapeutic applications.
# Rational drug discovery
In contrast to traditional methods of drug discovery which rely on trial-and-error testing of chemical substances on cultured cells or animals, and matching the apparent effects to treatments, rational drug design begins with a hypothesis that modulation of a specific biological target may have therapeutic value. In order for a biomolecule to be selected as a drug target, two essential pieces of information are required. The first is evidence that modulation of the target will have therapeutic value. This knowledge may come from, for example, disease linkage studies that show an association between mutations in the biological target and certain disease states. The second is that the target is "drugable". This means that it is capable of binding to a small molecule and that its activity can be modulated by the small molecule.
Once a suitable target has been identified, the target is normally cloned and expressed. The expressed target is then used to establish a screening assay. In addition, the three-dimensional structure of the target may be determined.
The search for small molecules that bind to the target is begun by screening libraries of potential drug compounds. This may be done by using the screening assay (a "wet screen"). In addition, if the structure of the target is available, a virtual screen may be preformed of candidate drugs. Ideally the candidate drug compounds should be "drug-like", that is they should possess properties that are predicted to lead to oral bioavailability, adequate chemical and metabolic stability, and minimal toxic effects. One way of estimating druglikeness is Lipinski's Rule of Five. Several methods for predicting drug metabolism have been proposed in the scientific literature, and a recent example is SPORCalc.[5] Due to the complexity of the drug design process, two terms of interest are still serendipity and bounded rationality. Those challenges are caused by the large chemical space describing potential new drugs without side-effects.
# Computer-assisted drug design
Computer-assisted drug design uses computational chemistry to discover, enhance, or study drugs and related biologically active molecules. The most fundamental goal is to predict whether a given molecule will bind to a target and if so how strongly. Molecular mechanics or molecular dynamics are most often used to predict the conformation of the small molecule and to model conformational changes in the biological target that may occur when the small molecule binds to it. Semi-empirical, ab initio quantum chemistry methods, or density functional theory are often used to provide optimized parameters for the molecular mechanics calculations and also provide an estimate of the electronic properties (electrostatic potential, polarizability, etc.) of the drug candidate which will influence binding affinity.
Molecular mechanics methods may also be used to provide semi-quantitative prediction of the binding affinity. Alternatively knowledge based scoring function may be used to provide binding affinity estimates. These methods use linear regression, machine learning, neural nets or other statistical techniques to derive predictive binding affinity equations by fitting experimental affinities to computationally derived interaction energies between the small molecule and the target.
Ideally the computational method should be able to predict affinity before a compound is synthesized and hence in theory only one compound needs to be synthesized. The reality however is that present computational methods provide at best only qualitative accurate estimates of affinity. Therefore in practice it still takes several iterations of design, synthesis, and testing before an optimal molecule is discovered. On the other hand, computational methods have accelerated discovery by reducing the number of iterations required and in addition have often provided more novel small molecule structures.
Drug design with the help of computers may be used at any of the following stages of drug discovery:
- hit identification using virtual screening (structure- or ligand-based design)
- hit-to-lead optimization of affinity and selectivity (structure-based design, QSAR, etc.)
- lead optimization optimization of other pharmaceutical properties while maintaining affinity
# Examples
A particular example of rational drug design involves the use of three-dimensional information about biomolecules obtained from such techniques as x-ray crystallography and NMR spectroscopy. This approach to drug discovery is sometimes referred to as structure-based drug design. The first unequivocal example of the application of structure-based drug design leading to an approved drug is the carbonic anhydrase inhibitor dorzolamide which was approved in 1995.[6][7]
Another important case study in rational drug design is imatinib, a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein that is characteristic for Philadelphia chromosome-positive leukemias (chronic myelogenous leukemia and occasionally acute lymphocytic leukemia). Imatinib is substantially different from previous drugs for cancer, as most agents of chemotherapy simply target rapidly dividing cells, not differentiating between cancer cells and other tissues.
Additional examples include:
- Cimetidine, the prototypical H2-receptor antagonist from which the later members of the class were developed
- dorzolamide, a carbonic anhydrase inhibitor used to treat glaucoma
- Many of the atypical antipsychotics
- Selective COX-2 inhibitor NSAIDs
- SSRIs (selective serotonin reuptake inhibitors), a class of antidepressants
- Zanamivir, an antiviral drug
- Enfuvirtide, a peptide HIV entry inhibitor
- Probenecid
- nonbenzodiazepines like Zolpidem and Zopiclone | https://www.wikidoc.org/index.php/Drug_design | |
a4dd12d2d3bf76c53675abd8cf2af1e1819a9a98 | wikidoc | Dulaglutide | Dulaglutide
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# Black Box Warning
# Overview
Dulaglutide is a glucagon-like peptide-1 receptor agonist that is FDA approved for the treatment of glycemic control in adults with type 2 diabetes mellitus.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include (abdominal pain, decrease in appetite, diarrhea, nausea, vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dulaglutide™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- Dulaglutide is not recommended as a first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans.
- Prescribe dulaglutide only to patients for whom the potential benefits outweigh the potential risk .
- Dulaglutide has not been studied in patients with a history of pancreatitis . Consider other antidiabetic therapies in patients with a history of pancreatitis.
- Dulaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. dulaglutide is not a substitute for insulin.
- Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. The use of dulaglutide is not recommended in patients with pre-existing severe gastrointestinal disease
- The concurrent use of dulaglutide and basal insulin has not been studied.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dulaglutide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dulaglutide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Dulaglutide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dulaglutide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dulaglutide in pediatric patients.
# Contraindications
- Dulaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) .
- Dulaglutide is contraindicated in patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the product components
# Warnings
In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure Glucagon-like peptide (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether dulaglutide will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.
- One case of MTC was reported in a patient treated with dulaglutide. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.
- Dulaglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of dulaglutide and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
- Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with dulaglutide. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
- In Phase 2 and Phase 3 clinical studies, 12 (3.4 cases per 1000 patient years) pancreatitis related adverse reactions were reported in patients exposed to dulaglutide versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analyses of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to dulaglutide (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient years).
- After initiation of dulaglutide, observe patients carefully for signs and symptoms of pancreatitis, including persistent severe abdominal pain. If pancreatitis is suspected, promptly discontinue dulaglutide. If pancreatitis is confirmed, dulaglutide should not be restarted. dulaglutide has not been evaluated in patients with a prior history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
- The risk of hypoglycemia is increased when dulaglutide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting .
- Systemic hypersensitivity reactions were observed in patients receiving dulaglutide in clinical trials. If a hypersensitivity reaction occurs, the patient should discontinue dulaglutide and promptly seek medical advice.
- In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Because these reactions may worsen renal function, use caution when initiating or escalating doses of dulaglutide in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions.
- Use of dulaglutide may be associated with gastrointestinal adverse reactions, sometimes severe . Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with dulaglutide or any other antidiabetic drug.
# Adverse Reactions
## Clinical Trials Experience
- The following serious reactions are described below or elsewhere in the prescribing information:
- Risk of Thyroid C-cell Tumors
- Pancreatitis
- Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
- Hypersensitivity reactions
- Renal impairment
- Severe Gastrointestinal Disease
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- The data in TABLE 1 are derived from the placebo-controlled trials .
- These data reflect exposure of 1670 patients to dulaglutide and a mean duration of exposure to dulaglutide of 23.8 weeks. Across the treatment arms, the mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population in these studies was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.0 years and had a mean HbA1c of 8.0%. At baseline, 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60mL/min/1.73 m2) in 96.0% of the pooled study populations.
- Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of dulaglutide in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on dulaglutide than on placebo, and occurred in at least 5% of patients treated with dulaglutide.
Note: Percentages reflect the number of patients that reported at least 1 treatment- emergent occurrence of the adverse reaction.Gastrointestinal Adverse Reactions
- In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving dulaglutide than placebo (placebo 21.3%, 0.75 mg 31.6%, 1.5 mg 41.0%). More patients receiving dulaglutide 0.75 mg (1.3%) and dulaglutide 1.5 mg (3.5%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.2%). Investigators graded the severity of gastrointestinal adverse reactions occurring on 0.75 mg and 1.5 mg of dulaglutide as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively.
- In addition to the reactions in TABLE 1, the following adverse reactions were reported more frequently in dulaglutide-treated patients than placebo (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%, 3.9%, 3.7%), flatulence (1.4%, 1.4%, 3.4%), abdominal distension (0.7%, 2.9%, 2.3%), gastroesophageal reflux disease (0.5%, 1.7%, 2.0%), and eructation (0.2%, 0.6%, 1.6%).
- The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 6 placebo- and active-controlled trials evaluating the use of dulaglutide as monotherapy and add-on therapy to oral medications or insulin.In this pool, a total of 3342 patients with type 2 diabetes were treated with dulaglutide for a mean duration of 52 weeks. The mean age of patients was 56 years, 2% were 75 years or older and 51% were male. The population in these studies was 71% White, 7% Black or African American, 11% Asian; 32% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.2 years and had a mean HbA1c of 7.6-8.5%. At baseline, 5.2% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 ml/min/1.73 m2) in 95.7% of the dulaglutide population.
- In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in TABLE 1.
- TABLE 2 summarizes the incidence of documented symptomatic (≤70 mg/dL glucose threshold) and severe hypoglycemia in the placebo-controlled clinical studies.
- Hypoglycemia was more frequent when dulaglutide was used in combination with a sulfonylurea or insulin . Documented symptomatic hypoglycemia occurred in 39% and 40% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with a sulfonylurea. Documented symptomatic hypoglycemia occurred in 85% and 80% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with prandial insulin. Severe hypoglycemia occurred in 2.4% and 3.4% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with prandial insulin.
- Dulaglutide 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm). The long-term clinical effects of the increase in HR have not been established
- Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to dulaglutide. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patient treated with placebo, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively. Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4% and 1.6% of patients treated with placebo, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, were reported in 0.7%, 1.3% and 2.2% of patient treated with placebo, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively.
- Across four Phase 2 and five Phase 3 clinical studies, 64 (1.6%) dulaglutide treated patients developed anti-drug antibodies (ADAs) to the active ingredient in dulaglutide (i.e., dulaglutide).
- Of the 64 dulaglutide-treated patients that developed dulaglutide ADAs, 34 patients (0.9% of the overall population) had dulaglutide-neutralizing antibodies, and 36 patients (0.9% of the overall population) developed antibodies against native GLP-1.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to dulaglutide cannot be directly compared with the incidence of antibodies of other products.
- Systemic hypersensitivity adverse reactions sometimes severe (e.g., severe urticaria, systemic rash, facial edema, lip swelling) occurred in 0.5% of patients on dulaglutide in the four Phase 2 and five Phase 3 studies.
- In the placebo-controlled studies, injection-site reactions (e.g., injection-site rash, erythema) were reported in 0.5% of dulaglutide-treated patients and in 0.0% of placebo-treated patients.
- A mean increase from baseline in PR interval of 2-3 milliseconds was observed in dulaglutide-treated patients in contrast to a mean decrease of 0.9 millisecond in placebo-treated patients. The adverse reaction of first degree AV block occurred more frequently in patients treated with dulaglutide than placebo (0.9%, 1.7% and 2.3% for placebo, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively). On electrocardiograms, a PR interval increase to at least 220 milliseconds was observed in 0.7%, 2.5% and 3.2% of patients treated with placebo, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively.
- Patients exposed to dulaglutide had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebo-treated patients had mean increases of up to 3%.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Dulaglutide in the drug label.
# Drug Interactions
- Dulaglutide slows gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with dulaglutide. Drug levels of oral medications with a narrow therapeutic index should be adequately monitored when concomitantly administered with dulaglutide. In clinical pharmacology studies, dulaglutide did not affect the absorption of the tested, orally administered medications to a clinically relevant degree
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of dulaglutide in pregnant women. The risk of birth defects, loss, or other adverse outcomes is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes to maintain good metabolic control before conception and throughout pregnancy.
- dulaglutide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In rats and rabbits, dulaglutide administered during the major period of organogenesis produced fetal growth reductions and/or skeletal anomalies and ossification deficits in association with decreased maternal weight and food consumption attributed to the pharmacology of dulaglutide.
- In pregnant rats given subcutaneous doses of 0.49, 1.63, or 4.89 mg/kg dulaglutide on Gestation Days 6, 9, 12, and 15 (organogenesis), reduced fetal weights associated with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide were observed at ≥1.63 mg/kg, a systemic exposure ≥14-fold the MRHD based on AUC. Irregular skeletal ossifications and increases in post implantation loss also were observed at 4.89 mg/kg, a systemic exposure 44-fold the MRHD based on AUC. No developmental adverse effects were observed at 4-fold the MRHD based on AUC.
- In pregnant rabbits given subcutaneous doses of 0.04, 0.12, or 0.41 mg/kg dulaglutide on Gestation Days 7, 10, 13, 16, and 19 (organogenesis), fetal skeletal malformations of the vertebrae and/or ribs were observed in conjunction with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide at 0.41 mg/kg, a systemic exposure 13-fold the MRHD based on AUC. No developmental adverse effects were observed at 4-fold the MRHD based on AUC.
- In a prenatal-postnatal study in F0 maternal rats given subcutaneous doses of 0.2, 0.49, or 1.63 mg/kg every third day from implantation through lactation, F1 pups from F0 maternal rats given 1.63 mg/kg dulaglutide had statistically significantly lower mean body weight from birth through post-natal day 63 for males and post-natal day 84 for females. F1 offspring from F0 maternal rats receiving 1.63 mg/kg dulaglutide had decreased forelimb and hindlimb grip strength and males had delayed balano-preputial separation. Females had decreased startle response. These physical findings may relate to the decreased size of the offspring relative to controls as they appeared at early postnatal assessments but were not observed at a later assessment. F1 female offspring of the F0 maternal rats given 1.63 mg/kg of dulaglutide had a longer mean escape time and a higher mean number of errors relative to concurrent control during 1 of 2 trials in the memory evaluation portion of the Biel water maze. These findings occurred in conjunction with decreased F0 maternal food intake and decreased weight gain attributed to the pharmacologic activity at 1.63 mg/kg, a systemic exposure 16-fold the MRHD based on AUC. *The human relevance of these memory deficits in the F1 female rats is not known.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dulaglutide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dulaglutide during labor and delivery.
### Nursing Mothers
- It is not known whether dulaglutide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for clinical adverse reactions from dulaglutide in nursing infants, a decision should be made whether to discontinue nursing or to discontinue dulaglutide, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of dulaglutide have not been established in pediatric patients. dulaglutide is not recommended for use in pediatric patients younger than 18 years.
### Geriatic Use
- In the pool of placebo- and active-controlled trials , 620 (18.6%) dulaglutide-treated patients were 65 years of age and over and 65 dulaglutide-treated patients (1.9%) patients were 75 years of age and over. No overall differences in safety or efficacy were detected between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Dulaglutide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dulaglutide with respect to specific racial populations.
### Renal Impairment
- In the four Phase 2 and five Phase 3 randomized clinical studies, at baseline, 50 (1.2%) dulaglutide-treated patients had mild renal impairment (eGFR ≥60 but <90 mL/min/1.73 m2), 171 (4.3%) dulaglutide-treated patients had moderate renal impairment (eGFR ≥30 but <60 mL/min/1.73 m2) and no dulaglutide-treated patients had severe renal impairment (eGFR <30 mL/min/1.73 m2). No overall differences in safety or effectiveness were observed relative to patients with normal renal function, though conclusions are limited due to small numbers. In a clinical pharmacology study in subjects with renal impairment including end-stage renal disease (ESRD), no clinically relevant change in dulaglutide PK was observed .
- There is limited clinical experience in patients with severe renal impairment or ESRD. dulaglutide should be used with caution, and if these patients experience adverse gastrointestinal side effects, renal function should be closely monitored
### Hepatic Impairment
- There is limited clinical experience in patients with mild, moderate, or severe hepatic impairment. Therefore, dulaglutide should be used with caution in these patient populations.
- In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no clinically relevant change in dulaglutide pharmacokinetics (PK) was observed
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dulaglutide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dulaglutide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Dulaglutide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Dulaglutide in the drug label.
# Overdosage
- Overdoses have been reported in clinical studies. Effects associated with these overdoses were primarily mild or moderate gastrointestinal events (e.g., nausea, vomiting) and non-severe hypoglycemia. In the event of overdose, appropriate supportive care (including frequent plasma glucose monitoring) should be initiated according to the patient's clinical signs and symptoms.
# Pharmacology
## Mechanism of Action
- Dulaglutide contains dulaglutide, which is a human GLP-1 receptor agonist with 90% amino acid sequence homology to endogenous human GLP-1 (7-37). Dulaglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase in pancreatic beta cells. Dulaglutide increases intracellular cyclic AMP (cAMP) in beta cells leading to glucose-dependent insulin release. Dulaglutide also decreases glucagon secretion and slows gastric emptying.
## Structure
- Dulaglutide, a human GLP-1 receptor agonist. The molecule is a fusion protein that consists of 2 identical, disulfide-linked chains, each containing an N-terminal GLP-1 analog sequence covalently linked to the Fc portion of a modified human immunoglobulin G4 (IgG4) heavy chain by a small peptide linker and is produced using mammalian cell culture. The GLP-1 analog portion of dulaglutide is 90% homologous to native human GLP-1 (7-37). Structural modifications were introduced in the GLP-1 part of the molecule responsible for interaction with the enzyme dipeptidyl-peptidase IV (DPP-4). Additional modifications were made in an area with a potential T-cell epitope and in the areas of the IgG4 Fc part of the molecule responsible for binding the high-affinity Fc receptors and half-antibody formation. The overall molecular weight of dulaglutide is approximately 63 kilodaltons.
Dulaglutide is a clear, colorless, sterile solution. Each 0.5 mL of dulaglutide solution contains 0.75 mg or 1.5 mg of dulaglutide. Each single-dose pen or prefilled syringe contains 0.5 mL of solution and the following excipients: citric acid anhydrous (0.07 mg), mannitol (23.2 mg), polysorbate 80 (0.10 mg), trisodium citrate dihydrate (1.37 mg), in water for injection.
## Pharmacodynamics
- Dulaglutide lowers fasting glucose and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus. The reduction in fasting and postprandial glucose can be observed after a single dose.
- Fasting and Postprandial Glucose
- In a clinical pharmacology study in adults with type 2 diabetes mellitus, treatment with once weekly dulaglutide resulted in a reduction of fasting and 2-hour PPG concentrations, and postprandial serum glucose incremental AUC, when compared to placebo (-25.6 mg/dL,-59.5 mg/dL, and -197 mg h/dL, respectively); these effects were sustained after 6 weeks of dosing with the 1.5 mg dose.
- First- and Second-Phase Insulin Secretion
- Both first-and second-phase insulin secretion were increased in patients with type 2 diabetes treated with dulaglutide compared with placebo.
- Insulin and Glucagon Secretion
- Dulaglutide stimulates glucose-dependent insulin secretion and reduces glucagon secretion. Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly increased fasting insulin from baseline at Week 26 by 35.38 and 17.50 pmol/L, respectively, and C-peptide concentration by 0.09 and 0.07 nmol/L, respectively, in a Phase 3 monotherapy study. In the same study, fasting glucagon concentration was reduced by 1.71 and 2.05 pmol/L from baseline with dulaglutide 0.75 mg and 1.5 mg, respectively.
- Gastric Motility
- Dulaglutide causes a delay of gastric emptying. The delay is largest after the first dose and diminishes with subsequent doses.
- Cardiac Electrophysiology (QTc)
- The effect of dulaglutide on cardiac repolarization was tested in a thorough QTc study. Dulaglutide did not produce QTc prolongation at supratherapeutic doses of 4 and 7 mg.
## Pharmacokinetics
- The pharmacokinetics of dulaglutide is similar between healthy subjects and patients with type 2 diabetes mellitus. Following subcutaneous administration, the time to maximum plasma concentration of dulaglutide at steady-state ranges from 24 to 72 hours, with a median of 48 hours. After multiple-dose administration of 1.5 mg to steady state, the mean peak plasma concentration (Cmax) and total systemic exposure (AUC) of dulaglutide were 114 ng/mL (range 56 to 231 ng/mL) and 14,000 ng*h/mL (range 6940 to 26,000 ng*h/mL), respectively; accumulation ratio was approximately 1.56. Steady-state plasma dulaglutide concentrations were achieved between 2 and 4 weeks following once weekly administration. Site of subcutaneous administration (abdomen, upper arm, and thigh) had no statistically significant effect on the exposure to dulaglutide.
- Absorption –
- The mean absolute bioavailability of dulaglutide following subcutaneous administration of single 0.75 mg and 1.5 mg doses was 65% and 47%, respectively.
- Distribution –
- The mean volumes of distribution after subcutaneous administration of dulaglutide 0.75 mg and 1.5 mg to steady state were approximately 19.2 L (range 14.3 to 26.4 L) and 17.4 L (range 9.3 to 33 L), respectively.
- Metabolism –
- Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways.
- Elimination –
- The mean apparent clearance at steady state of dulaglutide is approximately 0.111 L/h for the 0.75 mg dose, and 0.107 L/h for the 1.5 mg dose. The elimination half-life of dulaglutide for both doses is approximately 5 days.
- Specific Populations
- No dose adjustment of dulaglutide is needed based on age, gender, race, ethnicity, body weight, or renal or hepatic impairment. The effects of intrinsic factors on the PK of dulaglutide are shown in Figure1
- Renal –
- Dulaglutide systemic exposure was increased by 20, 28, 14 and 12% for mild, moderate, severe, and ESRD renal impairment sub-groups, respectively, compared to subjects with normal renal function. The corresponding values for increase in Cmax were 13, 23, 20 and 11%, respectively (FIGURE 1).
- Hepatic -
- Dulaglutide systemic exposure decreased by 23, 33 and 21% for mild, moderate and severe hepatic impairment groups, respectively, compared to subjects with normal hepatic function, and Cmax was decreased by a similar magnitude (FIGURE 1).
- Drug Interactions
- The potential effect of co-administered medications on the PK of dulaglutide and vice-versa was studied in several single- and multiple-dose studies in healthy subjects, patients with type 2 diabetes mellitus, and patients with hypertension.
- Potential for Dulaglutide to Influence the Pharmacokinetics of Other Drugs
- Dulaglutide slows gastric emptying and, as a result, may reduce the extent and rate of absorption of orally co-administered medications. In clinical pharmacology studies, dulaglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree.
- Pharmacokinetic (PK) measures indicating the magnitude of these interactions are presented in FIGURE 2. No dose adjustment is recommended for any of the evaluated co-administered medications
- Potential for Co-administered Drugs to Influence the Pharmacokinetics of Dulaglutide
- In a clinical pharmacology study, the coadministration of a single dose of dulaglutide (1.5 mg) with steady-state sitagliptin (100 mg) caused an increase in dulaglutide AUC and Cmax of approximately 38% and 27%, which is not considered clinically relevant.
## Nonclinical Toxicology
- A 2-year carcinogenicity study was conducted with dulaglutide in male and female rats at doses of 0.05, 0.5, 1.5, and 5.0 mg/kg (0.5-, 7-, 20-, and 58-fold the MRHD of 1.5 mg once weekly based on AUC) administered by subcutaneous injection twice weekly. In rats, dulaglutide caused a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) compared to controls, at ≥7-fold the MRHD based on AUC. A statistically significant increase in C-cell adenomas was observed in rats receiving dulaglutide at ≥0.5 mg/kg). Numerical increases in thyroid C-cell carcinomas occurred at 5 mg/kg (58 times the MRHD based on AUC) and were considered to be treatment-related despite the absence of statistical significance.
- A 6-month carcinogenicity study was conducted with dulaglutide in rasH2 transgenic mice at doses of 0.3, 1.0, and 3.0 mg/kg administered by subcutaneous injection twice weekly. *Dulaglutide did not produce increased incidences of thyroid C-cell hyperplasia or neoplasia at any dose.
- Dulaglutide is a recombinant protein; no genotoxicity studies have been conducted.
- Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies .
- In fertility and early embryonic development studies in male and female rats, no adverse effects of dulaglutide on sperm morphology, mating, fertility, conception, and embryonic survival were observed at up to 16.3 mg/kg (130-fold the MRHD based on AUC). In female rats, an increase in the number of females with prolonged diestrus and a dose-related decrease in the mean number of corpora lutea, implantation sites, and viable embryos were observed at ≥4.9 mg/kg (≥32-fold the MRHD based on AUC), which occurred in the presence of decreased maternal food consumption and body weight gain.
- Zucker diabetic fatty (ZDF) rats were given 0.5, 1.5, or 5.0 mg/kg/twice weekly of dulaglutide (3-, 8-, and 30-fold the MRHD based on AUC) for 3 months. Increases of 12% to 33% in total and pancreatic amylase, but not lipase, were observed at all doses without microscopic pancreatic inflammatory correlates in individual animals. Other changes in the dulaglutide-treated animals included increased interlobular ductal epithelium without active ductal cell proliferation (≥0.5 mg/kg), increased acinar atrophy with/without inflammation (≥1.5 mg/kg), and increased neutrophilic inflammation of the acinar pancreas (5 mg/kg).
- Treatment of monkeys for 12 months with 8.15 mg/kg/twice weekly of dulaglutide (nearly 500-fold the MRHD based on AUC) demonstrated no evidence of pancreatic inflammation or pancreatic intraepithelial neoplasia. In 4 of 19 monkeys on dulaglutide treatment, there was an increase in goblet cells within the pancreatic ducts, but no differences from the control group in total amylase or lipase at study termination. There were no proliferative changes in the thyroid C-cells.
- Add-on to Metformin
- In this 104-week placebo-controlled, double-blind study (52-week primary endpoint), 972 patients were randomized to placebo, dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or sitagliptin 100 mg/day (after 26 weeks, patients in the placebo treatment group received blinded sitagliptin 100 mg/day for the remainder of the study), all as add-on to metformin. Randomization occurred after an 11-week lead-in period to allow for a metformin titration period, followed by a 6-week glycemic stabilization period. Patients had a mean age of 54 years; mean duration of type 2 diabetes of 7 years; 48% were male; race: White, Black and Asian were 53%, 4% and 27%, respectively; and 24% of the study population were in the US.
- At the 26 week placebo-controlled time point, the HbA1c change was 0.1%, -1.0%, -1.2%, and -0.6% for placebo, dulaglutide 0.75 mg, dulaglutide 1.5 mg, and sitagliptin, respectively. The percentage of patients who achieved HbA1c <7.0% was 22%, 56%, 62%, 39% for placebo, dulaglutide 0.75 mg, dulaglutide 1.5 mg, and sitagliptin, respectively. At 26 weeks, there was a mean weight reduction of 1.4 kg, 2.7 kg, 3.0 kg, and 1.4 kg for placebo, dulaglutide 0.75 mg, dulaglutide 1.5 mg, and sitagliptin, respectively. There was a mean reduction of fasting glucose of 9 mg/dL, 35 mg/dL, 41 mg/dL, and 18 mg/dL for placebo, dulaglutide 0.75 mg, dulaglutide 1.5 mg, and sitagliptin, respectively.
- Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to sitagliptin (at 26 and 52), all in combination with metformin (TABLE 4 and FIGURE 4).
- Add-on to Metformin and Thiazolidinedione
- In this 52-week placebo-controlled study (26-week primary endpoint), 976 patients were randomized to placebo, dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or exenatide 10 mcg BID, all as add-on to maximally tolerated doses of metformin (≥1500 mg per day) and pioglitazone (up to 45 mg per day). Exenatide treatment group assignment was open-label while the treatment assignments to placebo, dulaglutide 0.75 mg, and dulaglutide 1.5 mg were blinded. After 26 weeks, patients in the placebo treatment group were randomized to either dulaglutide 0.75 mg once weekly or dulaglutide 1.5 mg once weekly to maintain study blind. Randomization occurred after a 12-week lead-in period; during the initial 4 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and pioglitazone; this was followed by an 8-week glycemic stabilization period prior to randomization. Patients randomized to exenatide started at a dose of 5 mcg BID for 4 weeks and then were escalated to 10 mcg BID. Patients had a mean age of 56 years; mean duration of type 2 diabetes of 9 years; 58% were male; race: White, Black and Asian were 74%, 8% and 3%, respectively; and 81% of the study population were in the US.
- Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to exenatide at 26 weeks (TABLE 5 and FIGURE 4). Over the 52-week study period, the percentage of patients who required glycemic rescue was 8.9% in the dulaglutide 0.75 mg once weekly + metformin and pioglitazone treatment group, 3.2% in the dulaglutide 1.5 mg once weekly + metformin and pioglitazone treatment group, and 8.7% in the exenatide BID + metformin and pioglitazone treatment group.
- Add-on to Metformin and Sulfonylurea
- In this 78-week (52-week primary endpoint) open-label comparator study (double-blind with respect to dulaglutide dose assignment), 807 patients were randomized to dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or insulin glargine once daily, all as add-on to maximally tolerated doses of metformin and glimepiride. Randomization occurred after a 10-week lead-in period; during the initial 2 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and glimepiride. This was followed by a 6- to 8-week glycemic stabilization period prior to randomization.
- Patients randomized to insulin glargine were started on a dose of 10 U once daily. Insulin glargine dose adjustments occurred twice weekly for the first 4 weeks of treatment based on self-measured fasting plasma glucose (FPG), followed by once weekly titration through Week 8 of study treatment, utilizing an algorithm that targeted a fasting plasma glucose of <100 mg/dL. Only 24% of patients were titrated to goal at the 52 week primary endpoint. The dose of glimepiride could be reduced or discontinued after randomization (at the discretion of the investigator) in the event of persistent hypoglycemia. The dose of glimepiride was reduced or discontinued in 28%, 32%, and 29% of patients randomized to dulaglutide 0.75 mg, dulaglutide 1.5 mg, and glargine.
- Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9 years; 51% were male; race: White, Black and Asian were 71%, 1% and 17%, respectively; and 0% of the study population were in the US.
- Treatment with dulaglutide once weekly resulted in a reduction in HbA1c from baseline at 52 weeks when used in combination with metformin and sulfonylurea (TABLE 6). The difference in observed effect size between dulaglutide 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%.
- Add-on to Prandial Insulin, with or without Metformin
- In this 52-week (26-week primary endpoint) open-label comparator study (double-blind with respect to dulaglutide dose assignment), 884 patients on 1 or 2 insulin injections per day were enrolled. Randomization occurred after a 9-week lead-in period; during the initial 2 weeks of the lead-in period, patients continued their pre-study insulin regimen but could be initiated and/or up-titrated on metformin, based on investigator discretion; this was followed by a 7-week glycemic stabilization period prior to randomization.
- At randomization, patients discontinued their pre-study insulin regimen and were randomized to dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro 3 times daily, with or without metformin. Insulin lispro was titrated in each arm based on preprandial and bedtime glucose, and insulin glargine was titrated to a fasting plasma glucose goal of <100 mg/dL. Only 36% of patients randomized to glargine were titrated to the fasting glucose goal at the 26 week primary timepoint.
- Patients had a mean age of 59 years; mean duration of type 2 diabetes of 13 years; 54% were male; race: White, Black and Asian were 79%, 10% and 4%, respectively; and 33% of the study population were in the US.
- Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c from baseline. The difference in observed effect size between dulaglutide 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%.
# Clinical Studies
There is limited information regarding Clinical Studies of Dulaglutide in the drug label.
# How Supplied
- Each dulaglutide single-dose pen or prefilled syringe is packaged in a cardboard outer carton.
- Carton of 4 Single-Dose Pens
- 0.75 mg/0.5 mL solution in a single-dose pen (NDC 0002-1433-80)
- 1.5 mg/0.5 mL solution in a single-dose pen (NDC 0002-1434-80)
- Carton of 4 Prefilled Syringes
- 0.75 mg/0.5 mL solution in a single-dose prefilled syringe (NDC 0002-1431-80)
- 1.5 mg/0.5 mL solution in a single-dose prefilled syringe (NDC 0002-1432-80)
## Storage
- Store dulaglutide in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not use dulaglutide beyond the expiration date.
- If needed, each single-dose pen or prefilled syringe can be kept at room temperature, not to exceed 86°F (30°C) for a total of 14 days.
- Do not freeze dulaglutide. Do not use dulaglutide if it has been frozen.
- Dulaglutide must be protected from light. Storage of dulaglutide in the original carton is recommended until time of administration.
- Discard the dulaglutide single-dose pen or prefilled syringe after use in a puncture-resistant container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients that dulaglutide causes benign and malignant thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their physician .
- Inform patients that persistent severe abdominal pain, that may radiate to the back and which may (or may not) be accompanied by vomiting, is the hallmark symptom of acute pancreatitis.
- Instruct patients to discontinue dulaglutide promptly, and to contact their physician, if persistent severe abdominal pain occurs .
- The risk of hypoglycemia may be increased when dulaglutide is used in combination with a medicine that can cause hypoglycemia, such as a sulfonylurea or insulin. Review and reinforce instructions for hypoglycemia management when initiating dulaglutide therapy, particularly when concomitantly administered with a sulfonylurea or insulin
- Patients treated with dulaglutide should be advised of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion, Inform *patients treated with dulaglutide of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs.
- Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of GLP-1 receptor agonists. If symptoms of hypersensitivity reactions occur, patients must stop taking dulaglutide and seek medical advice promptly.
- Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant.
- Prior to initiation of dulaglutide, train patients on proper injection technique to ensure a full dose is delivered. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations.
- Inform patients of the potential risks and benefits of dulaglutide and of alternative modes of therapy. Inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and advise patients to seek medical advice promptly.
- Each weekly dose of dulaglutide can be administered at any time of day, with or without food. The day of once weekly administration can be changed if necessary, as long as the last dose was administered 3 or more days before. If a dose is missed and there are at least 3 days (72 hours) until the next scheduled dose, it should be administered as soon as possible. *Thereafter, patients can resume their usual once weekly dosing schedule. If a dose is missed and the next regularly scheduled dose is due in 1 or 2 days, the patient should not administer the missed dose and instead resume dulaglutide with the next regularly scheduled dose.
- Advise patients treated with dulaglutide of the potential risk of gastrointestinal side effects
- Instruct patients to read the Medication Guide and the Instructions for Use before starting dulaglutide therapy and review them each time the prescription is refilled. Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
- Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels towards the normal range. HbA1c is especially useful for evaluating long-term glycemic control.
# Precautions with Alcohol
- Alcohol-Dulaglutide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Trulicity
# Look-Alike Drug Names
There is limited information regarding Dulaglutide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Dulaglutide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Black Box Warning
# Overview
Dulaglutide is a glucagon-like peptide-1 receptor agonist that is FDA approved for the treatment of glycemic control in adults with type 2 diabetes mellitus.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include (abdominal pain, decrease in appetite, diarrhea, nausea, vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dulaglutide™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- Dulaglutide is not recommended as a first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans.
- Prescribe dulaglutide only to patients for whom the potential benefits outweigh the potential risk .
- Dulaglutide has not been studied in patients with a history of pancreatitis . Consider other antidiabetic therapies in patients with a history of pancreatitis.
- Dulaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. dulaglutide is not a substitute for insulin.
- Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. The use of dulaglutide is not recommended in patients with pre-existing severe gastrointestinal disease
- The concurrent use of dulaglutide and basal insulin has not been studied.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dulaglutide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dulaglutide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Dulaglutide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dulaglutide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dulaglutide in pediatric patients.
# Contraindications
- Dulaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) .
- Dulaglutide is contraindicated in patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the product components
# Warnings
In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure Glucagon-like peptide (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether dulaglutide will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.
- One case of MTC was reported in a patient treated with dulaglutide. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.
- Dulaglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of dulaglutide and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
- Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with dulaglutide. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
- In Phase 2 and Phase 3 clinical studies, 12 (3.4 cases per 1000 patient years) pancreatitis related adverse reactions were reported in patients exposed to dulaglutide versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analyses of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to dulaglutide (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient years).
- After initiation of dulaglutide, observe patients carefully for signs and symptoms of pancreatitis, including persistent severe abdominal pain. If pancreatitis is suspected, promptly discontinue dulaglutide. If pancreatitis is confirmed, dulaglutide should not be restarted. dulaglutide has not been evaluated in patients with a prior history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
- The risk of hypoglycemia is increased when dulaglutide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting .
- Systemic hypersensitivity reactions were observed in patients receiving dulaglutide in clinical trials. If a hypersensitivity reaction occurs, the patient should discontinue dulaglutide and promptly seek medical advice.
- In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Because these reactions may worsen renal function, use caution when initiating or escalating doses of dulaglutide in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions.
- Use of dulaglutide may be associated with gastrointestinal adverse reactions, sometimes severe . Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with dulaglutide or any other antidiabetic drug.
# Adverse Reactions
## Clinical Trials Experience
- The following serious reactions are described below or elsewhere in the prescribing information:
- Risk of Thyroid C-cell Tumors
- Pancreatitis
- Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
- Hypersensitivity reactions
- Renal impairment
- Severe Gastrointestinal Disease
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- The data in TABLE 1 are derived from the placebo-controlled trials .
- These data reflect exposure of 1670 patients to dulaglutide and a mean duration of exposure to dulaglutide of 23.8 weeks. Across the treatment arms, the mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population in these studies was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.0 years and had a mean HbA1c of 8.0%. At baseline, 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60mL/min/1.73 m2) in 96.0% of the pooled study populations.
- Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of dulaglutide in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on dulaglutide than on placebo, and occurred in at least 5% of patients treated with dulaglutide.
Note: Percentages reflect the number of patients that reported at least 1 treatment- emergent occurrence of the adverse reaction.Gastrointestinal Adverse Reactions
- In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving dulaglutide than placebo (placebo 21.3%, 0.75 mg 31.6%, 1.5 mg 41.0%). More patients receiving dulaglutide 0.75 mg (1.3%) and dulaglutide 1.5 mg (3.5%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.2%). Investigators graded the severity of gastrointestinal adverse reactions occurring on 0.75 mg and 1.5 mg of dulaglutide as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively.
- In addition to the reactions in TABLE 1, the following adverse reactions were reported more frequently in dulaglutide-treated patients than placebo (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%, 3.9%, 3.7%), flatulence (1.4%, 1.4%, 3.4%), abdominal distension (0.7%, 2.9%, 2.3%), gastroesophageal reflux disease (0.5%, 1.7%, 2.0%), and eructation (0.2%, 0.6%, 1.6%).
- The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 6 placebo- and active-controlled trials evaluating the use of dulaglutide as monotherapy and add-on therapy to oral medications or insulin.In this pool, a total of 3342 patients with type 2 diabetes were treated with dulaglutide for a mean duration of 52 weeks. The mean age of patients was 56 years, 2% were 75 years or older and 51% were male. The population in these studies was 71% White, 7% Black or African American, 11% Asian; 32% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.2 years and had a mean HbA1c of 7.6-8.5%. At baseline, 5.2% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 ml/min/1.73 m2) in 95.7% of the dulaglutide population.
- In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in TABLE 1.
- TABLE 2 summarizes the incidence of documented symptomatic (≤70 mg/dL glucose threshold) and severe hypoglycemia in the placebo-controlled clinical studies.
- Hypoglycemia was more frequent when dulaglutide was used in combination with a sulfonylurea or insulin . Documented symptomatic hypoglycemia occurred in 39% and 40% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with a sulfonylurea. Documented symptomatic hypoglycemia occurred in 85% and 80% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with prandial insulin. Severe hypoglycemia occurred in 2.4% and 3.4% of patients when dulaglutide 0.75 mg and 1.5 mg, respectively, was co-administered with prandial insulin.
- Dulaglutide 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm). The long-term clinical effects of the increase in HR have not been established
- Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to dulaglutide. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patient treated with placebo, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively. Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4% and 1.6% of patients treated with placebo, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, were reported in 0.7%, 1.3% and 2.2% of patient treated with placebo, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively.
- Across four Phase 2 and five Phase 3 clinical studies, 64 (1.6%) dulaglutide treated patients developed anti-drug antibodies (ADAs) to the active ingredient in dulaglutide (i.e., dulaglutide).
- Of the 64 dulaglutide-treated patients that developed dulaglutide ADAs, 34 patients (0.9% of the overall population) had dulaglutide-neutralizing antibodies, and 36 patients (0.9% of the overall population) developed antibodies against native GLP-1.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to dulaglutide cannot be directly compared with the incidence of antibodies of other products.
- Systemic hypersensitivity adverse reactions sometimes severe (e.g., severe urticaria, systemic rash, facial edema, lip swelling) occurred in 0.5% of patients on dulaglutide in the four Phase 2 and five Phase 3 studies.
- In the placebo-controlled studies, injection-site reactions (e.g., injection-site rash, erythema) were reported in 0.5% of dulaglutide-treated patients and in 0.0% of placebo-treated patients.
- A mean increase from baseline in PR interval of 2-3 milliseconds was observed in dulaglutide-treated patients in contrast to a mean decrease of 0.9 millisecond in placebo-treated patients. The adverse reaction of first degree AV block occurred more frequently in patients treated with dulaglutide than placebo (0.9%, 1.7% and 2.3% for placebo, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively). On electrocardiograms, a PR interval increase to at least 220 milliseconds was observed in 0.7%, 2.5% and 3.2% of patients treated with placebo, dulaglutide 0.75 mg and dulaglutide 1.5 mg, respectively.
- Patients exposed to dulaglutide had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebo-treated patients had mean increases of up to 3%.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Dulaglutide in the drug label.
# Drug Interactions
- Dulaglutide slows gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with dulaglutide. Drug levels of oral medications with a narrow therapeutic index should be adequately monitored when concomitantly administered with dulaglutide. In clinical pharmacology studies, dulaglutide did not affect the absorption of the tested, orally administered medications to a clinically relevant degree
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of dulaglutide in pregnant women. The risk of birth defects, loss, or other adverse outcomes is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes to maintain good metabolic control before conception and throughout pregnancy.
- dulaglutide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In rats and rabbits, dulaglutide administered during the major period of organogenesis produced fetal growth reductions and/or skeletal anomalies and ossification deficits in association with decreased maternal weight and food consumption attributed to the pharmacology of dulaglutide.
- In pregnant rats given subcutaneous doses of 0.49, 1.63, or 4.89 mg/kg dulaglutide on Gestation Days 6, 9, 12, and 15 (organogenesis), reduced fetal weights associated with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide were observed at ≥1.63 mg/kg, a systemic exposure ≥14-fold the MRHD based on AUC. Irregular skeletal ossifications and increases in post implantation loss also were observed at 4.89 mg/kg, a systemic exposure 44-fold the MRHD based on AUC. No developmental adverse effects were observed at 4-fold the MRHD based on AUC.
- In pregnant rabbits given subcutaneous doses of 0.04, 0.12, or 0.41 mg/kg dulaglutide on Gestation Days 7, 10, 13, 16, and 19 (organogenesis), fetal skeletal malformations of the vertebrae and/or ribs were observed in conjunction with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide at 0.41 mg/kg, a systemic exposure 13-fold the MRHD based on AUC. No developmental adverse effects were observed at 4-fold the MRHD based on AUC.
- In a prenatal-postnatal study in F0 maternal rats given subcutaneous doses of 0.2, 0.49, or 1.63 mg/kg every third day from implantation through lactation, F1 pups from F0 maternal rats given 1.63 mg/kg dulaglutide had statistically significantly lower mean body weight from birth through post-natal day 63 for males and post-natal day 84 for females. F1 offspring from F0 maternal rats receiving 1.63 mg/kg dulaglutide had decreased forelimb and hindlimb grip strength and males had delayed balano-preputial separation. Females had decreased startle response. These physical findings may relate to the decreased size of the offspring relative to controls as they appeared at early postnatal assessments but were not observed at a later assessment. F1 female offspring of the F0 maternal rats given 1.63 mg/kg of dulaglutide had a longer mean escape time and a higher mean number of errors relative to concurrent control during 1 of 2 trials in the memory evaluation portion of the Biel water maze. These findings occurred in conjunction with decreased F0 maternal food intake and decreased weight gain attributed to the pharmacologic activity at 1.63 mg/kg, a systemic exposure 16-fold the MRHD based on AUC. *The human relevance of these memory deficits in the F1 female rats is not known.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dulaglutide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dulaglutide during labor and delivery.
### Nursing Mothers
- It is not known whether dulaglutide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for clinical adverse reactions from dulaglutide in nursing infants, a decision should be made whether to discontinue nursing or to discontinue dulaglutide, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of dulaglutide have not been established in pediatric patients. dulaglutide is not recommended for use in pediatric patients younger than 18 years.
### Geriatic Use
- In the pool of placebo- and active-controlled trials [see Adverse Reactions (6.1)], 620 (18.6%) dulaglutide-treated patients were 65 years of age and over and 65 dulaglutide-treated patients (1.9%) patients were 75 years of age and over. No overall differences in safety or efficacy were detected between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Dulaglutide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dulaglutide with respect to specific racial populations.
### Renal Impairment
- In the four Phase 2 and five Phase 3 randomized clinical studies, at baseline, 50 (1.2%) dulaglutide-treated patients had mild renal impairment (eGFR ≥60 but <90 mL/min/1.73 m2), 171 (4.3%) dulaglutide-treated patients had moderate renal impairment (eGFR ≥30 but <60 mL/min/1.73 m2) and no dulaglutide-treated patients had severe renal impairment (eGFR <30 mL/min/1.73 m2). No overall differences in safety or effectiveness were observed relative to patients with normal renal function, though conclusions are limited due to small numbers. In a clinical pharmacology study in subjects with renal impairment including end-stage renal disease (ESRD), no clinically relevant change in dulaglutide PK was observed .
- There is limited clinical experience in patients with severe renal impairment or ESRD. dulaglutide should be used with caution, and if these patients experience adverse gastrointestinal side effects, renal function should be closely monitored
### Hepatic Impairment
- There is limited clinical experience in patients with mild, moderate, or severe hepatic impairment. Therefore, dulaglutide should be used with caution in these patient populations.
- In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no clinically relevant change in dulaglutide pharmacokinetics (PK) was observed
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dulaglutide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dulaglutide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Dulaglutide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Dulaglutide in the drug label.
# Overdosage
- Overdoses have been reported in clinical studies. Effects associated with these overdoses were primarily mild or moderate gastrointestinal events (e.g., nausea, vomiting) and non-severe hypoglycemia. In the event of overdose, appropriate supportive care (including frequent plasma glucose monitoring) should be initiated according to the patient's clinical signs and symptoms.
# Pharmacology
## Mechanism of Action
- Dulaglutide contains dulaglutide, which is a human GLP-1 receptor agonist with 90% amino acid sequence homology to endogenous human GLP-1 (7-37). Dulaglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase in pancreatic beta cells. Dulaglutide increases intracellular cyclic AMP (cAMP) in beta cells leading to glucose-dependent insulin release. Dulaglutide also decreases glucagon secretion and slows gastric emptying.
## Structure
- Dulaglutide, a human GLP-1 receptor agonist. The molecule is a fusion protein that consists of 2 identical, disulfide-linked chains, each containing an N-terminal GLP-1 analog sequence covalently linked to the Fc portion of a modified human immunoglobulin G4 (IgG4) heavy chain by a small peptide linker and is produced using mammalian cell culture. The GLP-1 analog portion of dulaglutide is 90% homologous to native human GLP-1 (7-37). Structural modifications were introduced in the GLP-1 part of the molecule responsible for interaction with the enzyme dipeptidyl-peptidase IV (DPP-4). Additional modifications were made in an area with a potential T-cell epitope and in the areas of the IgG4 Fc part of the molecule responsible for binding the high-affinity Fc receptors and half-antibody formation. The overall molecular weight of dulaglutide is approximately 63 kilodaltons.
Dulaglutide is a clear, colorless, sterile solution. Each 0.5 mL of dulaglutide solution contains 0.75 mg or 1.5 mg of dulaglutide. Each single-dose pen or prefilled syringe contains 0.5 mL of solution and the following excipients: citric acid anhydrous (0.07 mg), mannitol (23.2 mg), polysorbate 80 (0.10 mg), trisodium citrate dihydrate (1.37 mg), in water for injection.
## Pharmacodynamics
- Dulaglutide lowers fasting glucose and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus. The reduction in fasting and postprandial glucose can be observed after a single dose.
- Fasting and Postprandial Glucose
- In a clinical pharmacology study in adults with type 2 diabetes mellitus, treatment with once weekly dulaglutide resulted in a reduction of fasting and 2-hour PPG concentrations, and postprandial serum glucose incremental AUC, when compared to placebo (-25.6 mg/dL,-59.5 mg/dL, and -197 mg h/dL, respectively); these effects were sustained after 6 weeks of dosing with the 1.5 mg dose.
- First- and Second-Phase Insulin Secretion
- Both first-and second-phase insulin secretion were increased in patients with type 2 diabetes treated with dulaglutide compared with placebo.
- Insulin and Glucagon Secretion
- Dulaglutide stimulates glucose-dependent insulin secretion and reduces glucagon secretion. Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly increased fasting insulin from baseline at Week 26 by 35.38 and 17.50 pmol/L, respectively, and C-peptide concentration by 0.09 and 0.07 nmol/L, respectively, in a Phase 3 monotherapy study. In the same study, fasting glucagon concentration was reduced by 1.71 and 2.05 pmol/L from baseline with dulaglutide 0.75 mg and 1.5 mg, respectively.
- Gastric Motility
- Dulaglutide causes a delay of gastric emptying. The delay is largest after the first dose and diminishes with subsequent doses.
- Cardiac Electrophysiology (QTc)
- The effect of dulaglutide on cardiac repolarization was tested in a thorough QTc study. Dulaglutide did not produce QTc prolongation at supratherapeutic doses of 4 and 7 mg.
## Pharmacokinetics
- The pharmacokinetics of dulaglutide is similar between healthy subjects and patients with type 2 diabetes mellitus. Following subcutaneous administration, the time to maximum plasma concentration of dulaglutide at steady-state ranges from 24 to 72 hours, with a median of 48 hours. After multiple-dose administration of 1.5 mg to steady state, the mean peak plasma concentration (Cmax) and total systemic exposure (AUC) of dulaglutide were 114 ng/mL (range 56 to 231 ng/mL) and 14,000 ng*h/mL (range 6940 to 26,000 ng*h/mL), respectively; accumulation ratio was approximately 1.56. Steady-state plasma dulaglutide concentrations were achieved between 2 and 4 weeks following once weekly administration. Site of subcutaneous administration (abdomen, upper arm, and thigh) had no statistically significant effect on the exposure to dulaglutide.
- Absorption –
- The mean absolute bioavailability of dulaglutide following subcutaneous administration of single 0.75 mg and 1.5 mg doses was 65% and 47%, respectively.
- Distribution –
- The mean volumes of distribution after subcutaneous administration of dulaglutide 0.75 mg and 1.5 mg to steady state were approximately 19.2 L (range 14.3 to 26.4 L) and 17.4 L (range 9.3 to 33 L), respectively.
- Metabolism –
- Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways.
- Elimination –
- The mean apparent clearance at steady state of dulaglutide is approximately 0.111 L/h for the 0.75 mg dose, and 0.107 L/h for the 1.5 mg dose. The elimination half-life of dulaglutide for both doses is approximately 5 days.
- Specific Populations
- No dose adjustment of dulaglutide is needed based on age, gender, race, ethnicity, body weight, or renal or hepatic impairment. The effects of intrinsic factors on the PK of dulaglutide are shown in Figure1
- Renal –
- Dulaglutide systemic exposure was increased by 20, 28, 14 and 12% for mild, moderate, severe, and ESRD renal impairment sub-groups, respectively, compared to subjects with normal renal function. The corresponding values for increase in Cmax were 13, 23, 20 and 11%, respectively (FIGURE 1).
- Hepatic -
- Dulaglutide systemic exposure decreased by 23, 33 and 21% for mild, moderate and severe hepatic impairment groups, respectively, compared to subjects with normal hepatic function, and Cmax was decreased by a similar magnitude (FIGURE 1).
- Drug Interactions
- The potential effect of co-administered medications on the PK of dulaglutide and vice-versa was studied in several single- and multiple-dose studies in healthy subjects, patients with type 2 diabetes mellitus, and patients with hypertension.
- Potential for Dulaglutide to Influence the Pharmacokinetics of Other Drugs
- Dulaglutide slows gastric emptying and, as a result, may reduce the extent and rate of absorption of orally co-administered medications. In clinical pharmacology studies, dulaglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree.
- Pharmacokinetic (PK) measures indicating the magnitude of these interactions are presented in FIGURE 2. No dose adjustment is recommended for any of the evaluated co-administered medications
- Potential for Co-administered Drugs to Influence the Pharmacokinetics of Dulaglutide
- In a clinical pharmacology study, the coadministration of a single dose of dulaglutide (1.5 mg) with steady-state sitagliptin (100 mg) caused an increase in dulaglutide AUC and Cmax of approximately 38% and 27%, which is not considered clinically relevant.
## Nonclinical Toxicology
- A 2-year carcinogenicity study was conducted with dulaglutide in male and female rats at doses of 0.05, 0.5, 1.5, and 5.0 mg/kg (0.5-, 7-, 20-, and 58-fold the MRHD of 1.5 mg once weekly based on AUC) administered by subcutaneous injection twice weekly. In rats, dulaglutide caused a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) compared to controls, at ≥7-fold the MRHD based on AUC. A statistically significant increase in C-cell adenomas was observed in rats receiving dulaglutide at ≥0.5 mg/kg). Numerical increases in thyroid C-cell carcinomas occurred at 5 mg/kg (58 times the MRHD based on AUC) and were considered to be treatment-related despite the absence of statistical significance.
- A 6-month carcinogenicity study was conducted with dulaglutide in rasH2 transgenic mice at doses of 0.3, 1.0, and 3.0 mg/kg administered by subcutaneous injection twice weekly. *Dulaglutide did not produce increased incidences of thyroid C-cell hyperplasia or neoplasia at any dose.
- Dulaglutide is a recombinant protein; no genotoxicity studies have been conducted.
- Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies .
- In fertility and early embryonic development studies in male and female rats, no adverse effects of dulaglutide on sperm morphology, mating, fertility, conception, and embryonic survival were observed at up to 16.3 mg/kg (130-fold the MRHD based on AUC). In female rats, an increase in the number of females with prolonged diestrus and a dose-related decrease in the mean number of corpora lutea, implantation sites, and viable embryos were observed at ≥4.9 mg/kg (≥32-fold the MRHD based on AUC), which occurred in the presence of decreased maternal food consumption and body weight gain.
- Zucker diabetic fatty (ZDF) rats were given 0.5, 1.5, or 5.0 mg/kg/twice weekly of dulaglutide (3-, 8-, and 30-fold the MRHD based on AUC) for 3 months. Increases of 12% to 33% in total and pancreatic amylase, but not lipase, were observed at all doses without microscopic pancreatic inflammatory correlates in individual animals. Other changes in the dulaglutide-treated animals included increased interlobular ductal epithelium without active ductal cell proliferation (≥0.5 mg/kg), increased acinar atrophy with/without inflammation (≥1.5 mg/kg), and increased neutrophilic inflammation of the acinar pancreas (5 mg/kg).
- Treatment of monkeys for 12 months with 8.15 mg/kg/twice weekly of dulaglutide (nearly 500-fold the MRHD based on AUC) demonstrated no evidence of pancreatic inflammation or pancreatic intraepithelial neoplasia. In 4 of 19 monkeys on dulaglutide treatment, there was an increase in goblet cells within the pancreatic ducts, but no differences from the control group in total amylase or lipase at study termination. There were no proliferative changes in the thyroid C-cells.
- Add-on to Metformin
- In this 104-week placebo-controlled, double-blind study (52-week primary endpoint), 972 patients were randomized to placebo, dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or sitagliptin 100 mg/day (after 26 weeks, patients in the placebo treatment group received blinded sitagliptin 100 mg/day for the remainder of the study), all as add-on to metformin. Randomization occurred after an 11-week lead-in period to allow for a metformin titration period, followed by a 6-week glycemic stabilization period. Patients had a mean age of 54 years; mean duration of type 2 diabetes of 7 years; 48% were male; race: White, Black and Asian were 53%, 4% and 27%, respectively; and 24% of the study population were in the US.
- At the 26 week placebo-controlled time point, the HbA1c change was 0.1%, -1.0%, -1.2%, and -0.6% for placebo, dulaglutide 0.75 mg, dulaglutide 1.5 mg, and sitagliptin, respectively. The percentage of patients who achieved HbA1c <7.0% was 22%, 56%, 62%, 39% for placebo, dulaglutide 0.75 mg, dulaglutide 1.5 mg, and sitagliptin, respectively. At 26 weeks, there was a mean weight reduction of 1.4 kg, 2.7 kg, 3.0 kg, and 1.4 kg for placebo, dulaglutide 0.75 mg, dulaglutide 1.5 mg, and sitagliptin, respectively. There was a mean reduction of fasting glucose of 9 mg/dL, 35 mg/dL, 41 mg/dL, and 18 mg/dL for placebo, dulaglutide 0.75 mg, dulaglutide 1.5 mg, and sitagliptin, respectively.
- Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to sitagliptin (at 26 and 52), all in combination with metformin (TABLE 4 and FIGURE 4).
- Add-on to Metformin and Thiazolidinedione
- In this 52-week placebo-controlled study (26-week primary endpoint), 976 patients were randomized to placebo, dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or exenatide 10 mcg BID, all as add-on to maximally tolerated doses of metformin (≥1500 mg per day) and pioglitazone (up to 45 mg per day). Exenatide treatment group assignment was open-label while the treatment assignments to placebo, dulaglutide 0.75 mg, and dulaglutide 1.5 mg were blinded. After 26 weeks, patients in the placebo treatment group were randomized to either dulaglutide 0.75 mg once weekly or dulaglutide 1.5 mg once weekly to maintain study blind. Randomization occurred after a 12-week lead-in period; during the initial 4 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and pioglitazone; this was followed by an 8-week glycemic stabilization period prior to randomization. Patients randomized to exenatide started at a dose of 5 mcg BID for 4 weeks and then were escalated to 10 mcg BID. Patients had a mean age of 56 years; mean duration of type 2 diabetes of 9 years; 58% were male; race: White, Black and Asian were 74%, 8% and 3%, respectively; and 81% of the study population were in the US.
- Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to exenatide at 26 weeks (TABLE 5 and FIGURE 4). Over the 52-week study period, the percentage of patients who required glycemic rescue was 8.9% in the dulaglutide 0.75 mg once weekly + metformin and pioglitazone treatment group, 3.2% in the dulaglutide 1.5 mg once weekly + metformin and pioglitazone treatment group, and 8.7% in the exenatide BID + metformin and pioglitazone treatment group.
- Add-on to Metformin and Sulfonylurea
- In this 78-week (52-week primary endpoint) open-label comparator study (double-blind with respect to dulaglutide dose assignment), 807 patients were randomized to dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or insulin glargine once daily, all as add-on to maximally tolerated doses of metformin and glimepiride. Randomization occurred after a 10-week lead-in period; during the initial 2 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and glimepiride. This was followed by a 6- to 8-week glycemic stabilization period prior to randomization.
- Patients randomized to insulin glargine were started on a dose of 10 U once daily. Insulin glargine dose adjustments occurred twice weekly for the first 4 weeks of treatment based on self-measured fasting plasma glucose (FPG), followed by once weekly titration through Week 8 of study treatment, utilizing an algorithm that targeted a fasting plasma glucose of <100 mg/dL. Only 24% of patients were titrated to goal at the 52 week primary endpoint. The dose of glimepiride could be reduced or discontinued after randomization (at the discretion of the investigator) in the event of persistent hypoglycemia. The dose of glimepiride was reduced or discontinued in 28%, 32%, and 29% of patients randomized to dulaglutide 0.75 mg, dulaglutide 1.5 mg, and glargine.
- Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9 years; 51% were male; race: White, Black and Asian were 71%, 1% and 17%, respectively; and 0% of the study population were in the US.
- Treatment with dulaglutide once weekly resulted in a reduction in HbA1c from baseline at 52 weeks when used in combination with metformin and sulfonylurea (TABLE 6). The difference in observed effect size between dulaglutide 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%.
- Add-on to Prandial Insulin, with or without Metformin
- In this 52-week (26-week primary endpoint) open-label comparator study (double-blind with respect to dulaglutide dose assignment), 884 patients on 1 or 2 insulin injections per day were enrolled. Randomization occurred after a 9-week lead-in period; during the initial 2 weeks of the lead-in period, patients continued their pre-study insulin regimen but could be initiated and/or up-titrated on metformin, based on investigator discretion; this was followed by a 7-week glycemic stabilization period prior to randomization.
- At randomization, patients discontinued their pre-study insulin regimen and were randomized to dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro 3 times daily, with or without metformin. Insulin lispro was titrated in each arm based on preprandial and bedtime glucose, and insulin glargine was titrated to a fasting plasma glucose goal of <100 mg/dL. Only 36% of patients randomized to glargine were titrated to the fasting glucose goal at the 26 week primary timepoint.
- Patients had a mean age of 59 years; mean duration of type 2 diabetes of 13 years; 54% were male; race: White, Black and Asian were 79%, 10% and 4%, respectively; and 33% of the study population were in the US.
- Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c from baseline. The difference in observed effect size between dulaglutide 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%.
# Clinical Studies
There is limited information regarding Clinical Studies of Dulaglutide in the drug label.
# How Supplied
- Each dulaglutide single-dose pen or prefilled syringe is packaged in a cardboard outer carton.
- Carton of 4 Single-Dose Pens
- 0.75 mg/0.5 mL solution in a single-dose pen (NDC 0002-1433-80)
- 1.5 mg/0.5 mL solution in a single-dose pen (NDC 0002-1434-80)
- Carton of 4 Prefilled Syringes
- 0.75 mg/0.5 mL solution in a single-dose prefilled syringe (NDC 0002-1431-80)
- 1.5 mg/0.5 mL solution in a single-dose prefilled syringe (NDC 0002-1432-80)
## Storage
- Store dulaglutide in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not use dulaglutide beyond the expiration date.
- If needed, each single-dose pen or prefilled syringe can be kept at room temperature, not to exceed 86°F (30°C) for a total of 14 days.
- Do not freeze dulaglutide. Do not use dulaglutide if it has been frozen.
- Dulaglutide must be protected from light. Storage of dulaglutide in the original carton is recommended until time of administration.
- Discard the dulaglutide single-dose pen or prefilled syringe after use in a puncture-resistant container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients that dulaglutide causes benign and malignant thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their physician .
- Inform patients that persistent severe abdominal pain, that may radiate to the back and which may (or may not) be accompanied by vomiting, is the hallmark symptom of acute pancreatitis.
- Instruct patients to discontinue dulaglutide promptly, and to contact their physician, if persistent severe abdominal pain occurs .
- The risk of hypoglycemia may be increased when dulaglutide is used in combination with a medicine that can cause hypoglycemia, such as a sulfonylurea or insulin. Review and reinforce instructions for hypoglycemia management when initiating dulaglutide therapy, particularly when concomitantly administered with a sulfonylurea or insulin
- Patients treated with dulaglutide should be advised of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion, Inform *patients treated with dulaglutide of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs.
- Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of GLP-1 receptor agonists. If symptoms of hypersensitivity reactions occur, patients must stop taking dulaglutide and seek medical advice promptly.
- Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant.
- Prior to initiation of dulaglutide, train patients on proper injection technique to ensure a full dose is delivered. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations.
- Inform patients of the potential risks and benefits of dulaglutide and of alternative modes of therapy. Inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and advise patients to seek medical advice promptly.
- Each weekly dose of dulaglutide can be administered at any time of day, with or without food. The day of once weekly administration can be changed if necessary, as long as the last dose was administered 3 or more days before. If a dose is missed and there are at least 3 days (72 hours) until the next scheduled dose, it should be administered as soon as possible. *Thereafter, patients can resume their usual once weekly dosing schedule. If a dose is missed and the next regularly scheduled dose is due in 1 or 2 days, the patient should not administer the missed dose and instead resume dulaglutide with the next regularly scheduled dose.
- Advise patients treated with dulaglutide of the potential risk of gastrointestinal side effects
- Instruct patients to read the Medication Guide and the Instructions for Use before starting dulaglutide therapy and review them each time the prescription is refilled. Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
- Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels towards the normal range. HbA1c is especially useful for evaluating long-term glycemic control.
# Precautions with Alcohol
- Alcohol-Dulaglutide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Trulicity
# Look-Alike Drug Names
There is limited information regarding Dulaglutide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dulaglutide | |
76160a3ba6c1ac8219a4a9c55436fd87ba4210f7 | wikidoc | Microtubule | Microtubule
Microtubules are one of the components of the cytoskeleton. They have diameter of ~ 24 nm and length varying from several micrometers to possibly millimeters in axons of nerve cells. Microtubules serve as structural components within cells and are involved in many cellular processes including mitosis, cytokinesis, and vesicular transport.
# Structure
Microtubules are polymers of α- and β-tubulin dimers. The tubulin dimers polymerize end to end in protofilaments. The protofilaments then bundle in hollow cylindrical filaments. Typically, the protofilaments arrange themselves in an imperfect helix with one turn of the helix containing 13 tubulin dimers each from a different protofilament. The image above illustrates a small section of microtubule, a few αβ dimers in length.
Another important feature of microtubule structure is polarity. Tubulin polymerizes end to end with the α subunit of one tubulin dimer contacting the β subunit of the next. Therefore, in a protofilament, one end will have the α subunit exposed while the other end will have the β subunit exposed. These ends are designated (−) and (+) respectively. The protofilaments bundle parallel to one another, so in a microtubule, there is one end, the (+) end, with only β subunits exposed while the other end, the (−) end, only has α subunits exposed.
# Organization within cells
Microtubules are nucleated and organized by the microtubule organizing centers (MTOCs), such as centrosomes and basal bodies. They are part of a structural network (the cytoskeleton) within the cell's cytoplasm, but, in addition to structural support, microtubules take part in many other processes, as well. They are capable of growing and shrinking in order to generate force, and there are also motor proteins that move along the microtubule. A notable structure involving microtubules is the mitotic spindle used by eukaryotic cells to segregate their chromosomes correctly during cell division. Microtubules are also part of the cilia and flagella of eukaryotic cells (prokaryote flagella are entirely different). Microtubules also move organelles and cell structures to new locations.
# Nucleation and growth
Polymerization of microtubules is nucleated in a microtubule organizing center. Contained within the MTOC is another type of tubulin, γ-tubulin, which is distinct from the α and β subunits which compose the microtubules themselves. The γ-tubulin combines with several other associated proteins to form a circular structure known as the "γ-tubulin ring complex." This complex acts as a scaffold for α/β tubulin dimers to begin polymerization; it acts as a cap of the (−) end while microtubule growth continues away from the MTOC in the (+) direction.
# Dynamic instability
During polymerization, both the α- and β-subunits of the tubulin dimer are bound to a molecule of GTP. The GTP bound to α-tubulin is stable, but the GTP bound to β-tubulin may be hydrolized to GDP shortly after assembly. The kinetics of GDP-tubulin are different from those of GTP-tubulin; GDP-tubulin is prone to depolymerization. A GDP-bound tubulin subunit at the tip of a microtubule will fall off, though a GDP-bound tubulin in the middle of a microtubule cannot spontaneously pop out. Since tubulin adds onto the end of the microtubule only in the GTP-bound state, there is generally a cap of GTP-bound tubulin at the tip of the microtubule, protecting it from disassembly. When hydrolysis catches up to the tip of the microtubule, it begins a rapid depolymerization and shrinkage. This switch from growth to shrinking is called a catastrophe. GTP-bound tubulin can begin adding to the tip of the microtubule again, providing a new cap and protecting the microtubule from shrinking. This is referred to as rescue.
In vivo microtubule dynamics vary considerably. Assembly, disassembly and catastrophe rates depend on which microtubule-associated proteins (MAPs) are present.
## Chemical effects on microtubule dynamics
Microtubule dynamics can also be altered by drugs. For example, the taxane drug class (e.g. paclitaxel or docetaxel), used in the treatment of cancer, blocks dynamic instability by stabilizing GDP-bound tubulin in the microtubule. Thus, even when hydrolysis of GTP reaches the tip of the microtubule, there is no depolymerization and the microtubule does not shrink back. Nocodazole and Colchicine have the opposite effect, blocking the polymerization of tubulin into microtubules.
# Motor proteins
In addition to movement generated by the dynamic instability of the microtubule itself, the fibers are substrates along which motor proteins can move. The major microtubule motor proteins are kinesin, which generally moves towards the (+) end of the microtubule, and dynein, which generally moves towards the (−) end.
# Microtubules and consciousness
Roger Penrose, a mathematician and Stuart Hameroff, an anesthesiologist developed a speculative theory linking microtubules to consciousness. Their theory, known as Orch-OR (orchestrated objective reduction), states that consciousness is a result of quantum computing in the brain, based on tubulin molecules in microtubules as qubits. There have been no empirical tests of the theory and it is regarded with skepticism in the scientific community.
# Microtubules as drug target
# Additional images
- Proteins in different cellular compartments and structures tagged with green fluorescent protein.
ca:Microtúbul
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da:Mikrotubuli
de:Mikrotubulus
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lt:Mikrovamzdeliai
mk:Микротубула
nl:Microtubulus
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fi:Mikrotubulus | Microtubule
Microtubules are one of the components of the cytoskeleton. They have diameter of ~ 24 nm and length varying from several micrometers to possibly millimeters in axons of nerve cells. Microtubules serve as structural components within cells and are involved in many cellular processes including mitosis, cytokinesis, and vesicular transport.
# Structure
Microtubules are polymers of α- and β-tubulin dimers. The tubulin dimers polymerize end to end in protofilaments. The protofilaments then bundle in hollow cylindrical filaments. Typically, the protofilaments arrange themselves in an imperfect helix with one turn of the helix containing 13 tubulin dimers each from a different protofilament. The image above illustrates a small section of microtubule, a few αβ dimers in length.
Another important feature of microtubule structure is polarity. Tubulin polymerizes end to end with the α subunit of one tubulin dimer contacting the β subunit of the next. Therefore, in a protofilament, one end will have the α subunit exposed while the other end will have the β subunit exposed. These ends are designated (−) and (+) respectively. The protofilaments bundle parallel to one another, so in a microtubule, there is one end, the (+) end, with only β subunits exposed while the other end, the (−) end, only has α subunits exposed.
# Organization within cells
Microtubules are nucleated and organized by the microtubule organizing centers (MTOCs), such as centrosomes and basal bodies. They are part of a structural network (the cytoskeleton) within the cell's cytoplasm, but, in addition to structural support, microtubules take part in many other processes, as well. They are capable of growing and shrinking in order to generate force, and there are also motor proteins that move along the microtubule. A notable structure involving microtubules is the mitotic spindle used by eukaryotic cells to segregate their chromosomes correctly during cell division. Microtubules are also part of the cilia and flagella of eukaryotic cells (prokaryote flagella are entirely different). Microtubules also move organelles and cell structures to new locations.
# Nucleation and growth
Polymerization of microtubules is nucleated in a microtubule organizing center. Contained within the MTOC is another type of tubulin, γ-tubulin, which is distinct from the α and β subunits which compose the microtubules themselves. The γ-tubulin combines with several other associated proteins to form a circular structure known as the "γ-tubulin ring complex." This complex acts as a scaffold for α/β tubulin dimers to begin polymerization; it acts as a cap of the (−) end while microtubule growth continues away from the MTOC in the (+) direction.
# Dynamic instability
During polymerization, both the α- and β-subunits of the tubulin dimer are bound to a molecule of GTP. The GTP bound to α-tubulin is stable, but the GTP bound to β-tubulin may be hydrolized to GDP shortly after assembly. The kinetics of GDP-tubulin are different from those of GTP-tubulin; GDP-tubulin is prone to depolymerization. A GDP-bound tubulin subunit at the tip of a microtubule will fall off, though a GDP-bound tubulin in the middle of a microtubule cannot spontaneously pop out. Since tubulin adds onto the end of the microtubule only in the GTP-bound state, there is generally a cap of GTP-bound tubulin at the tip of the microtubule, protecting it from disassembly. When hydrolysis catches up to the tip of the microtubule, it begins a rapid depolymerization and shrinkage. This switch from growth to shrinking is called a catastrophe. GTP-bound tubulin can begin adding to the tip of the microtubule again, providing a new cap and protecting the microtubule from shrinking. This is referred to as rescue.
In vivo microtubule dynamics vary considerably. Assembly, disassembly and catastrophe rates depend on which microtubule-associated proteins (MAPs) are present.
## Chemical effects on microtubule dynamics
Microtubule dynamics can also be altered by drugs. For example, the taxane drug class (e.g. paclitaxel or docetaxel), used in the treatment of cancer, blocks dynamic instability by stabilizing GDP-bound tubulin in the microtubule. Thus, even when hydrolysis of GTP reaches the tip of the microtubule, there is no depolymerization and the microtubule does not shrink back. Nocodazole and Colchicine have the opposite effect, blocking the polymerization of tubulin into microtubules.
# Motor proteins
In addition to movement generated by the dynamic instability of the microtubule itself, the fibers are substrates along which motor proteins can move. The major microtubule motor proteins are kinesin, which generally moves towards the (+) end of the microtubule, and dynein, which generally moves towards the (−) end.
# Microtubules and consciousness
Roger Penrose, a mathematician and Stuart Hameroff, an anesthesiologist developed a speculative theory linking microtubules to consciousness. Their theory, known as Orch-OR (orchestrated objective reduction), states that consciousness is a result of quantum computing in the brain, based on tubulin molecules in microtubules as qubits. There have been no empirical tests of the theory and it is regarded with skepticism in the scientific community.
# Microtubules as drug target
http://www.scienceboard.net/community/perspectives.165.html
# Additional images
- Proteins in different cellular compartments and structures tagged with green fluorescent protein.
ca:Microtúbul
cs:Mikrotubulus
da:Mikrotubuli
de:Mikrotubulus
it:Microtubulo
lt:Mikrovamzdeliai
mk:Микротубула
nl:Microtubulus
sk:Mikrotubuly
sr:Микротубуле
fi:Mikrotubulus
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Dynamic_instability | |
31d10c37939721f540f06f3b35f5993a978ad10d | wikidoc | Triamterene | Triamterene
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Triamterene is a potassium-sparing diuretic that is FDA approved for the treatment of edema associated with congestive heart failure, cirrhosis, nephrotic syndrome, steroid, and secondary hyperaldosteronism. There is a Black Box Warning for this drug as shown here. Common adverse reactions include electrolyte disturbances and hyperuricemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dyrenium (triamterene) is indicated in the treatment of edema associated with congestive heart failure, cirrhosis of the liver and the nephrotic syndrome; steroid-induced edema, idiopathic edema and edema due to secondary hyperaldosteronism.
- Dyrenium may be used alone or with other diuretics, either for its added diuretic effect or its potassium-sparing potential. It also promotes increased diuresis when patients prove resistant or only partially responsive to thiazides or other diuretics because of secondary hyperaldosteronism.
- When Dyrenium (triamterene) is added to other diuretic therapy or when patients are switched to Dyrenium from other diuretics, all potassium supplementation should be discontinued.
- Dosing Information
- When used alone, the usual starting dose is 100 mg PO bid after meals.
- When combined with another diuretic or antihypertensive agent, the total daily dosage of each agent should usually be lowered initially and then adjusted to the patient’s needs. The total daily dosage should not exceed 300 mg.
- The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.
- Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Diuretics are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy. Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triamterene in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 200 mg PO qd
- 50 mg PO qd in combination with chlorthalidone 50 mg
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triamterene in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- 1–2 mg/kg in 2 divided doses
# Contraindications
- Anuria
- Severe or progressive kidney disease or dysfunction, with the possible exception of nephrosis
- Severe hepatic disease
- Hypersensitivity to the drug or any of its components
- Hyperkalemia
- Dyrenium (triamterene) should not be used in patients with pre-existing elevated serum potassium, as is sometimes seen in patients with impaired renal function or azotemia, or in patients who develop hyperkalemia while on the drug. Patients should not be placed on dietary potassium supplements, potassium salts or potassium-containing salt substitutes in conjunction with Dyrenium.
- Dyrenium should not be given to patients receiving other potassium-sparing agents, such as spironolactone, amiloride hydrochloride, or other formulations containing triamterene. Two deaths have been reported in patients receiving concomitant spironolactone and Dyrenium or Dyazide®. Although dosage recommendations were exceeded in one case and in the other serum electrolytes were not properly monitored, these two drugs should not be given concomitantly.
# Warnings
- There have been isolated reports of hypersensitivity reactions; therefore, patients should be observed regularly for the possible occurrence of blood dyscrasias, liver damage or other idiosyncratic reactions.
- Periodic BUN and serum potassium determinations should be made to check kidney function, especially in patients with suspected or confirmed renal insufficiency. It is particularly important to make serum potassium determinations in elderly or diabetic patients receiving the drug; these patients should be observed carefully for possible serum potassium increases.
- If hyperkalemia is present or suspected, an electrocardiogram should be obtained. If the ECG shows no widening of the QRS or arrhythmia in the presence of hyperkalemia, it is usually sufficient to discontinue Dyrenium (triamterene) and any potassium supplementation, and substitute a thiazide alone. Sodium polystyrene sulfonate (Kayexalate®, Sanofi Synthelabo) may be administered to enhance the excretion of excess potassium. The presence of a widened QRS complex or arrhythmia in association with hyperkalemia requires prompt additional therapy. For tachyarrhythmia, infuse 44 mEq of sodium bicarbonate or 10 mL of 10% calcium gluconate or calcium chloride over several minutes. For asystole, bradycardia or A-V block transvenous pacing is also recommended.
- The effect of calcium and sodium bicarbonate is transient and repeated administration may be required. When indicated by the clinical situation, excess K+ may be removed by dialysis or oral or rectal administration of Kayexalate®. Infusion of glucose and insulin has also been used to treat hyperkalemia.
### Precautions
- Dyrenium (triamterene) tends to conserve potassium rather than to promote the excretion as do many diuretics and, occasionally, can cause increases in serum potassium which, in some instances, can result in hyperkalemia. In rare instances, hyperkalemia has been associated with cardiac irregularities.
- Electrolyte imbalance often encountered in such diseases as congestive heart failure, renal disease or cirrhosis may be aggravated or caused independently by any effective diuretic agent includingDyrenium. The use of full doses of a diuretic when salt intake is restricted can result in a low-salt syndrome.
- Triamterene can cause mild nitrogen retention, which is reversible upon withdrawal of the drug, and is seldom observed with intermittent (every-other-day) therapy.
- Triamterene may cause a decreasing alkali reserve, with the possibility of metabolic acidosis.
- By the very nature of their illness, cirrhotics with splenomegaly sometimes have marked variations in their blood. Since triamterene is a weak folic acid antagonist, it may contribute to the appearance of megaloblastosis in cases where folic acid stores have been depleted. Therefore, periodic blood studies in these patients are recommended. They should also be observed for exacerbations of underlying liver disease.
- Triamterene has elevated uric acid, especially in persons predisposed to gouty arthritis.
- Triamterene has been reported in renal stones in association with other calculus components. Dyrenium should be used with caution in patients with histories of renal stones.
- Laboratory Tests
- Hyperkalemia will rarely occur in patients with adequate urinary output, but it is a possibility if large doses are used for considerable periods of time. If hyperkalemia is observed, Dyrenium (triamterene) should be withdrawn. The normal adult range of serum potassium is 3.5 to 5.0 mEq per liter, with 4.5 mEq often being used for a reference point. Potassium levels persistently above 6 mEq per liter require careful observation and treatment. Normal potassium levels tend to be higher in neonates (7.7 mEq per liter) than in adults. Serum potassium levels do not necessarily indicate true body potassium concentration. A rise in plasma pH may cause a decrease in plasma potassium concentration and an increase in the intracellular potassium concentration. Because Dyrenium conserves potassium, it has been theorized that in patients who have received intensive therapy or been given the drug for prolonged periods, a rebound kaliuresis could occur upon abrupt withdrawal. In such patients, withdrawal of Dyrenium should be gradual.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Triamterene in the drug label.
## Postmarketing Experience
- Adverse effects are listed in decreasing order of frequency; however, the most serious adverse effects are listed first, regardless of frequency. All adverse effects occur rarely (that is, 1 in 1000, or less).
Anaphylaxis, rash, photosensitivity.
Hyperkalemia, hypokalemia.
Azotemia, elevated BUN and creatinine, renal stones, acute interstitial nephritis (rare), acute renal failure.
Jaundice and/or liver enzyme abnormalities, nausea and vomiting, diarrhea.
Thrombocytopenia, megaloblastic anemia.
Weakness, fatigue, dizziness, headache, dry mouth.
# Drug Interactions
- Caution should be used when lithium and diuretics are used concomitantly because diuretic-induced sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity. Patients receiving such combined therapy should have serum lithium levels monitored closely and the lithium dosage adjusted if necessary.
- A possible interaction resulting in acute renal failure has been reported in a few subjects when indomethacin, a nonsteroidal anti-inflammatory agent, was given with triamterene. Caution is advised in administering nonsteroidal anti-inflammatory agents with triamterene.
- The effects of the following drugs may be potentiated when given together with triamterene: antihypertensive medication, other diuretics, preanesthetic and anesthetic agents, skeletal muscle relaxants (nondepolarizing).
- Potassium-sparing agents should be used with caution in conjunction with angiotensin-converting enzyme (ACE) inhibitors due to an increased risk of hyperkalemia.
- The following agents, given together with triamterene, may promote serum potassium accumulation and possibly result in hyperkalemia because of the potassium-sparing nature of triamterene, especially in patients with renal insufficiency: blood from blood bank (may contain up to 30 mEq of potassium per liter of plasma or up to 65 mEq per liter of whole blood when stored for more than 10 days); low-salt milk (may contain up to 60 mEq of potassium per liter); potassium-containing medications (such as parenteral penicillin G potassium); salt substitutes (most contain substantial amounts of potassium).
- Dyrenium (triamterene) may raise blood glucose levels; for adult-onset diabetes, dosage adjustments of hypoglycemic agents may be necessary during and/or after therapy; concurrent use with chlorpropamide may increase the risk of severe hyponatremia.
- Drug/Laboratory Test Interactions
- Triamterene and quinidine have similar fluorescence spectra; thus, triamterene will interfere with the fluorescent measurement of quinidine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratogenic Effects:
- Reproduction studies have been performed in rats at doses as high as 20 times the Maximum Recommended Human Dose (MRHD) on the basis of body weight, and 6 times the MRHD on the basis of body-surface area, without evidence of harm to the fetus due to triamterene. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
- Nonteratogenic Effects:
- Triamterene has been shown to cross the placental barrier and appear in cord blood. The use of triamterene in pregnant women requires that the anticipated benefits be weighed against possible hazards to the fetus. These possible hazards include adverse reactions which have occurred in the adult.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Triamterene in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Triamterene during labor and delivery.
### Nursing Mothers
- Triamterene has not been studied in nursing mothers. Triamterene appears in animal milk and is likely present in human milk. If use of the drug product is deemed essential, the patient should stop nursing.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Triamterene with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Triamterene with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Triamterene with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Triamterene in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Triamterene in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Triamterene in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Triamterene in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Since uncorrected hyperkalemia may be fatal, serum potassium levels must be monitored at frequent intervals especially in patients receiving Dyrenium, when dosages are changed or with any illness that may influence renal function.
# IV Compatibility
There is limited information regarding IV Compatibility of Triamterene in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In the event of overdosage, it can be theorized that electrolyte imbalance would be the major concern, with particular attention to possible hyperkalemia. Other symptoms that might be seen would be nausea and vomiting, other G.I. disturbances and weakness. It is conceivable that some hypotension could occur. As with an overdose of any drug, immediate evacuation of the stomach should be induced through emesis and gastric lavage. Careful evaluation of the electrolyte pattern and fluid balance should be made.
- Reversible acute renal failure following ingestion of 50 tablets of a product containing a combination of 50 mg triamterene and 25 mg hydrochlorothiazide has been reported.
- The oral LD50 in mice is 380 mg/kg. The amount of drug in a single dose ordinarily associated with symptoms of overdose or likely to be life-threatening is not known.
### Management
- There is no specific antidote.
- Although triamterene is 67% protein bound, there may be some benefit to dialysis in cases of overdosage.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Triamterene in the drug label.
# Pharmacology
## Mechanism of Action
- Triamterene has a unique mode of action; it inhibits the reabsorption of sodium ions in exchange for potassium and hydrogen ions at that segment of the distal tubule under the control of adrenal mineralocorticoids (especially aldosterone). This activity is not directly related to aldosterone secretion or antagonism; it is a result of a direct effect on the renal tubule.
## Structure
- Each capsule for oral use, with opaque red cap and body, contains Triamterene USP, 50 or 100 mg, and is imprinted with the product name, DYRENIUM, strength (50 mg or 100 mg) and WPC 002 (for the 50-mg strength) and WPC 003 (for the 100-mg strength). Inactive ingredients consist of D&C Red No. 33, FD&C Yellow No. 6, Gelatin NF, Lactose NF, Magnesium Stearate NF, Sodium Lauryl Sulfate NF, Titanium Dioxide USP and Silicon Dioxide NF.
- Triamterene is 2,4,7-triamino-6-phenyl-pteridine:
- Its molecular weight is 253.27. At 50°C, triamterene is slightly soluble in water. It is soluble in dilute ammonia, dilute aqueous sodium hydroxide and dimethylformamide. It is sparingly soluble in methanol.
## Pharmacodynamics
- The fraction of filtered sodium reaching this distal tubular exchange site is relatively small, and the amount which is exchanged depends on the level of mineralocorticoid activity. Thus, the degree of natriuresis and diuresis produced by inhibition of the exchange mechanism is necessarily limited. Increasing the amount of available sodium and the level of mineralocorticoid activity by the use of more proximally acting diuretics will increase the degree of diuresis and potassium conservation.
- Triamterene occasionally causes increases in serum potassium which can result in hyperkalemia. It does not produce alkalosis, because it does not cause excessive excretion of titratable acid and ammonium.
- Triamterene has been shown to cross the placental barrier and appear in the cord blood of animals.
## Pharmacokinetics
- Onset of action is 2 to 4 hours after ingestion. In normal volunteers the mean peak serum levels were 30 ng/mL at 3 hours. The average percent of drug recovered in the urine (0 to 48 hours) was 21%. Triamterene is primarily metabolized to the sulfate conjugate of hydroxytriamterene. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels. Triamterene is rapidly absorbed, with somewhat less than 50% of the oral dose reaching the urine. Most patients will respond to Dyrenium (triamterene) during the first day of treatment.
- Maximum therapeutic effect, however, may not be seen for several days. Duration of diuresis depends on several factors, especially renal function, but it generally tapers off 7 to 9 hours after administration.
## Nonclinical Toxicology
- Carcinogenesis
- In studies conducted under the auspices of the National Toxicology Program, groups of rats were fed diets containing 0, 150, 300 or 600 ppm of triamterene, and groups of mice were fed diets containing 0, 100, 200 or 400 ppm triamterene. Male and female rats exposed to the highest tested concentration received triamterene at about 25 and 30 mg/kg/day, respectively. Male and female mice exposed to the highest tested concentration received triamterene at about 45 and 60 mg/kg/day, respectively.
- There was an increased incidence of hepatocellular neoplasia (primarily adenomas) in male and female mice at the highest dosage level. These doses represent 7.5X and 10X the - aximum Recommended Human Dose (MRHD) of 300 mg/kg/day (or 6 mg/kg/day based on a 50 kg patient) for male and female mice, respectively, when based on body weight and 0.7X and 0.9X the MRHD when based on body-surface area.
- Although hepatocellular neoplasia (exclusively adenomas) in the rat study was limited to triamterene-exposed males, incidence was not dose dependent and there was no statistically significant difference from control incidence at any dose level.
- Mutagenesis
- Triamterene was not mutagenic in bacteria (Salmonella typhimurium strains TA98, TA100, TA1535 or TA1537) with or without metabolic activation. It did not induce chromosomal aberrations in Chinese hamster ovary (CHO) cells in vitro with or without metabolic activation, but it did induce sister chromatid exchanges in CHO cells in vitro with and without metabolic activation.
- Impairment of Fertility
- Studies of the effects of triamterene on animal reproductive function have not been conducted.
# Clinical Studies
There is limited information regarding Clinical Studies of Triamterene in the drug label.
# How Supplied
- Capsules: 50 mg in bottles of 100, and 100 mg in bottles of 100.
- Storage
- Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) . Dispense in a tight, light resistant container.
## Storage
There is limited information regarding Triamterene Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- To help avoid stomach upset, it is recommended that the drug be taken after meals.
- If a single daily dose is prescribed, it may be preferable to take it in the morning to minimize the effect of increased frequency of urination on nighttime sleep.
- If a dose is missed, the patient should not take more than the prescribed dose at the next dosing interval.
# Precautions with Alcohol
- Alcohol-Triamterene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Dyrenium®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Triamterene
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Triamterene is a potassium-sparing diuretic that is FDA approved for the treatment of edema associated with congestive heart failure, cirrhosis, nephrotic syndrome, steroid, and secondary hyperaldosteronism. There is a Black Box Warning for this drug as shown here. Common adverse reactions include electrolyte disturbances and hyperuricemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dyrenium (triamterene) is indicated in the treatment of edema associated with congestive heart failure, cirrhosis of the liver and the nephrotic syndrome; steroid-induced edema, idiopathic edema and edema due to secondary hyperaldosteronism.
- Dyrenium may be used alone or with other diuretics, either for its added diuretic effect or its potassium-sparing potential. It also promotes increased diuresis when patients prove resistant or only partially responsive to thiazides or other diuretics because of secondary hyperaldosteronism.
- When Dyrenium (triamterene) is added to other diuretic therapy or when patients are switched to Dyrenium from other diuretics, all potassium supplementation should be discontinued.
- Dosing Information
- When used alone, the usual starting dose is 100 mg PO bid after meals.
- When combined with another diuretic or antihypertensive agent, the total daily dosage of each agent should usually be lowered initially and then adjusted to the patient’s needs. The total daily dosage should not exceed 300 mg.
- The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.
- Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Diuretics are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy. Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triamterene in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 200 mg PO qd[1][2]
- 50 mg PO qd in combination with chlorthalidone 50 mg[3]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triamterene in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- 1–2 mg/kg in 2 divided doses[4][5]
# Contraindications
- Anuria
- Severe or progressive kidney disease or dysfunction, with the possible exception of nephrosis
- Severe hepatic disease
- Hypersensitivity to the drug or any of its components
- Hyperkalemia
- Dyrenium (triamterene) should not be used in patients with pre-existing elevated serum potassium, as is sometimes seen in patients with impaired renal function or azotemia, or in patients who develop hyperkalemia while on the drug. Patients should not be placed on dietary potassium supplements, potassium salts or potassium-containing salt substitutes in conjunction with Dyrenium.
- Dyrenium should not be given to patients receiving other potassium-sparing agents, such as spironolactone, amiloride hydrochloride, or other formulations containing triamterene. Two deaths have been reported in patients receiving concomitant spironolactone and Dyrenium or Dyazide®. Although dosage recommendations were exceeded in one case and in the other serum electrolytes were not properly monitored, these two drugs should not be given concomitantly.
# Warnings
- There have been isolated reports of hypersensitivity reactions; therefore, patients should be observed regularly for the possible occurrence of blood dyscrasias, liver damage or other idiosyncratic reactions.
- Periodic BUN and serum potassium determinations should be made to check kidney function, especially in patients with suspected or confirmed renal insufficiency. It is particularly important to make serum potassium determinations in elderly or diabetic patients receiving the drug; these patients should be observed carefully for possible serum potassium increases.
- If hyperkalemia is present or suspected, an electrocardiogram should be obtained. If the ECG shows no widening of the QRS or arrhythmia in the presence of hyperkalemia, it is usually sufficient to discontinue Dyrenium (triamterene) and any potassium supplementation, and substitute a thiazide alone. Sodium polystyrene sulfonate (Kayexalate®, Sanofi Synthelabo) may be administered to enhance the excretion of excess potassium. The presence of a widened QRS complex or arrhythmia in association with hyperkalemia requires prompt additional therapy. For tachyarrhythmia, infuse 44 mEq of sodium bicarbonate or 10 mL of 10% calcium gluconate or calcium chloride over several minutes. For asystole, bradycardia or A-V block transvenous pacing is also recommended.
- The effect of calcium and sodium bicarbonate is transient and repeated administration may be required. When indicated by the clinical situation, excess K+ may be removed by dialysis or oral or rectal administration of Kayexalate®. Infusion of glucose and insulin has also been used to treat hyperkalemia.
### Precautions
- Dyrenium (triamterene) tends to conserve potassium rather than to promote the excretion as do many diuretics and, occasionally, can cause increases in serum potassium which, in some instances, can result in hyperkalemia. In rare instances, hyperkalemia has been associated with cardiac irregularities.
- Electrolyte imbalance often encountered in such diseases as congestive heart failure, renal disease or cirrhosis may be aggravated or caused independently by any effective diuretic agent includingDyrenium. The use of full doses of a diuretic when salt intake is restricted can result in a low-salt syndrome.
- Triamterene can cause mild nitrogen retention, which is reversible upon withdrawal of the drug, and is seldom observed with intermittent (every-other-day) therapy.
- Triamterene may cause a decreasing alkali reserve, with the possibility of metabolic acidosis.
- By the very nature of their illness, cirrhotics with splenomegaly sometimes have marked variations in their blood. Since triamterene is a weak folic acid antagonist, it may contribute to the appearance of megaloblastosis in cases where folic acid stores have been depleted. Therefore, periodic blood studies in these patients are recommended. They should also be observed for exacerbations of underlying liver disease.
- Triamterene has elevated uric acid, especially in persons predisposed to gouty arthritis.
- Triamterene has been reported in renal stones in association with other calculus components. Dyrenium should be used with caution in patients with histories of renal stones.
- Laboratory Tests
- Hyperkalemia will rarely occur in patients with adequate urinary output, but it is a possibility if large doses are used for considerable periods of time. If hyperkalemia is observed, Dyrenium (triamterene) should be withdrawn. The normal adult range of serum potassium is 3.5 to 5.0 mEq per liter, with 4.5 mEq often being used for a reference point. Potassium levels persistently above 6 mEq per liter require careful observation and treatment. Normal potassium levels tend to be higher in neonates (7.7 mEq per liter) than in adults. Serum potassium levels do not necessarily indicate true body potassium concentration. A rise in plasma pH may cause a decrease in plasma potassium concentration and an increase in the intracellular potassium concentration. Because Dyrenium conserves potassium, it has been theorized that in patients who have received intensive therapy or been given the drug for prolonged periods, a rebound kaliuresis could occur upon abrupt withdrawal. In such patients, withdrawal of Dyrenium should be gradual.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Triamterene in the drug label.
## Postmarketing Experience
- Adverse effects are listed in decreasing order of frequency; however, the most serious adverse effects are listed first, regardless of frequency. All adverse effects occur rarely (that is, 1 in 1000, or less).
Anaphylaxis, rash, photosensitivity.
Hyperkalemia, hypokalemia.
Azotemia, elevated BUN and creatinine, renal stones, acute interstitial nephritis (rare), acute renal failure.
Jaundice and/or liver enzyme abnormalities, nausea and vomiting, diarrhea.
Thrombocytopenia, megaloblastic anemia.
Weakness, fatigue, dizziness, headache, dry mouth.
# Drug Interactions
- Caution should be used when lithium and diuretics are used concomitantly because diuretic-induced sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity. Patients receiving such combined therapy should have serum lithium levels monitored closely and the lithium dosage adjusted if necessary.
- A possible interaction resulting in acute renal failure has been reported in a few subjects when indomethacin, a nonsteroidal anti-inflammatory agent, was given with triamterene. Caution is advised in administering nonsteroidal anti-inflammatory agents with triamterene.
- The effects of the following drugs may be potentiated when given together with triamterene: antihypertensive medication, other diuretics, preanesthetic and anesthetic agents, skeletal muscle relaxants (nondepolarizing).
- Potassium-sparing agents should be used with caution in conjunction with angiotensin-converting enzyme (ACE) inhibitors due to an increased risk of hyperkalemia.
- The following agents, given together with triamterene, may promote serum potassium accumulation and possibly result in hyperkalemia because of the potassium-sparing nature of triamterene, especially in patients with renal insufficiency: blood from blood bank (may contain up to 30 mEq of potassium per liter of plasma or up to 65 mEq per liter of whole blood when stored for more than 10 days); low-salt milk (may contain up to 60 mEq of potassium per liter); potassium-containing medications (such as parenteral penicillin G potassium); salt substitutes (most contain substantial amounts of potassium).
- Dyrenium (triamterene) may raise blood glucose levels; for adult-onset diabetes, dosage adjustments of hypoglycemic agents may be necessary during and/or after therapy; concurrent use with chlorpropamide may increase the risk of severe hyponatremia.
- Drug/Laboratory Test Interactions
- Triamterene and quinidine have similar fluorescence spectra; thus, triamterene will interfere with the fluorescent measurement of quinidine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratogenic Effects:
- Reproduction studies have been performed in rats at doses as high as 20 times the Maximum Recommended Human Dose (MRHD) on the basis of body weight, and 6 times the MRHD on the basis of body-surface area, without evidence of harm to the fetus due to triamterene. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
- Nonteratogenic Effects:
- Triamterene has been shown to cross the placental barrier and appear in cord blood. The use of triamterene in pregnant women requires that the anticipated benefits be weighed against possible hazards to the fetus. These possible hazards include adverse reactions which have occurred in the adult.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Triamterene in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Triamterene during labor and delivery.
### Nursing Mothers
- Triamterene has not been studied in nursing mothers. Triamterene appears in animal milk and is likely present in human milk. If use of the drug product is deemed essential, the patient should stop nursing.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Triamterene with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Triamterene with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Triamterene with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Triamterene in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Triamterene in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Triamterene in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Triamterene in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Since uncorrected hyperkalemia may be fatal, serum potassium levels must be monitored at frequent intervals especially in patients receiving Dyrenium, when dosages are changed or with any illness that may influence renal function.
# IV Compatibility
There is limited information regarding IV Compatibility of Triamterene in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In the event of overdosage, it can be theorized that electrolyte imbalance would be the major concern, with particular attention to possible hyperkalemia. Other symptoms that might be seen would be nausea and vomiting, other G.I. disturbances and weakness. It is conceivable that some hypotension could occur. As with an overdose of any drug, immediate evacuation of the stomach should be induced through emesis and gastric lavage. Careful evaluation of the electrolyte pattern and fluid balance should be made.
- Reversible acute renal failure following ingestion of 50 tablets of a product containing a combination of 50 mg triamterene and 25 mg hydrochlorothiazide has been reported.
- The oral LD50 in mice is 380 mg/kg. The amount of drug in a single dose ordinarily associated with symptoms of overdose or likely to be life-threatening is not known.
### Management
- There is no specific antidote.
- Although triamterene is 67% protein bound, there may be some benefit to dialysis in cases of overdosage.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Triamterene in the drug label.
# Pharmacology
## Mechanism of Action
- Triamterene has a unique mode of action; it inhibits the reabsorption of sodium ions in exchange for potassium and hydrogen ions at that segment of the distal tubule under the control of adrenal mineralocorticoids (especially aldosterone). This activity is not directly related to aldosterone secretion or antagonism; it is a result of a direct effect on the renal tubule.
## Structure
- Each capsule for oral use, with opaque red cap and body, contains Triamterene USP, 50 or 100 mg, and is imprinted with the product name, DYRENIUM, strength (50 mg or 100 mg) and WPC 002 (for the 50-mg strength) and WPC 003 (for the 100-mg strength). Inactive ingredients consist of D&C Red No. 33, FD&C Yellow No. 6, Gelatin NF, Lactose NF, Magnesium Stearate NF, Sodium Lauryl Sulfate NF, Titanium Dioxide USP and Silicon Dioxide NF.
- Triamterene is 2,4,7-triamino-6-phenyl-pteridine:
- Its molecular weight is 253.27. At 50°C, triamterene is slightly soluble in water. It is soluble in dilute ammonia, dilute aqueous sodium hydroxide and dimethylformamide. It is sparingly soluble in methanol.
## Pharmacodynamics
- The fraction of filtered sodium reaching this distal tubular exchange site is relatively small, and the amount which is exchanged depends on the level of mineralocorticoid activity. Thus, the degree of natriuresis and diuresis produced by inhibition of the exchange mechanism is necessarily limited. Increasing the amount of available sodium and the level of mineralocorticoid activity by the use of more proximally acting diuretics will increase the degree of diuresis and potassium conservation.
- Triamterene occasionally causes increases in serum potassium which can result in hyperkalemia. It does not produce alkalosis, because it does not cause excessive excretion of titratable acid and ammonium.
- Triamterene has been shown to cross the placental barrier and appear in the cord blood of animals.
## Pharmacokinetics
- Onset of action is 2 to 4 hours after ingestion. In normal volunteers the mean peak serum levels were 30 ng/mL at 3 hours. The average percent of drug recovered in the urine (0 to 48 hours) was 21%. Triamterene is primarily metabolized to the sulfate conjugate of hydroxytriamterene. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels. Triamterene is rapidly absorbed, with somewhat less than 50% of the oral dose reaching the urine. Most patients will respond to Dyrenium (triamterene) during the first day of treatment.
- Maximum therapeutic effect, however, may not be seen for several days. Duration of diuresis depends on several factors, especially renal function, but it generally tapers off 7 to 9 hours after administration.
## Nonclinical Toxicology
- Carcinogenesis
- In studies conducted under the auspices of the National Toxicology Program, groups of rats were fed diets containing 0, 150, 300 or 600 ppm of triamterene, and groups of mice were fed diets containing 0, 100, 200 or 400 ppm triamterene. Male and female rats exposed to the highest tested concentration received triamterene at about 25 and 30 mg/kg/day, respectively. Male and female mice exposed to the highest tested concentration received triamterene at about 45 and 60 mg/kg/day, respectively.
- There was an increased incidence of hepatocellular neoplasia (primarily adenomas) in male and female mice at the highest dosage level. These doses represent 7.5X and 10X the * aximum Recommended Human Dose (MRHD) of 300 mg/kg/day (or 6 mg/kg/day based on a 50 kg patient) for male and female mice, respectively, when based on body weight and 0.7X and 0.9X the MRHD when based on body-surface area.
- Although hepatocellular neoplasia (exclusively adenomas) in the rat study was limited to triamterene-exposed males, incidence was not dose dependent and there was no statistically significant difference from control incidence at any dose level.
- Mutagenesis
- Triamterene was not mutagenic in bacteria (Salmonella typhimurium strains TA98, TA100, TA1535 or TA1537) with or without metabolic activation. It did not induce chromosomal aberrations in Chinese hamster ovary (CHO) cells in vitro with or without metabolic activation, but it did induce sister chromatid exchanges in CHO cells in vitro with and without metabolic activation.
- Impairment of Fertility
- Studies of the effects of triamterene on animal reproductive function have not been conducted.
# Clinical Studies
There is limited information regarding Clinical Studies of Triamterene in the drug label.
# How Supplied
- Capsules: 50 mg in bottles of 100, and 100 mg in bottles of 100.
- Storage
- Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light resistant container.
## Storage
There is limited information regarding Triamterene Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- To help avoid stomach upset, it is recommended that the drug be taken after meals.
- If a single daily dose is prescribed, it may be preferable to take it in the morning to minimize the effect of increased frequency of urination on nighttime sleep.
- If a dose is missed, the patient should not take more than the prescribed dose at the next dosing interval.
# Precautions with Alcohol
- Alcohol-Triamterene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Dyrenium®[6]
# Look-Alike Drug Names
- N/A[7]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dyrenium | |
eebb4d17d347f38be312479231af26506fe61df2 | wikidoc | Dyscalculia | Dyscalculia
# Overview
Dyscalculia (difficulty in learning or comprehending mathematics) was originally identified in case studies of patients who suffered specific arithmetic disabilities as a result of damage to specific regions of the brain. Recent research suggests that dyscalculia can also occur developmentally, as a genetically-linked learning disability which affects a person's ability to understand, remember, and/or manipulate numbers and/or number facts (e.g. the multiplication tables). The term is often used to refer specifically to the inability to perform arithmetic operations, but is defined by some educational professionals and cognitive psychologists as a more fundamental inability to conceptualize numbers as abstract concepts of comparative quantities (a deficit in "number sense"). Those who argue for this more constrained definition of dyscalculia sometimes prefer to use the technical term Arithmetic Difficulties (AD) to refer to calculation and number memory deficits.
Dyscalculia is a lesser known disability, similar and potentially related to dyslexia and Developmental Dyspraxia. Dyscalculia occurs in people across the whole IQ range, and sufferers often, but not always, also have difficulties with time, measurement, and spatial reasoning. Current estimates suggest it may affect about 5% of the population. Although some researchers believe that dyscalculia necessarily implies mathematical reasoning difficulties as well as difficulties with arithmetic operations, there is evidence (especially from brain damaged patients) that arithmetic (e.g. calculation and number fact memory) and mathematical (abstract reasoning with numbers) abilities can be dissociated. That is (some researchers argue), an individual might suffer arithmetic difficulties (or dyscalculia), with no impairment of, or even giftedness in, abstract mathematical reasoning abilities.
The word dyscalculia comes from Greek and Latin which means: "counting badly". The prefix "dys" comes from Greek and means "badly". "Calculia" comes from the Latin "calculare", which means "to count". That word "calculare" again comes from "calculus", which means "pebble" or one of the counters on an abacus.
Dyscalculia can be detected at a young age and measures can be taken to ease the problems faced by younger students. The main problem is understanding the way mathematics is taught to children. In the way that dyslexia can be dealt with by using a slightly different approach to teaching, so can dyscalculia. However, dyscalculia is the lesser known of these learning disorders and so is often not recognized.
Another common manifestation of the condition emerges when the individual is faced with equation type of problems which contain both integers and letters (3A + 4C). It can be difficult for the person to differentiate between the integers and the letters. Confusion such as reading a '5' for an 'S' or not being able to distinguish between a zero '0' for the letter 'O' can keep algebra from being mastered. This particular form of dyscalculia is often not diagnosed until middle or high school is entered.
# Potential symptoms
- Frequent difficulties with arithmetic, confusing the signs: +, −, ÷ and ×.
- Inability to tell which of two numbers is the larger.
- Reliance on 'counting-on' strategies, e.g., using fingers, rather than any more efficient mental arithmetic strategies.
- Difficulty with everyday tasks like checking change and reading analog clocks.
- Inability to comprehend financial planning or budgeting, sometimes even at a basic level; for example, estimating the cost of the items in a shopping basket or balancing a checkbook.
- Difficulty with times-tables, mental arithmetic, etc.
- May do fairly well in subjects such as science and geometry, which require logic rather than formulas, until a higher level requiring calculations is needed.
- Difficulty with conceptualizing time and judging the passing of time.
- Problems differentiating between left and right.
- Having a poor sense of direction (i.e., north, south, east, and west), potentially even with a compass.
- Difficulty navigating or mentally "turning" the map to face the current direction rather than the common North=Top usage.
- Having difficulty mentally estimating the measurement of an object or distance (e.g., whether something is 10 or 20 feet away).
- Inability to grasp and remember mathematical concepts, rules, formulae, and sequences.
- An inability to read a sequence of numbers, or rotating them when repeated such turning 56 into 65.
- Difficulty keeping score during games.
- Difficulty with games such as poker with more flexible rules for scoring.
- Difficulty in activities requiring sequential processing, from the physical (such as dance steps) to the abstract (reading, writing and signaling things in the right order). May have trouble even with a calculator due to difficulties in the process of feeding in variables.
- The condition may lead in extreme cases to a phobia of mathematics and mathematical devices.
# Potential causes
Scientists have yet to understand the causes of dyscalculia. They have been investigating in several domains.
- Neurological: Dyscalculia has been associated with lesions to the supramarginal and angular gyri at the junction between the temporal and parietal lobes of the cerebral cortex.
- Deficits in working memory: Adams and Hitch argue that working memory is a major factor in mental addition. From this base, Geary conducted a study that suggested there was a working memory deficit for those who suffered from dyscalculia. However, working memory problems are confounded with general learning difficulties, thus Geary's findings may not be specific to dyscalculia but rather may reflect a greater learning deficit.
Studies of mathematically gifted students have shown increased EEG activity in the right hemisphere during algorithmic computational processing. There is some evidence of right hemisphere deficits in dyscalculia.
Other causes may be:
- Short term memory being disturbed or reduced, making it difficult to remember calculations.
- Congenital or hereditary disorders. Studies show indications of this, but it is not yet concrete.
- A combination of these factors. | Dyscalculia
For patient information, click here
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dyscalculia (difficulty in learning or comprehending mathematics) was originally identified in case studies of patients who suffered specific arithmetic disabilities as a result of damage to specific regions of the brain. Recent research suggests that dyscalculia can also occur developmentally, as a genetically-linked learning disability which affects a person's ability to understand, remember, and/or manipulate numbers and/or number facts (e.g. the multiplication tables). The term is often used to refer specifically to the inability to perform arithmetic operations, but is defined by some educational professionals and cognitive psychologists as a more fundamental inability to conceptualize numbers as abstract concepts of comparative quantities (a deficit in "number sense"[1]). Those who argue for this more constrained definition of dyscalculia sometimes prefer to use the technical term Arithmetic Difficulties (AD) to refer to calculation and number memory deficits.
Dyscalculia is a lesser known disability, similar and potentially related to dyslexia and Developmental Dyspraxia. Dyscalculia occurs in people across the whole IQ range, and sufferers often, but not always, also have difficulties with time, measurement, and spatial reasoning. Current estimates suggest it may affect about 5% of the population. Although some researchers believe that dyscalculia necessarily implies mathematical reasoning difficulties as well as difficulties with arithmetic operations, there is evidence (especially from brain damaged patients) that arithmetic (e.g. calculation and number fact memory) and mathematical (abstract reasoning with numbers) abilities can be dissociated. That is (some researchers argue), an individual might suffer arithmetic difficulties (or dyscalculia), with no impairment of, or even giftedness in, abstract mathematical reasoning abilities.
The word dyscalculia comes from Greek and Latin which means: "counting badly". The prefix "dys" comes from Greek and means "badly". "Calculia" comes from the Latin "calculare", which means "to count". That word "calculare" again comes from "calculus", which means "pebble" or one of the counters on an abacus.
Dyscalculia can be detected at a young age and measures can be taken to ease the problems faced by younger students. The main problem is understanding the way mathematics is taught to children. In the way that dyslexia can be dealt with by using a slightly different approach to teaching, so can dyscalculia. However, dyscalculia is the lesser known of these learning disorders and so is often not recognized.
Another common manifestation of the condition emerges when the individual is faced with equation type of problems which contain both integers and letters (3A + 4C). It can be difficult for the person to differentiate between the integers and the letters. Confusion such as reading a '5' for an 'S' or not being able to distinguish between a zero '0' for the letter 'O' can keep algebra from being mastered. This particular form of dyscalculia is often not diagnosed until middle or high school is entered.
# Potential symptoms
- Frequent difficulties with arithmetic, confusing the signs: +, −, ÷ and ×.
- Inability to tell which of two numbers is the larger.
- Reliance on 'counting-on' strategies, e.g., using fingers, rather than any more efficient mental arithmetic strategies.
- Difficulty with everyday tasks like checking change and reading analog clocks.
- Inability to comprehend financial planning or budgeting, sometimes even at a basic level; for example, estimating the cost of the items in a shopping basket or balancing a checkbook.
- Difficulty with times-tables, mental arithmetic, etc.
- May do fairly well in subjects such as science and geometry, which require logic rather than formulas, until a higher level requiring calculations is needed.
- Difficulty with conceptualizing time and judging the passing of time.
- Problems differentiating between left and right.
- Having a poor sense of direction (i.e., north, south, east, and west), potentially even with a compass.
- Difficulty navigating or mentally "turning" the map to face the current direction rather than the common North=Top usage.
- Having difficulty mentally estimating the measurement of an object or distance (e.g., whether something is 10 or 20 feet away).
- Inability to grasp and remember mathematical concepts, rules, formulae, and sequences.
- An inability to read a sequence of numbers, or rotating them when repeated such turning 56 into 65.
- Difficulty keeping score during games.
- Difficulty with games such as poker with more flexible rules for scoring.
- Difficulty in activities requiring sequential processing, from the physical (such as dance steps) to the abstract (reading, writing and signaling things in the right order). May have trouble even with a calculator due to difficulties in the process of feeding in variables.
- The condition may lead in extreme cases to a phobia of mathematics and mathematical devices.
# Potential causes
Scientists have yet to understand the causes of dyscalculia. They have been investigating in several domains.
- Neurological: Dyscalculia has been associated with lesions to the supramarginal and angular gyri at the junction between the temporal and parietal lobes of the cerebral cortex.[2][3]
- Deficits in working memory: Adams and Hitch[4] argue that working memory is a major factor in mental addition. From this base, Geary[5] conducted a study that suggested there was a working memory deficit for those who suffered from dyscalculia. However, working memory problems are confounded with general learning difficulties, thus Geary's findings may not be specific to dyscalculia but rather may reflect a greater learning deficit.
Studies of mathematically gifted students have shown increased EEG activity in the right hemisphere during algorithmic computational processing. There is some evidence of right hemisphere deficits in dyscalculia.
Other causes may be:
- Short term memory being disturbed or reduced, making it difficult to remember calculations.
- Congenital or hereditary disorders. Studies show indications of this, but it is not yet concrete.
- A combination of these factors. | https://www.wikidoc.org/index.php/Dyscalculia | |
9b67269fefc0aa439ff6a1c1f991eb77af5e161f | wikidoc | Dysesthesia | Dysesthesia
Dysaesthesia (dysesthesia in American English) is a tactile hallucination. It signals that damage is being done to tissue when none is occurring. However, recent advances in neuroinflammation indicate that the patient is not actually hallucinating. It is most commonly described as feeling like acid under the skin. Burning dysesthesia is now felt to accurately reflect an acidotic state in the synapses and perineural space. Some ion channels will open to a low pH, the acid sensing ion channel I has been shown to open at body temperature, in a model of nerve injury pain. This information leads many to believe hallucination is an unfit term, although a better word does not immediately present itself. Dysesthetic burning may be hallucinatory as to the cutaneous surface, but accurate as to what is occurring in the synapses.
Dysesthesia is commonly seen in diabetic patients, and can be relieved by using creams containing capsaicin.
# Symptoms include
- Impairment of sensation short of anesthesia.
- A condition in which a disagreeable sensation is produced by ordinary stimuli; caused by lesions of the sensory pathways, peripheral or central.
- Abnormal sensations experienced in the absence of stimulation, such as:
Burning
Wetness
Itching
Electric shock
Pins and needles
- Burning
- Wetness
- Itching
- Electric shock
- Pins and needles | Dysesthesia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Dysaesthesia (dysesthesia in American English) is a tactile hallucination. It signals that damage is being done to tissue when none is occurring. However, recent advances in neuroinflammation indicate that the patient is not actually hallucinating. It is most commonly described as feeling like acid under the skin. Burning dysesthesia is now felt to accurately reflect an acidotic state in the synapses and perineural space. Some ion channels will open to a low pH, the acid sensing ion channel I has been shown to open at body temperature, in a model of nerve injury pain. This information leads many to believe hallucination is an unfit term, although a better word does not immediately present itself. Dysesthetic burning may be hallucinatory as to the cutaneous surface, but accurate as to what is occurring in the synapses.
Dysesthesia is commonly seen in diabetic patients, and can be relieved by using creams containing capsaicin.
# Symptoms include
- Impairment of sensation short of anesthesia.
- A condition in which a disagreeable sensation is produced by ordinary stimuli; caused by lesions of the sensory pathways, peripheral or central.
- Abnormal sensations experienced in the absence of stimulation, such as:
Burning
Wetness
Itching
Electric shock
Pins and needles
- Burning
- Wetness
- Itching
- Electric shock
- Pins and needles | https://www.wikidoc.org/index.php/Dysesthesia | |
a09358181af36cf8232e1bcab6a3b1a471e5e24a | wikidoc | Dyshidrosis | Dyshidrosis
# Overview
Dyshidrosis, also termed Dyshidrotic Eczema, Pompholyx and Dyshidrotic Dermatitis, is a skin condition that is characterized by small blisters on the hands or feet. It is an acute, chronic, or recurrent dermatosis of the fingers, palms, and soles, characterized by a sudden onset of many deep-seated pruritic, clear vesicles; later, scaling, fissures and lichenification occur. Recurrence is common and for many can be chronic. Incidence/Prevalence is said to be 20/100,000 in the USA, however, many cases of eczema are diagnosed as garden-variety atopic eczema without further investigation, so it is possible this figure is misleading.
This condition is not contagious to others, but due to its unsightly nature can cause significant distress in regards to social interactions with others.
The name comes from the word "dyshidrotic," meaning "bad sweating," which was once believed to be the cause. Sometimes called pompholyx (Greek for "bubble") which is generally reserved for the cases with blisters; in some countries, pompholyx refers to hand dyshidrosis.
# Symptoms
Small blisters with the following characteristics:
- Blisters are very small (1 mm or less in diameter). They appear on the tips and sides of the fingers, toes, palms, and soles.
- Blisters are opaque and deep-seated; they are either flush with the skin or slightly elevated and do not break easily. Eventually, small blisters come together and form large blisters.
- Blisters may itch, cause pain, or produce no symptoms at all. They worsen after contact with soap, water, or irritating substances.
- Scratching blisters breaks them, releasing the fluid inside, causing the skin to crust and eventually crack. This cracking is painful as well as unsightly and often takes weeks, or even months to heal. The skin is dry and scaly during this period.
- Fluid from the blisters is serum that accumulates between the irritated skin cells. It is not sweat as was previously thought.
- In some cases, as the blistering takes place in the palms or finger. Lymph node swelling may accompany the outbreak. This is characterised by tingling feeling in the forearm and bumps present in the arm pits.
- Nails on affected fingers, or toes, may take on a pitted appearance.
# Causes
Causes of dyshidrosis are unknown, however, a number of triggers to the condition exist.
- Dyshidrosis has been historically linked to excessive sweating during periods of anxiety, stress, and frustration, however, many cases present that have no history of excessive sweating, and the hypothesis of dyshidrosis as a sweating disorder is largely rejected. Some patients reject this link to stress, though as a trigger of vesicular eruption it cannot be overlooked, as with other types of eczema.
- Vesicular eruption of the hands may also be caused by a local infection, with fungal infections being the most common. Sunlight is thought to bring on attacks, some patients link outbreaks to prolonged exposure to strong sunlight from late spring through to early autumn. Others have also noted outbreaks occurring in conjunction with exposure to chlorinated pool water or highly treated city tap waters.
- Soaps, detergents, fragrances and contact with fruit juices or fresh meat also can trigger outbreaks of dyshidrosis, as with other types of eczema.
- Systemic nickel allergies may be related.
- Keeping skin damp will trigger or worsen an outbreak. For this reason, people with dyshidrosis should wear gloves, socks, and shoes made of materials which "breathe well", such as cotton or silk. Certain fabrics may greatly irritate the condition, including wool, nylon and many synthetic fabrics.
- Inherited, not contagious. Often, patients will present with other types of dermatitis, such as seborrheic dermatitis or atopic eczema. For this reason, among others, dyshidrosis is often dismissed as atopic eczema or contact dermatitis.
- Can be the secondary effect of problems in the gut. Some sufferers claim diet can ease symptoms (relieving internal condition of IBS or intestinal yeast infection). Also Inflammatory bowel diseases of Ulcerative colitis and Crohn's disease.
- Bandages, plasters or other types of skin-tapes may be irritating to dyshidrosis and should be avoided. As the skin needs to breathe, anything that encourages maceration of the palms should be avoided. If the 'wounds' are raw enough to warrant covering, pure cotton gloves or gauze should be used. Liquid Band-Aid brand bandage may be tolerated and helpful, refer to the Treatment section, below.
- Latex and vinyl gloves may increase irritation.
- Multiple Chemical Sensitivity
- Allergic reaction to Potassium Dichromate (leather preservative)
- Dyshidrosis can sometimes even be caused by dust mite allergies, with sufferers having to wash and change bedding weekly, sometimes even every 2 days or even every day, to combat symptoms.
# Diagnosis
## Physical Examination
## Skin
- Dyshidrotic eczema. Adapted from Dermatology Atlas.
- Dyshidrotic eczema. Adapted from Dermatology Atlas.
- Dyshidrotic eczema. Adapted from Dermatology Atlas.
# Treatment
There are many treatments available for dyshidrosis, however, few of them have been developed or tested specifically on the condition.
- Topical steroids - while useful, can be dangerous long-term due to the skin-thinning side-effects, which are particularly troublesome in the context of hand dyshidrosis, due to the amount of toxins and bacteria the hands typically come in contact with.
- Nutritional deficiencies may be related, so addressing diet and vitamin intake is helpful
- Hydrogen Peroxide - posited as a key alleviating treatment (not a cure) on a popular website, it is used in dilutions between 3% and 27% strength, but side-effects of its use include burning and itching, and there is argument as to whether it only attacks the 'sick cells'.
- Potassium permanganate dilute solution soaks - also popular, and used to 'dry out' the vesicles, but can also be very painful and cause significant burning.
- Domeboro (OTC) helps alleviate itching in the short term.
- Emollients during the drying/scaling phase of the condition, to prevent cracking and itching. While petroleum jelly may work well as a barrier cream, it does not absorb into the skin and or allow it to breathe, so may actually be less helpful.
- Salt soaks
- White vinegar soaks
- Avoidance of known triggers - dyshidrosis sufferers may need to abstain from washing their own hair or bodies, or wearing gloves when they do so, however waterproof gloves are often potential irritants.
- Zinc oxide ointment
- Nickel-free diets
- When in the scaling phase of the condition, the scales may cause deep cracks and fissures in the skin. Filing (as with an emery board) may help to minimize this.
- Stress management counseling
- Light treatment: UVA-1, PUVA, Grenz Rays, Low Level Light Therapy using a Red + NIR (LED) combination
- Ciclosporin a strong immunosuppressant drug used to combat dyshidrosis caused by ulcerative colitis
- Efalizumab (Raptiva) a medication used to treat psoriasis
- Tacrolimus and Pimecrolimus, potent immunomodulators often used to prevent organ rejection in topical, ointment form, may be used in severe cases.
- Unbleached cotton gloves may be used to cover the hands to prevent scratching and vulnerability of the skin to bacteria
- Plantain (Plantago major) infused in olive or other oil can be soothing.
- Band-Aid brand liquid bandage regularly applied during the (often painful) peeling stage allows the skin to breathe while protecting it from further irritation. Some suffers have found that with regular application the skin will close and reform within 1 to 2 days. Protection is sufficient that the user can (gently) wash their hands with no irritation, however additional application after each hand wash is suggested. It does not cure the condition and only aids healing during the peeling stage. Other spray-on or brush-on liquid bandaids can contain irritating ingredients and have not been found to be helpful, some will aggravate the condition significantly.
- Avoid metal computer keyboards and track pads which contain nickel.
Many sufferers of dyshidrosis will find that treatments that were previously suitable for them no longer work or have induced sensitive reactions, which is common in most types of eczema.
- It may be prudent to wear light cotton gloves while reading newspapers, books and magazines. The inks and paper may irritate the condition.
- Avoid Purell and other hand sanitizing products which contain alcohol. These may aggravate the condition.
- Wash affected hands and feet with cool water and apply a moisturizer as soon as possible.
- Valium in small doses during flare ups
# Allergy testing
Allergy testing is a contested subject among eczema communities. Some dermatologists posit that if a sufferer is allergic to a substance, then a general allergy test on the forearm will suffice, yet others believe that in conditions like dyshidrosis, the suspect substances need to be applied to the affected area to induce a reaction. | Dyshidrosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
Dyshidrosis, also termed Dyshidrotic Eczema, Pompholyx and Dyshidrotic Dermatitis, is a skin condition that is characterized by small blisters on the hands or feet. It is an acute, chronic, or recurrent dermatosis of the fingers, palms, and soles, characterized by a sudden onset of many deep-seated pruritic, clear vesicles; later, scaling, fissures and lichenification occur. Recurrence is common and for many can be chronic. Incidence/Prevalence is said to be 20/100,000 in the USA, however, many cases of eczema are diagnosed as garden-variety atopic eczema without further investigation, so it is possible this figure is misleading.
This condition is not contagious to others, but due to its unsightly nature can cause significant distress in regards to social interactions with others.
The name comes from the word "dyshidrotic," meaning "bad sweating," which was once believed to be the cause. Sometimes called pompholyx (Greek for "bubble") which is generally reserved for the cases with blisters; in some countries, pompholyx refers to hand dyshidrosis.
# Symptoms
Small blisters with the following characteristics:
- Blisters are very small (1 mm or less in diameter). They appear on the tips and sides of the fingers, toes, palms, and soles.
- Blisters are opaque and deep-seated; they are either flush with the skin or slightly elevated and do not break easily. Eventually, small blisters come together and form large blisters.
- Blisters may itch, cause pain, or produce no symptoms at all. They worsen after contact with soap, water, or irritating substances.
- Scratching blisters breaks them, releasing the fluid inside, causing the skin to crust and eventually crack. This cracking is painful as well as unsightly and often takes weeks, or even months to heal. The skin is dry and scaly during this period.
- Fluid from the blisters is serum that accumulates between the irritated skin cells. It is not sweat as was previously thought.
- In some cases, as the blistering takes place in the palms or finger. Lymph node swelling may accompany the outbreak. This is characterised by tingling feeling in the forearm and bumps present in the arm pits.
- Nails on affected fingers, or toes, may take on a pitted appearance.
# Causes
Causes of dyshidrosis are unknown, however, a number of triggers to the condition exist.
- Dyshidrosis has been historically linked to excessive sweating during periods of anxiety, stress, and frustration, however, many cases present that have no history of excessive sweating, and the hypothesis of dyshidrosis as a sweating disorder is largely rejected. Some patients reject this link to stress, though as a trigger of vesicular eruption it cannot be overlooked, as with other types of eczema.
- Vesicular eruption of the hands may also be caused by a local infection, with fungal infections being the most common. Sunlight is thought to bring on attacks, some patients link outbreaks to prolonged exposure to strong sunlight from late spring through to early autumn. Others have also noted outbreaks occurring in conjunction with exposure to chlorinated pool water or highly treated city tap waters.
- Soaps, detergents, fragrances and contact with fruit juices or fresh meat also can trigger outbreaks of dyshidrosis, as with other types of eczema.
- Systemic nickel allergies may be related.
- Keeping skin damp will trigger or worsen an outbreak. For this reason, people with dyshidrosis should wear gloves, socks, and shoes made of materials which "breathe well", such as cotton or silk. Certain fabrics may greatly irritate the condition, including wool, nylon and many synthetic fabrics.
- Inherited, not contagious. Often, patients will present with other types of dermatitis, such as seborrheic dermatitis or atopic eczema. For this reason, among others, dyshidrosis is often dismissed as atopic eczema or contact dermatitis.
- Can be the secondary effect of problems in the gut. Some sufferers claim diet can ease symptoms (relieving internal condition of IBS or intestinal yeast infection). Also Inflammatory bowel diseases of Ulcerative colitis and Crohn's disease.
- Bandages, plasters or other types of skin-tapes may be irritating to dyshidrosis and should be avoided. As the skin needs to breathe, anything that encourages maceration of the palms should be avoided. If the 'wounds' are raw enough to warrant covering, pure cotton gloves or gauze should be used. Liquid Band-Aid brand bandage may be tolerated and helpful, refer to the Treatment section, below.
- Latex and vinyl gloves may increase irritation.
- Multiple Chemical Sensitivity
- Allergic reaction to Potassium Dichromate (leather preservative)
- Dyshidrosis can sometimes even be caused by dust mite allergies, with sufferers having to wash and change bedding weekly, sometimes even every 2 days or even every day, to combat symptoms.
# Diagnosis
## Physical Examination
## Skin
- Dyshidrotic eczema. Adapted from Dermatology Atlas.[1]
- Dyshidrotic eczema. Adapted from Dermatology Atlas.[1]
- Dyshidrotic eczema. Adapted from Dermatology Atlas.[1]
# Treatment
There are many treatments available for dyshidrosis, however, few of them have been developed or tested specifically on the condition.
- Topical steroids[2] - while useful, can be dangerous long-term due to the skin-thinning side-effects, which are particularly troublesome in the context of hand dyshidrosis, due to the amount of toxins and bacteria the hands typically come in contact with.
- Nutritional deficiencies may be related, so addressing diet and vitamin intake is helpful
- Hydrogen Peroxide - posited as a key alleviating treatment (not a cure) on a popular website, it is used in dilutions between 3% and 27% strength, but side-effects of its use include burning and itching, and there is argument as to whether it only attacks the 'sick cells'.
- Potassium permanganate dilute solution soaks - also popular, and used to 'dry out' the vesicles, but can also be very painful and cause significant burning.
- Domeboro (OTC) helps alleviate itching in the short term.
- Emollients during the drying/scaling phase of the condition, to prevent cracking and itching. While petroleum jelly may work well as a barrier cream, it does not absorb into the skin and or allow it to breathe, so may actually be less helpful.
- Salt soaks
- White vinegar soaks
- Avoidance of known triggers - dyshidrosis sufferers may need to abstain from washing their own hair or bodies, or wearing gloves when they do so, however waterproof gloves are often potential irritants.
- Zinc oxide ointment
- Nickel-free diets
- When in the scaling phase of the condition, the scales may cause deep cracks and fissures in the skin. Filing (as with an emery board) may help to minimize this.
- Stress management counseling
- Light treatment: UVA-1, PUVA, Grenz Rays, Low Level Light Therapy using a Red + NIR (LED) combination
- Ciclosporin a strong immunosuppressant drug used to combat dyshidrosis caused by ulcerative colitis
- Efalizumab (Raptiva) a medication used to treat psoriasis
- Tacrolimus and Pimecrolimus, potent immunomodulators often used to prevent organ rejection in topical, ointment form, may be used in severe cases.
- Unbleached cotton gloves may be used to cover the hands to prevent scratching and vulnerability of the skin to bacteria
- Plantain (Plantago major) infused in olive or other oil can be soothing.
- Band-Aid brand liquid bandage regularly applied during the (often painful) peeling stage allows the skin to breathe while protecting it from further irritation. Some suffers have found that with regular application the skin will close and reform within 1 to 2 days. Protection is sufficient that the user can (gently) wash their hands with no irritation, however additional application after each hand wash is suggested. It does not cure the condition and only aids healing during the peeling stage. Other spray-on or brush-on liquid bandaids can contain irritating ingredients and have not been found to be helpful, some will aggravate the condition significantly.
- Avoid metal computer keyboards and track pads which contain nickel.
Many sufferers of dyshidrosis will find that treatments that were previously suitable for them no longer work or have induced sensitive reactions, which is common in most types of eczema.
- It may be prudent to wear light cotton gloves while reading newspapers, books and magazines. The inks and paper may irritate the condition.
- Avoid Purell and other hand sanitizing products which contain alcohol. These may aggravate the condition.
- Wash affected hands and feet with cool water and apply a moisturizer as soon as possible.
- Valium in small doses during flare ups
# Allergy testing
Allergy testing is a contested subject among eczema communities. Some dermatologists posit that if a sufferer is allergic to a substance, then a general allergy test on the forearm will suffice, yet others believe that in conditions like dyshidrosis, the suspect substances need to be applied to the affected area to induce a reaction. | https://www.wikidoc.org/index.php/Dyshidrosis | |
366e8f17be0e08007797427b3b0187357d9381cf | wikidoc | Dyskaryosis | Dyskaryosis
Dyskaryosis of the uterine cervix is a condition in which some of the epithelial cells near the os show abnormalities in their cellular nuclei.
These changes are often quite subtle, and are often seen as temporary changes in girls between the ages of fifteen and twenty-five. Apparent dyskaryosis in girls below the age of twenty-five is not regarded as significant, and accordingly in most countries where a cervical screening programme exists, the age of entry into the programme is twenty-five. The programme terminates at the age of sixty-five, assuming no abnormal smears in the previous ten years.
Cervical dyskaryosis is classified into four degrees of severity - borderline, mild, moderate and severe. While any dyskaryotic cervix might develop malignant change, so all must be followed up, the risk is increasingly high with higher grades of dyskayosis. Most borderline changes will resolve spontaneously, as will many mild ones. Moderate and severe changes are usually treated, by electrocautery, cryocautery or loop excision, with the object of completely removing the abnormal area.
Dyskaryosis is caused by an infection with Human Papilloma Virus (HPV) which exists in a number of different strains; type 16 and type 18 cause dyskaryosis more readily than do other types. These viruses are nearly always sexually transmitted. Immunization, which is now available against HPV 16 and 18, will prevent further infection by these strains. But if infection has occurred before immunization, and cellular change has already occurred, the vaccine does not reduce the risk of developing dyskaryotic change. | Dyskaryosis
Dyskaryosis of the uterine cervix is a condition in which some of the epithelial cells near the os show abnormalities in their cellular nuclei.
These changes are often quite subtle, and are often seen as temporary changes in girls between the ages of fifteen and twenty-five. Apparent dyskaryosis in girls below the age of twenty-five is not regarded as significant, and accordingly in most countries where a cervical screening programme exists, the age of entry into the programme is twenty-five. The programme terminates at the age of sixty-five, assuming no abnormal smears in the previous ten years.
Cervical dyskaryosis is classified into four degrees of severity - borderline, mild, moderate and severe. While any dyskaryotic cervix might develop malignant change, so all must be followed up, the risk is increasingly high with higher grades of dyskayosis. Most borderline changes will resolve spontaneously, as will many mild ones. Moderate and severe changes are usually treated, by electrocautery, cryocautery or loop excision, with the object of completely removing the abnormal area.
Dyskaryosis is caused by an infection with Human Papilloma Virus (HPV) which exists in a number of different strains; type 16 and type 18 cause dyskaryosis more readily than do other types.[1] These viruses are nearly always sexually transmitted. Immunization, which is now available against HPV 16 and 18, will prevent further infection by these strains. But if infection has occurred before immunization, and cellular change has already occurred, the vaccine does not reduce the risk of developing dyskaryotic change. | https://www.wikidoc.org/index.php/Dyskaryosis | |
bff4a6af30fa785d5fcfb0b6ac2406a92b38a60c | wikidoc | E-Detailing | E-Detailing
E-detailing is the technological equivalent of the pharmaceutical representative’s traditional sales aid, used as part of their sales visits to healthcare providers.
Either internet based or loaded onto a tablet PC, an e-detail is an interactive presentation which is backed up by robust CRM systems to allow for a tailored marketing approach for every single customer. Internet based e-detailing is seen by some as a method to overcome the challenge sales reps face to secure physician meeting, the e-detail effectively replacing the face-to-face contact.
Tablet based e-detailing will be presented in much the same way as paper detail aids and require contact time, however the electronic detail aid is capable of providing interaction, video content, sound, and animation which are believed to increase engagement and therefore the messages have higher salience and retention.
As an e-detail is stored electronically, CRM systems can be used to select appropriate content depending on the physician data and can be used to track results. The format also allows for electronic storage of clinical papers, articles and so forth, which are then easily accessible when required.
The electronic detail aid also means that updates are much easier as they involve uploading new content and there is no requirement to re-print another version.
Because it is an interactive medium, the belief is that the physician will be more engaged in the messages that she or he is exposed to and thus the message will have higher salience and retention.
There are a number of practitioners of e-detailing, in Europe, perhaps most prominently Creative Lynx a Manchester based creative agency who have won awards for their work in this field.
In the United States, The Allscripts Physicians Interactive Group is a clear leader and purveyor of e-detailing services and physician relationship building.
In Austria the Medizin Medien Austria is the "golden standard" for pharmaceutical contents. | E-Detailing
E-detailing is the technological equivalent of the pharmaceutical representative’s traditional sales aid, used as part of their sales visits to healthcare providers.
Either internet based or loaded onto a tablet PC, an e-detail is an interactive presentation which is backed up by robust CRM systems to allow for a tailored marketing approach for every single customer. Internet based e-detailing is seen by some as a method to overcome the challenge sales reps face to secure physician meeting, the e-detail effectively replacing the face-to-face contact.
Tablet based e-detailing will be presented in much the same way as paper detail aids and require contact time, however the electronic detail aid is capable of providing interaction, video content, sound, and animation which are believed to increase engagement and therefore the messages have higher salience and retention.
As an e-detail is stored electronically, CRM systems can be used to select appropriate content depending on the physician data and can be used to track results. The format also allows for electronic storage of clinical papers, articles and so forth, which are then easily accessible when required.
The electronic detail aid also means that updates are much easier as they involve uploading new content and there is no requirement to re-print another version.
[1] Because it is an interactive medium, the belief is that the physician will be more engaged in the messages that she or he is exposed to and thus the message will have higher salience and retention.
There are a number of practitioners of e-detailing, in Europe, perhaps most prominently Creative Lynx a Manchester based creative agency who have won awards for their work in this field.
In the United States, The Allscripts Physicians Interactive Group is a clear leader and purveyor of e-detailing services and physician relationship building.
In Austria the Medizin Medien Austria is the "golden standard" for pharmaceutical contents. | https://www.wikidoc.org/index.php/E-Detailing | |
4e43b1a19d551a918e9318ffec4affd073ba9155 | wikidoc | E-cigarette | E-cigarette
Several companies are currently selling an electronic version of a cigarette.
The device takes the form of a tiny rod which is slightly longer than a normal cigarette. The mouthpiece of the device contains a replaceable cartridge filled with liquid. The main substances contained in the liquid are nicotine and propylene glycol.
When air flows through the device, it is detected by a microprocessor. This microprocessor then activates an atomizer which injects tiny droplets of the liquid into the flowing air. This produces a vapor mist which is inhaled by the user. The addition of propylene glycol to the liquid makes the mist better resemble normal cigarette smoke. The microprocessor also activates an orange LED at the tip to simulate real smoking. It not only simulates cigarette smoke but also the temperature of common cigarette's smoke (50-60 °C).
The units use a rechargeable battery as a power source.
The technology is patented by European Patent EP 1 618 803 A1.
# Nicotine solution cartridges
The patent mentions four different recipes for the nicotine solution of the cartridge to be used with the electronic cigarette:
# Health issues
E-cigarettes are marketed as a "healthier" alternative for the consumption of tobacco (in comparison to smoking) since the atomisation of the substance does not produce the particulate matter which results from the combustion of plant material.
A toxicity study of the nicotine solutions (text in German) has been performed by Prof. Dr. Bernd Mayer.
# Legal situation in the EU
In the European Union some countries have stipulated a decision according to the legal status of e-cigarette products.
In principle, an e-cigarette is a Class IIa medical device (according to the EC directive 93/42/EEC) intended to administer medicines (nicotine solution) to the human body. The nicotine depots have to be considered as a medicinal product according to EC-directive 2001/83/EG (since the nicotine is a solution and not a tobacco plant product anymore). According to this classification, any type of e-cigarette needs to be CE-marked prior to distribution and for trade and distribution of the nicotine depots a registration as a medicinal products is inevitable. The Austrian Agency for Health-care Safety has issued their decision on April 18th 2007 expressing the above expert opinion. Since there is a first decision of a competent authority in one EU country, this decision is a guideline for all other EU countries. At present, none of the e-cigarette products can provide a medical device nor a medicinal registration. Any distribution within the European Union appears to be illegal.
# List of companies/products
(in alphabetic order)
- Cigartex (France)
- Crown Seven (USA)
- EMTAC (Germany)
- Rooney (Belgium)
- Rutoo E-cigarette (Europe)
- Smuke Europe Ltd. (Portugal)
- fujian mondex Ltd. (China, Wholesale)
- Sedansa (Belgium)
- Sottera Njoy (USA)
- SuperSmoker (Belgium)
- e-Cig.org (USA) | E-cigarette
Several companies are currently selling an electronic version of a cigarette.
The device takes the form of a tiny rod which is slightly longer than a normal cigarette. The mouthpiece of the device contains a replaceable cartridge filled with liquid. The main substances contained in the liquid are nicotine and propylene glycol.
When air flows through the device, it is detected by a microprocessor. This microprocessor then activates an atomizer which injects tiny droplets of the liquid into the flowing air. This produces a vapor mist which is inhaled by the user. The addition of propylene glycol to the liquid makes the mist better resemble normal cigarette smoke. The microprocessor also activates an orange LED at the tip to simulate real smoking. It not only simulates cigarette smoke but also the temperature of common cigarette's smoke (50-60 °C).
The units use a rechargeable battery as a power source.
The technology is patented by European Patent EP 1 618 803 A1.
# Nicotine solution cartridges
The patent mentions four different recipes for the nicotine solution of the cartridge to be used with the electronic cigarette:
# Health issues
E-cigarettes are marketed as a "healthier" alternative for the consumption of tobacco (in comparison to smoking) since the atomisation of the substance does not produce the particulate matter which results from the combustion of plant material.
A toxicity study of the nicotine solutions (text in German) has been performed by Prof. Dr. Bernd Mayer.
# Legal situation in the EU
In the European Union some countries have stipulated a decision according to the legal status of e-cigarette products.
In principle, an e-cigarette is a Class IIa medical device (according to the EC directive 93/42/EEC) intended to administer medicines (nicotine solution) to the human body. The nicotine depots have to be considered as a medicinal product according to EC-directive 2001/83/EG (since the nicotine is a solution and not a tobacco plant product anymore). According to this classification, any type of e-cigarette needs to be CE-marked prior to distribution and for trade and distribution of the nicotine depots a registration as a medicinal products is inevitable. The Austrian Agency for Health-care Safety has issued their decision on April 18th 2007 expressing the above expert opinion. Since there is a first decision of a competent authority in one EU country, this decision is a guideline for all other EU countries. At present, none of the e-cigarette products can provide a medical device nor a medicinal registration. Any distribution within the European Union appears to be illegal.
# List of companies/products
(in alphabetic order)
- Cigartex (France)
- Crown Seven (USA)
- EMTAC (Germany)
- Rooney (Belgium)
- Rutoo E-cigarette (Europe)
- Smuke Europe Ltd. (Portugal)
- fujian mondex Ltd. (China, Wholesale)
- Sedansa (Belgium)
- Sottera Njoy (USA)
- SuperSmoker (Belgium)
- e-Cig.org (USA)
# External links
- A google map with locations of e-cigarette shops and users worldwide
- E-cigarette discussion forums:
Dutch
German
- Dutch
- German
hu:E-cigaretta
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/E-cigarette | |
f9d3900467dce1c43bd4b469ed2ca6456a78387f | wikidoc | Ear shaping | Ear shaping
Ear shaping is the process of altering the shape of the human ear(s) as a body modification practice, often resulting in a non-human appearance. The medical procedure via which ears are reshaped to give a normal appearance is known as otoplasty. Ear shaping is usually performed by cutters.
There are several ways in which human ears can be given a different appearance, including cropping, pointing, and the amputation of various parts. The various methods may be combined to give specific results.
# Amputation
In this form of ear shaping, the lobe or other portions of the ear are amputated to give the desired look. This may also be undertaken to remove stretched portions that are no longer wanted. Sutures or cauterizing may be required.
# Cropping
Ear cropping is commonly performed on animals, for both cosmetic and other reasons, but rarely on humans. In humans, cropping usually involves the removal of part of the upper ear with a scalpel. Suturing or cauterizing may be required.
# Cutting
Cutting involves removing small portions of tissue or cutting parts of the ear to produce a new shape or a decorative pattern.
# Pointing
Ear pointing by various methods is undertaken to give an elf-like appearance to the ears. A common method is to remove a small wedge-shaped portion at the top of the ear, and then suture the two edges. | Ear shaping
Ear shaping is the process of altering the shape of the human ear(s) as a body modification practice, often resulting in a non-human appearance. The medical procedure via which ears are reshaped to give a normal appearance is known as otoplasty. Ear shaping is usually performed by cutters.
There are several ways in which human ears can be given a different appearance, including cropping, pointing, and the amputation of various parts. The various methods may be combined to give specific results.
# Amputation
In this form of ear shaping, the lobe or other portions of the ear are amputated to give the desired look. This may also be undertaken to remove stretched portions that are no longer wanted. Sutures or cauterizing may be required.
# Cropping
Ear cropping is commonly performed on animals, for both cosmetic and other reasons, but rarely on humans. In humans, cropping usually involves the removal of part of the upper ear with a scalpel. Suturing or cauterizing may be required.
# Cutting
Cutting involves removing small portions of tissue or cutting parts of the ear to produce a new shape or a decorative pattern.
# Pointing
Ear pointing by various methods is undertaken to give an elf-like appearance to the ears. A common method is to remove a small wedge-shaped portion at the top of the ear, and then suture the two edges. | https://www.wikidoc.org/index.php/Ear_shaping | |
6f8c6d72ac02ada467a2e9cdf9acb374e3e01c0a | wikidoc | Ecallantide | Ecallantide
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Ecallantide is a Immune Modulator that is FDA approved for the treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, nausea, diarrhea, pyrexia, injection site reactions, and nasopharyngitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Ecallantide is indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older.
### Dosage
- The recommended dose of Ecallantide is 30 mg (3 mL), administered subcutaneously in three 10 mg (1 mL) injections. If the attack persists, an additional dose of 30 mg may be administered within a 24 hour period.
### DOSAGE FORMS AND STRENGTHS
- Ecallantide is a clear, colorless liquid free of preservatives. Each vial contains ecallantide at a concentration of 10 mg/mL.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ecallantide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ecallantide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Ecallantide is indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ecallantide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ecallantide in pediatric patients.
# Contraindications
- Do not administer KALBITOR to a patient who has known clinical hypersensitivity to KALBITOR.
# Warnings
- Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR. In 255 HAE patients treated with intravenous or subcutaneous KALBITOR in clinical studies, 10 patients (4%) experienced anaphylaxis. For the subgroup of 187 patients treated with subcutaneous KALBITOR, 5 patients (3%) experienced anaphylaxis. Symptoms associated with these reactions have included chest discomfort, flushing, pharyngeal edema, pruritus, rhinorrhea, sneezing, nasal congestion, throat irritation, urticaria, wheezing, and hypotension. These reactions occurred within the first hour after dosing.
- Other adverse reactions indicative of hypersensitivity reactions included the following: pruritus (5%), rash (3%), and urticaria (2%).
- Patients should be observed for an appropriate period of time after administration of KALBITOR, taking into account the time to onset of anaphylaxis seen in clinical trials. Given the similarity in hypersensitivity symptoms and acute HAE symptoms, patients should be monitored closely in the event of a hypersensitivity reaction.
- KALBITOR should not be administered to any patients with known clinical hypersensitivity to KALBITOR
# Adverse Reactions
## Clinical Trials Experience
- Hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety data described below reflect exposure to KALBITOR in 255 patients with HAE treated with either intravenous or subcutaneous KALBITOR. Of the 255 patients, 66% of patients were female and 86% were Caucasian. Patients treated with KALBITOR were between the ages of 10 and 78 years.
- Overall, the most common adverse reactions in 255 patients with HAE were headache (16%), nausea (13%), fatigue (12%), diarrhea (11%), upper respiratory tract infection (8%), injection site reactions (7%), nasopharyngitis (6%), vomiting (6%), pruritus (5%), upper abdominal pain (5%), and pyrexia (5%).
- Anaphylaxis was reported in 4% of patients with HAE. Injection site reactions were characterized by local pruritus, erythema, pain, irritation, urticaria, and/or bruising.
- The incidence of adverse reactions below is based upon 2 placebo-controlled, clinical trials (EDEMA3® and EDEMA4®) in a total of 143 unique patients with HAE. Patients were treated with KALBITOR 30 mg subcutaneous or placebo. Patients were permitted to participate sequentially in both placebo-controlled trials; safety data collected during exposure to KALBITOR was attributed to treatment with KALBITOR, and safety data collected during exposure to placebo was attributed to treatment with placebo. Table 1 shows adverse reactions occurring in ≥3% of KALBITOR-treated patients that also occurred at a higher rate than in the placebo-treated patients in the two controlled trials (EDEMA3 and EDEMA4) of the 30 mg subcutaneous dose.
- Some patients in EDEMA3 and EDEMA4 received a second, open-label 30 mg subcutaneous dose of KALBITOR within 24 hours following the initial dose. Adverse reactions reported by these patients who received the additional 30 mg subcutaneous dose of KALBITOR were consistent with those reported in the patients receiving a single dose.
- In the KALBITOR HAE program, patients developed antibodies to KALBITOR. Rates of seroconversion increased with exposure to KALBITOR over time. Overall, 20.2% of patients seroconverted to anti-ecallantide antibodies. Neutralizing antibodies to ecallantide were determined in vitro to be present in 8.8% of patients and were not associated with loss of efficacy.
- Anti-ecallantide IgE antibodies were detected at a rate of 4.7% for tested patients, and anti-P. pastoris IgE antibodies were also detected at a rate of 20.2%. Patients who seroconvert may be at a higher risk of a hypersensitivity reaction. The long-term effects of antibodies to KALBITOR are not known.
- The test results for the ecallantide program were determined using one of two assay formats: ELISA and bridging electrochemiluminescence (ECL). As with all therapeutic proteins, there is a potential for immunogenicity with the use of KALBITOR. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to KALBITOR with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- Similar adverse reactions have been observed postmarketing as described for clinical trial experience. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or to establish a causal relationship with drug exposure.
# Drug Interactions
- No formal drug interactions studies were performed. No in vitro metabolism studies were performed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled trials of KALBITOR in pregnant women. KALBITOR has been shown to cause developmental toxicity in rats, but not rabbits. Because animal reproductive studies are not always predictive of human response, KALBITOR should be used during pregnancy only if clearly needed.
- In rats, intravenous KALBITOR at an intravenous dose approximately 13 times the maximum recommended human dose (MRHD) (on a mg/kg basis at a maternal dose of 15 mg/kg/day in rats) caused increased numbers of early resorptions and percentages of resorbed conceptuses per litter in the presence of mild maternal toxicity. No development toxicity was observed in rats that received an intravenous dose approximately 8 times the MRHD (on a mg/kg basis at a maternal dose of 10 mg/kg/day in rats). There were no adverse effects of KALBITOR on embryofetal development in rats that received subcutaneous doses up to approximately 2.4 times the MRHD (on an AUC basis at a maternal dose of 20 mg/kg/day in rats), and in rabbits that received intravenous doses up to approximately 6 times the MRHD (on an AUC basis at a maternal dose of 5 mg/kg/day in rabbits).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ecallantide in women who are pregnant.
### Labor and Delivery
- No information is available on the effects of KALBITOR during labor and delivery.
### Nursing Mothers
- It is not known whether ecallantide is excreted in human milk. Caution should be exercised when ecallantide is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of KALBITOR have been established in patients 12 to 17 years of age. The efficacy of KALBITOR in the 12-15 year age group is extrapolated from efficacy in patients 16 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and adolescents . The safety profile observed in pediatric patients 12-17 years of age was similar to the adverse reactions observed in the overall clinical trial population .
Safety and effectiveness of KALBITOR in patients less than 12 years of age have not been established.
### Geriatic Use
- Clinical trials of KALBITOR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Ecallantide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ecallantide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ecallantide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ecallantide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ecallantide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ecallantide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
- KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.
- KALBITOR should be refrigerated and protected from the light. KALBITOR is a clear, colorless liquid; visually inspect each vial for particulate matter and discoloration prior to administration. If there is particulate matter or discoloration, the vial should not be used.
- Using aseptic technique, withdraw 1 mL (10 mg) of KALBITOR from the vial using a large bore needle. Change the needle on the syringe to a needle suitable for subcutaneous injection. The recommended needle size is 27 gauge. Inject KALBITOR into the skin of the abdomen, thigh, or upper arm. Repeat the procedure for each of the 3 vials comprising the KALBITOR dose. The injection site for each of the injections may be in the same or in different anatomic locations (abdomen, thigh, upper arm). There is no need for site rotation. Injection sites should be separated by at least 2 inches (5 cm) and away from the anatomical site of attack.
- The same instructions apply to an additional dose administered within 24 hours. Different injection sites or the same anatomical location (as used for the first administration) may be used.
### Monitoring
- Given the similarity in hypersensitivity symptoms and acute HAE symptoms, patients should be monitored closely in the event of a hypersensitivity reaction.
# IV Compatibility
There is limited information regarding IV Compatibility of Ecallantide in the drug label.
# Overdosage
- There have been no reports of overdose with KALBITOR. HAE patients have received single doses up to 90 mg intravenously without evidence of dose-related toxicity.
# Pharmacology
## Mechanism of Action
- Hereditary angioedema (HAE) is a rare genetic disorder caused by mutations to C1-esterase-inhibitor (C1-INH) located on Chromosome 11q and inherited as an autosomal dominant trait. HAE is characterized by low levels of C1-INH activity and low levels of C4. C1-INH functions to regulate the activation of the complement and intrinsic coagulation (contact system pathway) and is a major endogenous inhibitor of plasma kallikrein. The kallikrein-kinin system is a complex proteolytic cascade involved in the initiation of both inflammatory and coagulation pathways. One critical aspect of this pathway is the conversion of High Molecular Weight (HMW) kininogen to bradykinin by the protease plasma kallikrein. In HAE, normal regulation of plasma kallikrein activity and the classical complement cascade is therefore not present. During attacks, unregulated activity of plasma kallikrein results in excessive bradykinin generation. Bradykinin is a vasodilator which is thought by some to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain.
- KALBITOR is a potent (Ki = 25 pM), selective, reversible inhibitor of plasma kallikrein. KALBITOR binds to plasma kallikrein and blocks its binding site, inhibiting the conversion of HMW kininogen to bradykinin. By directly inhibiting plasma kallikrein, KALBITOR reduces the conversion of HMW kininogen to bradykinin and thereby treats symptoms of the disease during acute episodic attacks of HAE.
## Structure
- KALBITOR (ecallantide) is a human plasma kallikrein inhibitor for injection for subcutaneous use. Ecallantide is a 60-amino-acid protein produced in Pichia pastoris yeast cells by recombinant DNA technology.
- KALBITOR is a clear and colorless, sterile, and nonpyrogenic solution. Each vial contains 10 mg ecallantide as the active ingredient, and the following inactive ingredients: 0.76 mg disodium hydrogen orthophosphate (dihydrate), 0.2 mg monopotassium phosphate, 0.2 mg potassium chloride, and 8 mg sodium chloride in water for injection, USP. KALBITOR is preservative free, with a pH of approximately 7.0. A 30 mg dose is supplied as 3 vials each containing 1 mL of 10 mg/mL KALBITOR. Vials are intended for single use.
## Pharmacodynamics
- No exposure-response relationships for KALBITOR to components of the complement or kallikrein-kinin pathways have been established.
- The effect of KALBITOR on activated partial thromboplastin time (aPTT) was measured because of potential effect on the intrinsic coagulation pathway. Prolongation of aPTT has been observed following intravenous dosing of KALBITOR at doses ≥20 mg/m2. At 80 mg administered intravenously in healthy subjects, aPTT values were prolonged approximately two-fold over baseline values and returned to normal by 4 hours post-dose.
- For patients taking KALBITOR, no significant QT prolongation has been seen. In a randomized, placebo-controlled trial (EDEMA4) studying the 30 mg subcutaneous dose versus placebo, 12-lead ECGs were obtained at baseline, 2 hours and 4 hours post-dose (covering the time of expected Cmax), and at follow-up (day 7). ECGs were evaluated for PR interval, QRS complex, and QTc interval. KALBITOR had no significant effect on the QTc interval, heart rate, or any other components of the ECG.
## Pharmacokinetics
- Following the administration of a single 30 mg subcutaneous dose of KALBITOR to healthy subjects, a mean (± standard deviation) maximum plasma concentration of 586 ± 106 ng/mL was observed approximately 2 to 3 hours post-dose. The mean area under the concentration-time curve was 3017 ± 402 ng*hr/mL. Following administration, plasma concentration declined with a mean elimination half-life of 2.0 ± 0.5 hours. Plasma clearance was 153 ± 20 mL/min and the volume of distribution was 26.4 ± 7.8 L. Based on a population pharmacokinetic analysis, body weight, age, and gender were not found to affect KALBITOR exposure significantly. Ecallantide is a small protein (7054 Da) and renal elimination in the urine of treated subjects has been demonstrated.
- No pharmacokinetic data are available in patients or subjects with hepatic or renal impairment.
## Nonclinical Toxicology
- A two-year study was conducted in rats to assess the carcinogenic potential of KALBITOR. No evidence of tumorigenicity was observed in rats at ecallantide doses up to 10 mg/kg administered subcutaneously every three days (approximately 2-fold greater than the MRHD on an AUC basis).
- KALBITOR had no effects on fertility and reproductive performance in rats at subcutaneous doses up to 25 mg/kg/day (approximately 21 times the MRHD on a mg/kg basis).
# Clinical Studies
- The safety and efficacy of KALBITOR to treat acute attacks of hereditary angioedema in adolescents and adults were evaluated in 2 randomized, double-blind, placebo-controlled trials (EDEMA4 and EDEMA3) in 168 patients with HAE. Patients having an attack of hereditary angioedema, at any anatomic location, with at least 1 moderate or severe symptom, were treated with 30 mg subcutaneous KALBITOR or placebo. Because patients could participate in both trials, a total of 143 unique patients participated. Of the 143 patients, 94 were female, 123 were Caucasian, and the mean age was 36 years (range 11-77). There were 64 patients with abdominal attacks, 55 with peripheral attacks, and 24 with laryngeal attacks.
- In both trials, the effects of KALBITOR were evaluated using the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS). These endpoints evaluated attack severity (MSCS) and patient response to treatment (TOS) for an acute HAE attack.
- MSCS score is a point-in-time measure of symptom severity. At baseline, and post-dosing at 4 hours and 24 hours, patients rated the severity of each affected symptom on a categorical scale (0 = normal, 1 = mild, 2 = moderate, 3 = severe). Patient-reported severity was based on each patient’s assessment of symptom impact on their ability to perform routine activities. Ratings were averaged to obtain the MSCS score. The endpoint was reported as the change in MSCS score from baseline. A decrease in MSCS score reflected an improvement in symptom severity; the maximum possible change toward improvement was -3.
- TOS is a measure of symptom response to treatment. At 4 hours and 24 hours post-dosing, patient assessment of response for each anatomic site of attack involvement was recorded on a categorical scale (significant improvement , improvement , same , worsening , significant worsening ). The response at each anatomic site was weighted by baseline severity and then the weighted scores across all involved sites were averaged to calculate the TOS. A TOS value >0 reflected an improvement in symptoms from baseline. The maximum possible score was +100.
- EDEMA4 was a randomized, double-blind, placebo-controlled trial in which 96 patients were randomized 1:1 to receive KALBITOR 30 mg subcutaneous or placebo for acute attacks of HAE. The primary endpoint was the change from baseline in MSCS score at 4 hours, and the TOS at 4 hours was a key secondary endpoint. Patients treated with KALBITOR demonstrated a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients with placebo and the results were statistically significant (Table 2). At 24 hours, patients treated with KALBITOR also demonstrated a greater decrease from baseline in the MSCS than placebo (-1.5 vs. -1.1; p = 0.04) and a greater TOS (89 vs. 55, p = 0.03).
- More patients in the placebo group (24/48, 50%) required medical intervention to treat unresolved symptoms within 24 hours compared to the KALBITOR-treated group (16/48, 33%).
- Some patients reported improvement following a second 30 mg subcutaneous dose of KALBITOR, administered within 24 hours following the initial dose for symptom persistence or relapse, but efficacy was not systematically assessed for the second dose.
- EDEMA3 was a randomized, double-blind, placebo-controlled trial in which 72 patients were randomized 1:1 to receive KALBITOR or placebo for acute attacks of HAE. EDEMA3 was similar in design to EDEMA4 with the exception of the order of the prespecified efficacy endpoints. In EDEMA3, the primary endpoint was the TOS at 4 hours, and the key secondary efficacy endpoint was the change from baseline in MSCS at 4 hours. As in EDEMA4, patients treated with KALBITOR demonstrated a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients treated with placebo and the results were statistically significant (Table 2).
- In addition, more patients in the placebo group (13/36, 36%) required medical intervention to treat unresolved symptoms within 24 hours compared to the KALBITOR-treated group (5/36, 14%).
# How Supplied
- KALBITOR (ecallantide) is supplied as three 10 mg/mL single-use vials packaged in a carton. Each vial contains 10 mg of ecallantide. Each vial contains a slight overfill.
## Storage
- KALBITOR should be kept refrigerated (2ºC to 8ºC/36ºF to 46ºF). Vials removed from refrigeration should be stored below 86ºF/30ºC and used within 14 days or returned to refrigeration until use.
- Protect vials from light until use.
- Do not use beyond the expiration date.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
Kalbitor ecallantide 10 mg/mL 3 Vials
NDC: 47783-101-01
### Ingredients and Appearance
# Patient Counseling Information
- Advise patients that KALBITOR may cause anaphylaxis and other hypersensitivity reactions. Advise patients that KALBITOR should be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema. Instruct patients who have known clinical hypersensitivity to KALBITOR not to receive additional doses of KALBITOR.
Advise patients to consult the Medication Guide for additional information regarding the risk of anaphylaxis and other hypersensitivity reactions.
### MEDICATION GUIDE
(ecallantide)
- Read this Medication Guide before you start receiving KALBITOR and before each treatment. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or your treatment.
- Serious allergic reactions may happen in some people who receive KALBITOR. These allergic reactions can be life-threatening and usually happen within 1 hour after receiving KALBITOR.
- KALBITOR should be given to you by a doctor or nurse in a healthcare setting where serious allergic reactions and hereditary angioedema (HAE) can be treated.
- Symptoms of a serious allergic reaction to KALBITOR can be similar to the symptoms of HAE, the condition that you are being treated for. Your doctor or nurse should watch you for any signs of a serious allergic reaction after treatment with KALBITOR.
- Tell your doctor or nurse right away if you have any of these symptoms of a serious allergic reaction during or after treatment with KALBITOR:
- wheezing, shortness of breath, cough, chest tightness, or trouble breathing
- dizziness, fainting, fast or weak heartbeat, or feeling nervous
- reddening of the face, itching, hives, or feeling warm
- swelling of the throat or tongue, throat tightness, hoarse voice, or trouble swallowing
- runny nose, nasal congestion, or sneezing
- KALBITOR is a prescription medicine used to treat sudden attacks of hereditary angioedema (HAE) in people 12 years of age and older.
- KALBITOR is not a cure for HAE.
- It is not known if KALBITOR is safe and effective in children under 12 years of age.
- Do not receive KALBITOR if you are allergic to KALBITOR.
- Before receiving KALBITOR, tell your doctor if you:
- have ever had an allergic reaction to KALBITOR. See “Who should not receive KALBITOR?”
- are pregnant or plan to become pregnant. It is not known if KALBITOR will harm your unborn baby.
- are breast-feeding or plan to breast-feed. It is not known if KALBITOR passes into your breast milk.
- Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
- Know the medicines you take. Keep a list of them to show to your doctor and pharmacist when you get a new medicine.
- For each dose, you will receive 3 injections just under the skin (subcutaneous or SC injections) of your abdomen, thigh, or upper arm.
- KALBITOR can cause serious allergic reactions. See "What is the most important information I should know about KALBITOR?"
- Common side effects of KALBITOR include:
- headache
- nausea
- diarrhea
- fever
- injection site reactions, such as redness, rash, swelling, itching, or bruising
- stuffy nose
- Call your doctor for advice about side effects. You may report side effects to FDA at 1‑800-FDA-1088.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. This Medication Guide gives you the most important information about KALBITOR. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about KALBITOR that is written for health professionals.
- Active Ingredient: ecallantide
- Inactive ingredients: disodium hydrogen orthophosphate (dihydrate), monopotassium phosphate, potassium chloride, sodium chloride in water for injection.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Alcohol-Ecallantide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Kalbitor®
# Look-Alike Drug Names
There is limited information regarding Ecallantide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ecallantide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
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# Black Box Warning
# Overview
Ecallantide is a Immune Modulator that is FDA approved for the treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, nausea, diarrhea, pyrexia, injection site reactions, and nasopharyngitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Ecallantide is indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older.
### Dosage
- The recommended dose of Ecallantide is 30 mg (3 mL), administered subcutaneously in three 10 mg (1 mL) injections. If the attack persists, an additional dose of 30 mg may be administered within a 24 hour period.
### DOSAGE FORMS AND STRENGTHS
- Ecallantide is a clear, colorless liquid free of preservatives. Each vial contains ecallantide at a concentration of 10 mg/mL.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ecallantide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ecallantide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Ecallantide is indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ecallantide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ecallantide in pediatric patients.
# Contraindications
- Do not administer KALBITOR to a patient who has known clinical hypersensitivity to KALBITOR.
# Warnings
- Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR. In 255 HAE patients treated with intravenous or subcutaneous KALBITOR in clinical studies, 10 patients (4%) experienced anaphylaxis. For the subgroup of 187 patients treated with subcutaneous KALBITOR, 5 patients (3%) experienced anaphylaxis. Symptoms associated with these reactions have included chest discomfort, flushing, pharyngeal edema, pruritus, rhinorrhea, sneezing, nasal congestion, throat irritation, urticaria, wheezing, and hypotension. These reactions occurred within the first hour after dosing.
- Other adverse reactions indicative of hypersensitivity reactions included the following: pruritus (5%), rash (3%), and urticaria (2%).
- Patients should be observed for an appropriate period of time after administration of KALBITOR, taking into account the time to onset of anaphylaxis seen in clinical trials. Given the similarity in hypersensitivity symptoms and acute HAE symptoms, patients should be monitored closely in the event of a hypersensitivity reaction.
- KALBITOR should not be administered to any patients with known clinical hypersensitivity to KALBITOR
# Adverse Reactions
## Clinical Trials Experience
- Hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety data described below reflect exposure to KALBITOR in 255 patients with HAE treated with either intravenous or subcutaneous KALBITOR. Of the 255 patients, 66% of patients were female and 86% were Caucasian. Patients treated with KALBITOR were between the ages of 10 and 78 years.
- Overall, the most common adverse reactions in 255 patients with HAE were headache (16%), nausea (13%), fatigue (12%), diarrhea (11%), upper respiratory tract infection (8%), injection site reactions (7%), nasopharyngitis (6%), vomiting (6%), pruritus (5%), upper abdominal pain (5%), and pyrexia (5%).
- Anaphylaxis was reported in 4% of patients with HAE. Injection site reactions were characterized by local pruritus, erythema, pain, irritation, urticaria, and/or bruising.
- The incidence of adverse reactions below is based upon 2 placebo-controlled, clinical trials (EDEMA3® and EDEMA4®) in a total of 143 unique patients with HAE. Patients were treated with KALBITOR 30 mg subcutaneous or placebo. Patients were permitted to participate sequentially in both placebo-controlled trials; safety data collected during exposure to KALBITOR was attributed to treatment with KALBITOR, and safety data collected during exposure to placebo was attributed to treatment with placebo. Table 1 shows adverse reactions occurring in ≥3% of KALBITOR-treated patients that also occurred at a higher rate than in the placebo-treated patients in the two controlled trials (EDEMA3 and EDEMA4) of the 30 mg subcutaneous dose.
- Some patients in EDEMA3 and EDEMA4 received a second, open-label 30 mg subcutaneous dose of KALBITOR within 24 hours following the initial dose. Adverse reactions reported by these patients who received the additional 30 mg subcutaneous dose of KALBITOR were consistent with those reported in the patients receiving a single dose.
- In the KALBITOR HAE program, patients developed antibodies to KALBITOR. Rates of seroconversion increased with exposure to KALBITOR over time. Overall, 20.2% of patients seroconverted to anti-ecallantide antibodies. Neutralizing antibodies to ecallantide were determined in vitro to be present in 8.8% of patients and were not associated with loss of efficacy.
- Anti-ecallantide IgE antibodies were detected at a rate of 4.7% for tested patients, and anti-P. pastoris IgE antibodies were also detected at a rate of 20.2%. Patients who seroconvert may be at a higher risk of a hypersensitivity reaction. The long-term effects of antibodies to KALBITOR are not known.
- The test results for the ecallantide program were determined using one of two assay formats: ELISA and bridging electrochemiluminescence (ECL). As with all therapeutic proteins, there is a potential for immunogenicity with the use of KALBITOR. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to KALBITOR with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- Similar adverse reactions have been observed postmarketing as described for clinical trial experience. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or to establish a causal relationship with drug exposure.
# Drug Interactions
- No formal drug interactions studies were performed. No in vitro metabolism studies were performed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled trials of KALBITOR in pregnant women. KALBITOR has been shown to cause developmental toxicity in rats, but not rabbits. Because animal reproductive studies are not always predictive of human response, KALBITOR should be used during pregnancy only if clearly needed.
- In rats, intravenous KALBITOR at an intravenous dose approximately 13 times the maximum recommended human dose (MRHD) (on a mg/kg basis at a maternal dose of 15 mg/kg/day in rats) caused increased numbers of early resorptions and percentages of resorbed conceptuses per litter in the presence of mild maternal toxicity. No development toxicity was observed in rats that received an intravenous dose approximately 8 times the MRHD (on a mg/kg basis at a maternal dose of 10 mg/kg/day in rats). There were no adverse effects of KALBITOR on embryofetal development in rats that received subcutaneous doses up to approximately 2.4 times the MRHD (on an AUC basis at a maternal dose of 20 mg/kg/day in rats), and in rabbits that received intravenous doses up to approximately 6 times the MRHD (on an AUC basis at a maternal dose of 5 mg/kg/day in rabbits).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ecallantide in women who are pregnant.
### Labor and Delivery
- No information is available on the effects of KALBITOR during labor and delivery.
### Nursing Mothers
- It is not known whether ecallantide is excreted in human milk. Caution should be exercised when ecallantide is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of KALBITOR have been established in patients 12 to 17 years of age. The efficacy of KALBITOR in the 12-15 year age group is extrapolated from efficacy in patients 16 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and adolescents [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. The safety profile observed in pediatric patients 12-17 years of age was similar to the adverse reactions observed in the overall clinical trial population [see Adverse Reactions (6.1)].
Safety and effectiveness of KALBITOR in patients less than 12 years of age have not been established.
### Geriatic Use
- Clinical trials of KALBITOR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Ecallantide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ecallantide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ecallantide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ecallantide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ecallantide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ecallantide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
- KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.
- KALBITOR should be refrigerated and protected from the light. KALBITOR is a clear, colorless liquid; visually inspect each vial for particulate matter and discoloration prior to administration. If there is particulate matter or discoloration, the vial should not be used.
- Using aseptic technique, withdraw 1 mL (10 mg) of KALBITOR from the vial using a large bore needle. Change the needle on the syringe to a needle suitable for subcutaneous injection. The recommended needle size is 27 gauge. Inject KALBITOR into the skin of the abdomen, thigh, or upper arm. Repeat the procedure for each of the 3 vials comprising the KALBITOR dose. The injection site for each of the injections may be in the same or in different anatomic locations (abdomen, thigh, upper arm). There is no need for site rotation. Injection sites should be separated by at least 2 inches (5 cm) and away from the anatomical site of attack.
- The same instructions apply to an additional dose administered within 24 hours. Different injection sites or the same anatomical location (as used for the first administration) may be used.
### Monitoring
- Given the similarity in hypersensitivity symptoms and acute HAE symptoms, patients should be monitored closely in the event of a hypersensitivity reaction.
# IV Compatibility
There is limited information regarding IV Compatibility of Ecallantide in the drug label.
# Overdosage
- There have been no reports of overdose with KALBITOR. HAE patients have received single doses up to 90 mg intravenously without evidence of dose-related toxicity.
# Pharmacology
## Mechanism of Action
- Hereditary angioedema (HAE) is a rare genetic disorder caused by mutations to C1-esterase-inhibitor (C1-INH) located on Chromosome 11q and inherited as an autosomal dominant trait. HAE is characterized by low levels of C1-INH activity and low levels of C4. C1-INH functions to regulate the activation of the complement and intrinsic coagulation (contact system pathway) and is a major endogenous inhibitor of plasma kallikrein. The kallikrein-kinin system is a complex proteolytic cascade involved in the initiation of both inflammatory and coagulation pathways. One critical aspect of this pathway is the conversion of High Molecular Weight (HMW) kininogen to bradykinin by the protease plasma kallikrein. In HAE, normal regulation of plasma kallikrein activity and the classical complement cascade is therefore not present. During attacks, unregulated activity of plasma kallikrein results in excessive bradykinin generation. Bradykinin is a vasodilator which is thought by some to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain.
- KALBITOR is a potent (Ki = 25 pM), selective, reversible inhibitor of plasma kallikrein. KALBITOR binds to plasma kallikrein and blocks its binding site, inhibiting the conversion of HMW kininogen to bradykinin. By directly inhibiting plasma kallikrein, KALBITOR reduces the conversion of HMW kininogen to bradykinin and thereby treats symptoms of the disease during acute episodic attacks of HAE.
## Structure
- KALBITOR (ecallantide) is a human plasma kallikrein inhibitor for injection for subcutaneous use. Ecallantide is a 60-amino-acid protein produced in Pichia pastoris yeast cells by recombinant DNA technology.
- KALBITOR is a clear and colorless, sterile, and nonpyrogenic solution. Each vial contains 10 mg ecallantide as the active ingredient, and the following inactive ingredients: 0.76 mg disodium hydrogen orthophosphate (dihydrate), 0.2 mg monopotassium phosphate, 0.2 mg potassium chloride, and 8 mg sodium chloride in water for injection, USP. KALBITOR is preservative free, with a pH of approximately 7.0. A 30 mg dose is supplied as 3 vials each containing 1 mL of 10 mg/mL KALBITOR. Vials are intended for single use.
## Pharmacodynamics
- No exposure-response relationships for KALBITOR to components of the complement or kallikrein-kinin pathways have been established.
- The effect of KALBITOR on activated partial thromboplastin time (aPTT) was measured because of potential effect on the intrinsic coagulation pathway. Prolongation of aPTT has been observed following intravenous dosing of KALBITOR at doses ≥20 mg/m2. At 80 mg administered intravenously in healthy subjects, aPTT values were prolonged approximately two-fold over baseline values and returned to normal by 4 hours post-dose.
- For patients taking KALBITOR, no significant QT prolongation has been seen. In a randomized, placebo-controlled trial (EDEMA4) studying the 30 mg subcutaneous dose versus placebo, 12-lead ECGs were obtained at baseline, 2 hours and 4 hours post-dose (covering the time of expected Cmax), and at follow-up (day 7). ECGs were evaluated for PR interval, QRS complex, and QTc interval. KALBITOR had no significant effect on the QTc interval, heart rate, or any other components of the ECG.
## Pharmacokinetics
- Following the administration of a single 30 mg subcutaneous dose of KALBITOR to healthy subjects, a mean (± standard deviation) maximum plasma concentration of 586 ± 106 ng/mL was observed approximately 2 to 3 hours post-dose. The mean area under the concentration-time curve was 3017 ± 402 ng*hr/mL. Following administration, plasma concentration declined with a mean elimination half-life of 2.0 ± 0.5 hours. Plasma clearance was 153 ± 20 mL/min and the volume of distribution was 26.4 ± 7.8 L. Based on a population pharmacokinetic analysis, body weight, age, and gender were not found to affect KALBITOR exposure significantly. Ecallantide is a small protein (7054 Da) and renal elimination in the urine of treated subjects has been demonstrated.
- No pharmacokinetic data are available in patients or subjects with hepatic or renal impairment.
## Nonclinical Toxicology
- A two-year study was conducted in rats to assess the carcinogenic potential of KALBITOR. No evidence of tumorigenicity was observed in rats at ecallantide doses up to 10 mg/kg administered subcutaneously every three days (approximately 2-fold greater than the MRHD on an AUC basis).
- KALBITOR had no effects on fertility and reproductive performance in rats at subcutaneous doses up to 25 mg/kg/day (approximately 21 times the MRHD on a mg/kg basis).
# Clinical Studies
- The safety and efficacy of KALBITOR to treat acute attacks of hereditary angioedema in adolescents and adults were evaluated in 2 randomized, double-blind, placebo-controlled trials (EDEMA4 and EDEMA3) in 168 patients with HAE. Patients having an attack of hereditary angioedema, at any anatomic location, with at least 1 moderate or severe symptom, were treated with 30 mg subcutaneous KALBITOR or placebo. Because patients could participate in both trials, a total of 143 unique patients participated. Of the 143 patients, 94 were female, 123 were Caucasian, and the mean age was 36 years (range 11-77). There were 64 patients with abdominal attacks, 55 with peripheral attacks, and 24 with laryngeal attacks.
- In both trials, the effects of KALBITOR were evaluated using the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS). These endpoints evaluated attack severity (MSCS) and patient response to treatment (TOS) for an acute HAE attack.
- MSCS score is a point-in-time measure of symptom severity. At baseline, and post-dosing at 4 hours and 24 hours, patients rated the severity of each affected symptom on a categorical scale (0 = normal, 1 = mild, 2 = moderate, 3 = severe). Patient-reported severity was based on each patient’s assessment of symptom impact on their ability to perform routine activities. Ratings were averaged to obtain the MSCS score. The endpoint was reported as the change in MSCS score from baseline. A decrease in MSCS score reflected an improvement in symptom severity; the maximum possible change toward improvement was -3.
- TOS is a measure of symptom response to treatment. At 4 hours and 24 hours post-dosing, patient assessment of response for each anatomic site of attack involvement was recorded on a categorical scale (significant improvement [100], improvement [50], same [0], worsening [-50], significant worsening [-100]). The response at each anatomic site was weighted by baseline severity and then the weighted scores across all involved sites were averaged to calculate the TOS. A TOS value >0 reflected an improvement in symptoms from baseline. The maximum possible score was +100.
- EDEMA4 was a randomized, double-blind, placebo-controlled trial in which 96 patients were randomized 1:1 to receive KALBITOR 30 mg subcutaneous or placebo for acute attacks of HAE. The primary endpoint was the change from baseline in MSCS score at 4 hours, and the TOS at 4 hours was a key secondary endpoint. Patients treated with KALBITOR demonstrated a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients with placebo and the results were statistically significant (Table 2). At 24 hours, patients treated with KALBITOR also demonstrated a greater decrease from baseline in the MSCS than placebo (-1.5 vs. -1.1; p = 0.04) and a greater TOS (89 vs. 55, p = 0.03).
- More patients in the placebo group (24/48, 50%) required medical intervention to treat unresolved symptoms within 24 hours compared to the KALBITOR-treated group (16/48, 33%).
- Some patients reported improvement following a second 30 mg subcutaneous dose of KALBITOR, administered within 24 hours following the initial dose for symptom persistence or relapse, but efficacy was not systematically assessed for the second dose.
- EDEMA3 was a randomized, double-blind, placebo-controlled trial in which 72 patients were randomized 1:1 to receive KALBITOR or placebo for acute attacks of HAE. EDEMA3 was similar in design to EDEMA4 with the exception of the order of the prespecified efficacy endpoints. In EDEMA3, the primary endpoint was the TOS at 4 hours, and the key secondary efficacy endpoint was the change from baseline in MSCS at 4 hours. As in EDEMA4, patients treated with KALBITOR demonstrated a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients treated with placebo and the results were statistically significant (Table 2).
- In addition, more patients in the placebo group (13/36, 36%) required medical intervention to treat unresolved symptoms within 24 hours compared to the KALBITOR-treated group (5/36, 14%).
# How Supplied
- KALBITOR (ecallantide) is supplied as three 10 mg/mL single-use vials packaged in a carton. Each vial contains 10 mg of ecallantide. Each vial contains a slight overfill.
## Storage
- KALBITOR should be kept refrigerated (2ºC to 8ºC/36ºF to 46ºF). Vials removed from refrigeration should be stored below 86ºF/30ºC and used within 14 days or returned to refrigeration until use.
- Protect vials from light until use.
- Do not use beyond the expiration date.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
Kalbitor ecallantide 10 mg/mL 3 Vials
NDC: 47783-101-01
### Ingredients and Appearance
# Patient Counseling Information
- Advise patients that KALBITOR may cause anaphylaxis and other hypersensitivity reactions. Advise patients that KALBITOR should be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema. Instruct patients who have known clinical hypersensitivity to KALBITOR not to receive additional doses of KALBITOR. [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]
Advise patients to consult the Medication Guide for additional information regarding the risk of anaphylaxis and other hypersensitivity reactions.
### MEDICATION GUIDE
(ecallantide)
- Read this Medication Guide before you start receiving KALBITOR and before each treatment. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or your treatment.
- Serious allergic reactions may happen in some people who receive KALBITOR. These allergic reactions can be life-threatening and usually happen within 1 hour after receiving KALBITOR.
- KALBITOR should be given to you by a doctor or nurse in a healthcare setting where serious allergic reactions and hereditary angioedema (HAE) can be treated.
- Symptoms of a serious allergic reaction to KALBITOR can be similar to the symptoms of HAE, the condition that you are being treated for. Your doctor or nurse should watch you for any signs of a serious allergic reaction after treatment with KALBITOR.
- Tell your doctor or nurse right away if you have any of these symptoms of a serious allergic reaction during or after treatment with KALBITOR:
- wheezing, shortness of breath, cough, chest tightness, or trouble breathing
- dizziness, fainting, fast or weak heartbeat, or feeling nervous
- reddening of the face, itching, hives, or feeling warm
- swelling of the throat or tongue, throat tightness, hoarse voice, or trouble swallowing
- runny nose, nasal congestion, or sneezing
- KALBITOR is a prescription medicine used to treat sudden attacks of hereditary angioedema (HAE) in people 12 years of age and older.
- KALBITOR is not a cure for HAE.
- It is not known if KALBITOR is safe and effective in children under 12 years of age.
- Do not receive KALBITOR if you are allergic to KALBITOR.
- Before receiving KALBITOR, tell your doctor if you:
- have ever had an allergic reaction to KALBITOR. See “Who should not receive KALBITOR?”
- are pregnant or plan to become pregnant. It is not known if KALBITOR will harm your unborn baby.
- are breast-feeding or plan to breast-feed. It is not known if KALBITOR passes into your breast milk.
- Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
- Know the medicines you take. Keep a list of them to show to your doctor and pharmacist when you get a new medicine.
- For each dose, you will receive 3 injections just under the skin (subcutaneous or SC injections) of your abdomen, thigh, or upper arm.
- KALBITOR can cause serious allergic reactions. See "What is the most important information I should know about KALBITOR?"
- Common side effects of KALBITOR include:
- headache
- nausea
- diarrhea
- fever
- injection site reactions, such as redness, rash, swelling, itching, or bruising
- stuffy nose
- Call your doctor for advice about side effects. You may report side effects to FDA at 1‑800-FDA-1088.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. This Medication Guide gives you the most important information about KALBITOR. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about KALBITOR that is written for health professionals.
- Active Ingredient: ecallantide
- Inactive ingredients: disodium hydrogen orthophosphate (dihydrate), monopotassium phosphate, potassium chloride, sodium chloride in water for injection.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Alcohol-Ecallantide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Kalbitor®[1]
# Look-Alike Drug Names
There is limited information regarding Ecallantide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ecallantide | |
f4fd2d240fe395c2bbd4d44b78fa3ecd7e184136 | wikidoc | Echinostoma | Echinostoma
Echinostoma is an important genus that includes many parasites. Species listed under the echinostoma name include:
Human echinostomiasis is an intestinal parasitic disease caused by one of at least sixteen trematode flukes from the genus Echinostoma. Found largely in southeast Asia and the Far East, echinostomiasis is transmitted through the ingestion of one of several possible intermediate hosts, which could include snails or other mollusks, certain fresh water fish, crustaceans or amphibians. These flukes are of moderate size and are distinguished by an oral sucker surrounded by a characteristic collar of spines.
Upon infection of the human host, the worms aggregate in the small intestine where they may cause no symptoms, mild symptoms, or severe symptoms in rare cases, depending on the number of worms present. Effective drugs for treatment do exist, but the disease still remains a problem in endemic areas. What's more, prevention and control is possible through measures such as health education, altered eating habits so as not to include ingestion of raw fish, mollusks and other sources of the disease, and alteration of the environment for removal of wastewater and industrial discharge that may be home to the parasite.
Use the links at the left to navigate through the various pages that explain different aspects of echinostomiasis and the parasitic echinostomes that cause it. (attribution: Peter Rowe)
- Echinostoma caproni
- Echinostoma echinatum
- Echinostoma friedi
- Echinostoma jurini
- Echinostoma luisyrei
- Echinostoma miyagawai
- Echinostoma paraensei
- Echinostoma parvocirris
- Echinostoma revolutum
- Echinostoma trivolvis | Echinostoma
Echinostoma is an important genus that includes many parasites. Species listed under the echinostoma name include:
Human echinostomiasis is an intestinal parasitic disease caused by one of at least sixteen trematode flukes from the genus Echinostoma. Found largely in southeast Asia and the Far East, echinostomiasis is transmitted through the ingestion of one of several possible intermediate hosts, which could include snails or other mollusks, certain fresh water fish, crustaceans or amphibians. These flukes are of moderate size and are distinguished by an oral sucker surrounded by a characteristic collar of spines.
Upon infection of the human host, the worms aggregate in the small intestine where they may cause no symptoms, mild symptoms, or severe symptoms in rare cases, depending on the number of worms present. Effective drugs for treatment do exist, but the disease still remains a problem in endemic areas. What's more, prevention and control is possible through measures such as health education, altered eating habits so as not to include ingestion of raw fish, mollusks and other sources of the disease, and alteration of the environment for removal of wastewater and industrial discharge that may be home to the parasite.
Use the links at the left to navigate through the various pages that explain different aspects of echinostomiasis and the parasitic echinostomes that cause it. (attribution: Peter Rowe)
- Echinostoma caproni
- Echinostoma echinatum
- Echinostoma friedi
- Echinostoma jurini
- Echinostoma luisyrei
- Echinostoma miyagawai
- Echinostoma paraensei
- Echinostoma parvocirris
- Echinostoma revolutum
- Echinostoma trivolvis
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Echinostoma | |
efec9a538d7d7ff377c7c4d03b35ec9aceb2007c | wikidoc | Ecothiopate | Ecothiopate
# Overview
Echothiophate (Phospholine) is a parasympathomimetic and a phosphorothioate. It is an irreversible acetylcholinesterase inhibitor.
# Uses
It is used as an ocular antihypertensive in the treatment of chronic glaucoma and, in some cases, accommodative esotropia. It is available under several trade names such as Phospholine Iodide (Wyeth-Ayerst).
Echothiophate binds irreversibly to cholinesterase. Because of the very slow rate at which echothiophate is hydrolyzed by cholinesterase, its effects can last a week or more. Adverse effects include muscle spasm and other systemic effects.
# Mechanism of action
It covalently binds by its phosphate group to serine group at the active site of the cholinesterase. Once bound, the enzyme is permanently inactive and the cell has to make new enzymes.
# Shortage
Wyeth Pharmaceuticals stopped manufacturing echothiophate iodide in the US in 2003. After contacting the American Academy of Ophthalmology (AAO), Wyeth rescinded their decision and, according to AAO public relations representative Michelle Stephens, the AAO and Wyeth were in talks for about a year about manufacturing it.
In the meantime, a worldwide shortage of the drug has occurred.
# Chemistry
Echothiophate is made by reacting diethylchlorophosphoric acid with 2-dimethylaminoethylmercaptan, giving S-(2-dimethylaminoethyl)-O,O-diethylthiophosphate, which is alkylated by methyl iodide, forming echothiophate. | Ecothiopate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Echothiophate (Phospholine) is a parasympathomimetic and a phosphorothioate. It is an irreversible acetylcholinesterase inhibitor.[1]
# Uses
It is used as an ocular antihypertensive in the treatment of chronic glaucoma and, in some cases, accommodative esotropia. It is available under several trade names such as Phospholine Iodide (Wyeth-Ayerst).
Echothiophate binds irreversibly to cholinesterase. Because of the very slow rate at which echothiophate is hydrolyzed by cholinesterase, its effects can last a week or more. Adverse effects include muscle spasm and other systemic effects.
# Mechanism of action
It covalently binds by its phosphate group to serine group at the active site of the cholinesterase. Once bound, the enzyme is permanently inactive and the cell has to make new enzymes.
# Shortage
Wyeth Pharmaceuticals stopped manufacturing echothiophate iodide in the US in 2003. After contacting the American Academy of Ophthalmology (AAO), Wyeth rescinded their decision and, according to AAO public relations representative Michelle Stephens, the AAO and Wyeth were in talks for about a year about manufacturing it. [2]
In the meantime, a worldwide shortage of the drug has occurred.
# Chemistry
Echothiophate is made by reacting diethylchlorophosphoric acid with 2-dimethylaminoethylmercaptan, giving S-(2-dimethylaminoethyl)-O,O-diethylthiophosphate, which is alkylated by methyl iodide, forming echothiophate.[3] | https://www.wikidoc.org/index.php/Ecothiopate | |
c30f2da58b69ae28a05a2f3403bda2b1a1463db3 | wikidoc | Edrecolomab | Edrecolomab
# Overview
Edrecolomab (MAb17-1A, trade name Panorex) is a mouse-derived monoclonal antibody targeting the cell-surface glycoprotein EpCAM (17-1A), which is expressed on epithelial tissues and on various carcinomas.
Preliminary studies had shown promise of a possible use in patients with stage III colorectal carcinoma (with metastasis to the lymph nodes). However, when put to a phase III study (2,761 patients) it did not provide any benefit when compared to conventional chemotherapeutic agents. No effect has been demonstrated for stage II (locally advanced cancer without spread to the lymph nodes) colon cancer.
Edrecolomab was well tolerated in these studies and as such research has now concentrated on whether it can be of any use in other forms of cancer. | Edrecolomab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Edrecolomab (MAb17-1A, trade name Panorex) is a mouse-derived monoclonal antibody targeting the cell-surface glycoprotein EpCAM (17-1A), which is expressed on epithelial tissues and on various carcinomas.
Preliminary studies had shown promise of a possible use in patients with stage III colorectal carcinoma (with metastasis to the lymph nodes).[1][2] However, when put to a phase III study (2,761 patients) it did not provide any benefit when compared to conventional chemotherapeutic agents.[3] No effect has been demonstrated for stage II (locally advanced cancer without spread to the lymph nodes) colon cancer.[4]
Edrecolomab was well tolerated in these studies and as such research has now concentrated on whether it can be of any use in other forms of cancer. | https://www.wikidoc.org/index.php/Edrecolomab | |
ad0db381f48eb08b2a7ab45f055a4a6540d57bc5 | wikidoc | Edrophonium | Edrophonium
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Edrophonium is a Cholinesterase Inhibitor that is FDA approved for the diagnosis of myasthenia gravis and treatment of respiratory depression caused by curare overdosage. Common adverse reactions include Bradyarrhythmia, Hypotension, Sweating, Abnormal gastric secretion, Diarrhea, Dysphagia, Excessive salivation, Nausea, Vomiting, Seizure, Excessive tear production, Increased frequency of urination.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ENLON is recommended for the differential diagnosis of myasthenia gravis and as an adjunct in the evaluation of treatment requirements in this disease. It may also be used for evaluating emergency treatment in myasthenic crises. Because of its brief duration of action, it is not recommended for maintenance therapy in myasthenia gravis.
- ENLON is also useful whenever a curare antagonist is needed to reverse the neuromuscular block produced by curare, tubocurarine, gallamine triethiodide or dimethyl-tubocurarine. It is not effective against decamethonium bromide and succinylcholine chloride. It may be used adjunctively in the treatment of respiratory depression caused by curare overdosage.
### Dosage
- ENLON Test in the Differential Diagnosis of Myasthenia Gravis 1-8
- A tuberculin syringe containing 1 mL (10 mg) of ENLON is prepared with an intravenous needle, and 0.2 mL (2 mg) is injected intravenously within 15 to 30 seconds. The needle is left in situ. Only if no reaction occurs after 45 seconds is the remaining 0.8 mL (8 mg) injected. If a cholinergic reaction (muscarinic side effects, skeletal muscle fasciculations and increased muscle weakness) occurs after injection of 0.2 mL (2 mg), the test is discontinued and atropine sulfate, 0.4 mg to 0.5 mg, is administered intravenously. After one-half hour the test may be repeated.
- In adults with inaccessible veins, dosage for intramuscular injection is 1 mL (10 mg) of ENLON. Subjects who demonstrate hyperreactivity to this injection (cholinergic reaction), should be retested after one-half hour with 0.2 mL (2 mg) of ENLON intramuscularly to rule out false-negative reactions.
- The recommended dose is 0.1 mL to 0.2 mL (1 mg to 2 mg) of ENLON, administered intravenously one hour after oral intake of the drug being used in treatment.1-5 Response will be myasthenic in the undertreated patient, adequate in the controlled patient, and cholinergic in the overtreated patient. Responses to ENLON in myasthenic and nonmyasthenic individuals are summarized in the following chart.
- The term crisis is applied to the myasthenic whenever severe respiratory distress with objective ventilatory inadequacy occurs and the response to medication is not predictable. This state may be secondary to a sudden increase in severity of myasthenia gravis (myasthenic crisis), or to overtreatment with anticholinesterase drugs (cholinergic crisis).
- When a patient is apneic, controlled ventilation must be secured immediately in order to avoid cardiac arrest and irreversible central nervous system damage. No attempt is made to test with ENLON until respiratory exchange is adequate.
- Dosage used at this time is most important: If the patient is cholinergic, ENLON will cause increased oropharyngeal secretions and further weakness in the muscles of respiration. If the crisis is myasthenic, the test clearly improves respiration and the patient can be treated with longer-acting intravenous anticholinesterase medication. When the test is performed, there should not be more than 0.2 mL (2 mg) ENLON in the syringe. An intravenous dose of 0.1 mL (1 mg) is given initially. The patient’s heart action is carefully observed. If, after an interval of one minute, this dose does not further impair the patient, the remaining 0.1 mL (1 mg) can be injected. If no clear improvement of respiration occurs after 0.2 mL (2 mg) dose, it is usually wisest to discontinue all anticholinesterase drug therapy and secure controlled ventilation by tracheostomy with assisted respiration.5
### For Use as a Curare Antagonist
- ENLON should be administered by intravenous injection in 1 mL (10 mg) doses given slowly over a period of 30 to 45 seconds so that the onset of cholinergic reaction can be detected. This dosage may be repeated whenever necessary. The maximal dose for any one patient should be 4 mL (40 mg). Because of its brief effect, ENLON should not be given prior to the administration of curare, tubocurarine, gallamine triethiodide or dimethyl-tubocurarine: it should be used at the time when its effect is needed. When given to counteract curare overdosage, the effect of each dose on the respiration should be carefully observed before it is repeated, and assisted ventilation should always be employed.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Edrophonium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Edrophonium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indication
- Myasthenia gravis (diagnosis)
### Dosage
- The intravenous testing dose of ENLON in children weighing up to 75 lbs is 0.1 mL (1 mg); above this weight, the dose is 0.2 mL (2 mg). If there is no response after 45 seconds, it may be titrated up to 0.5 mL (5 mg) in children under 75 lbs, given in increments of 0.1 mL (1 mg) every 30 to 45 seconds and up to 1 mL (10 mg) in heavier children. In infants, the recommended dose is 0.05 mL (0.5 mg). Because of technical difficulty with intravenous injection in children, the intramuscular route may be used. In children weighing up to 75 lbs, 0.2 mL (2 mg) is injected intramuscularly. In children weighing more than 75 lbs, 0.5 mL (5 mg) is injected intramuscularly. All signs which would appear with the intravenous test appears with the intramuscular test except that there is a delay of two to ten minutes before a reaction is noted.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Edrophonium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Edrophonium in pediatric patients.
# Contraindications
- Known hypersensitivity to anticholinesterase agents; intestinal and urinary obstructions of mechanical type.
# Warnings
- Whenever anticholinesterase drugs are used for testing, a syringe containing 1 mg of atropine sulfate should be immediately available to be given in aliquots intravenously to counteract severe cholinergic reactions which may occur in the hypersensitive individual, whether he is normal or myasthenic. ENLON should be used with caution in patients with bronchial asthma or cardiac dysrhythmias. The transient bradycardia which sometimes occurs can be relieved by atropine sulfate. Isolated instances of cardiac and respiratory arrest following administration of ENLON have been reported. It is postulated that these are vagotonic effects.
- Contains sodium sulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
- The safety of ENLON during pregnancy or lactation in humans has not been established. Therefore, use of ENLON in women who may become pregnant requires weighing the drug’s potential benefits against its possible hazards to mother and child.
### Precautions
- Patients may develop “anticholinesterase insensitivity” for brief or prolonged periods. During these periods the patients should be carefully monitored and may need respiratory assistance. Dosages of anticholinesterase drugs should be reduced or withheld until patients again become sensitive to them.
# Adverse Reactions
## Clinical Trials Experience
- Careful observation should be made for severe cholinergic reactions in the hyperreactive individual. The myasthenic patient in crisis who is being tested with ENLON should be observed for bradycardia or cardiac standstill and cholinergic reactions if an overdose is given.
- The following reactions common to anticholinesterase agents may occur, although not all of these reactions have been reported with the administration of ENLON, probably because of its short duration of action and limited indications:
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Edrophonium in the drug label.
# Drug Interactions
- Care should be given when administering this drug to patients with symptoms of myasthenic weakness who are also on anticholinesterase drugs. Since symptoms of anticholinesterase overdose (cholinergic crisis) may mimic underdosage (myasthenic weakness), their condition may be worsened by the use of this drug.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- The safety of ENLON during pregnancy or lactation in humans has not been established. Therefore, use of ENLON in women who may become pregnant requires weighing the drug’s potential benefits against its possible hazards to mother and child.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Edrophonium in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Edrophonium during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Edrophonium with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Edrophonium with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Edrophonium with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Edrophonium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Edrophonium with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Edrophonium in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Edrophonium in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Edrophonium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Edrophonium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Intramuscular
### Monitoring
There is limited information regarding Monitoring of Edrophonium in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Edrophonium in the drug label.
# Overdosage
- With drugs of this type, muscarine-like symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions and bradycardia) often appear with overdosage (cholinergic crisis). An important complication that can arise is obstruction of the airway by bronchial secretions. These may be managed with suction (especially if tracheostomy has been performed) and by the use of atropine. Many experts have advocated a wide range of dosages of atropine (for ENLON, see atropine dosage below), but if there are copious secretions, up to 1.2 mg intravenously may be given initially and repeated every 20 minutes until secretions are controlled. Signs of atropine overdosage such as dry mouth, flush and tachycardia should be avoided as tenacious secretions and bronchial plugs may form. A total dose of atropine of 5 to 10 mg or even more may be required. The following steps should be taken in the management of overdosage of ENLON:
- Adequate respiratory exchange should be maintained by assuring an open airway and by the use of assisted respiration augmented by oxygen.
Cardiac function should be monitored until complete stabilization has been achieved
- Atropine sulfate in doses of 0.4 to 0.5 mg should be administered intravenously. This may be repeated every 3 to 10 minutes. Because of the short duration of action of ENLON the total dose required will seldom exceed 2 mg.
Pralidoxime chloride (a cholinesterase reactivator) may be given intravenously at the rate of 50 to 100 mg per minute; usually the total dose does not exceed 1000 mg. Extreme caution should be exercised in the use of pralidoxime chloride when the cholinergic symptoms are induced by double-bond phosphorous anticholinesterase drugs. 9
If convulsions occur or shock is present, appropriate measures should be instituted.
# Pharmacology
## Mechanism of Action
- ENLON is an anticholinesterase drug. Its pharmacologic action is due primarily to the inhibition or inactivation of acetylcholinesterase at sites of cholinergic transmission. Its effect is manifest within 30 to 60 seconds after injection and lasts an average of 10 minutes.
## Structure
- ENLON is a short and rapid-acting cholinergic drug. Chemically, edrophonium chloride is ethyl(m-hydroxyphenyl) dimethylammonium chloride and its structural formula is:
- Each mL contains, in a sterile solution, 10 mg edrophonium chloride compounded with 0.45% phenol as a preservative, and 0.2% sodium sulfite as an antioxidant, buffered with sodium citrate and citric acid, and pH adjusted to approximately 5.4.
ENLON is intended for IV and IM use.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Edrophonium in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Edrophonium in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Edrophonium in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Edrophonium in the drug label.
# How Supplied
- ENLON (edrophonium chloride injection, USP):
NDC 10019-873-15 15 mL vials
## Storage
- ENLON (edrophonium chloride injection, USP) should be stored at controlled room temperature 15º-30ºC (59º-86ºF)
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Edrophonium in the drug label.
# Precautions with Alcohol
- Alcohol-Edrophonium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Enlon®
# Look-Alike Drug Names
There is limited information regarding Edrophonium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Edrophonium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
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# Overview
Edrophonium is a Cholinesterase Inhibitor that is FDA approved for the diagnosis of myasthenia gravis and treatment of respiratory depression caused by curare overdosage. Common adverse reactions include Bradyarrhythmia, Hypotension, Sweating, Abnormal gastric secretion, Diarrhea, Dysphagia, Excessive salivation, Nausea, Vomiting, Seizure, Excessive tear production, Increased frequency of urination.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ENLON is recommended for the differential diagnosis of myasthenia gravis and as an adjunct in the evaluation of treatment requirements in this disease. It may also be used for evaluating emergency treatment in myasthenic crises. Because of its brief duration of action, it is not recommended for maintenance therapy in myasthenia gravis.
- ENLON is also useful whenever a curare antagonist is needed to reverse the neuromuscular block produced by curare, tubocurarine, gallamine triethiodide or dimethyl-tubocurarine. It is not effective against decamethonium bromide and succinylcholine chloride. It may be used adjunctively in the treatment of respiratory depression caused by curare overdosage.
### Dosage
- ENLON Test in the Differential Diagnosis of Myasthenia Gravis 1-8
- A tuberculin syringe containing 1 mL (10 mg) of ENLON is prepared with an intravenous needle, and 0.2 mL (2 mg) is injected intravenously within 15 to 30 seconds. The needle is left in situ. Only if no reaction occurs after 45 seconds is the remaining 0.8 mL (8 mg) injected. If a cholinergic reaction (muscarinic side effects, skeletal muscle fasciculations and increased muscle weakness) occurs after injection of 0.2 mL (2 mg), the test is discontinued and atropine sulfate, 0.4 mg to 0.5 mg, is administered intravenously. After one-half hour the test may be repeated.
- In adults with inaccessible veins, dosage for intramuscular injection is 1 mL (10 mg) of ENLON. Subjects who demonstrate hyperreactivity to this injection (cholinergic reaction), should be retested after one-half hour with 0.2 mL (2 mg) of ENLON intramuscularly to rule out false-negative reactions.
- The recommended dose is 0.1 mL to 0.2 mL (1 mg to 2 mg) of ENLON, administered intravenously one hour after oral intake of the drug being used in treatment.1-5 Response will be myasthenic in the undertreated patient, adequate in the controlled patient, and cholinergic in the overtreated patient. Responses to ENLON in myasthenic and nonmyasthenic individuals are summarized in the following chart.
- The term crisis is applied to the myasthenic whenever severe respiratory distress with objective ventilatory inadequacy occurs and the response to medication is not predictable. This state may be secondary to a sudden increase in severity of myasthenia gravis (myasthenic crisis), or to overtreatment with anticholinesterase drugs (cholinergic crisis).
- When a patient is apneic, controlled ventilation must be secured immediately in order to avoid cardiac arrest and irreversible central nervous system damage. No attempt is made to test with ENLON until respiratory exchange is adequate.
- Dosage used at this time is most important: If the patient is cholinergic, ENLON will cause increased oropharyngeal secretions and further weakness in the muscles of respiration. If the crisis is myasthenic, the test clearly improves respiration and the patient can be treated with longer-acting intravenous anticholinesterase medication. When the test is performed, there should not be more than 0.2 mL (2 mg) ENLON in the syringe. An intravenous dose of 0.1 mL (1 mg) is given initially. The patient’s heart action is carefully observed. If, after an interval of one minute, this dose does not further impair the patient, the remaining 0.1 mL (1 mg) can be injected. If no clear improvement of respiration occurs after 0.2 mL (2 mg) dose, it is usually wisest to discontinue all anticholinesterase drug therapy and secure controlled ventilation by tracheostomy with assisted respiration.5
### For Use as a Curare Antagonist
- ENLON should be administered by intravenous injection in 1 mL (10 mg) doses given slowly over a period of 30 to 45 seconds so that the onset of cholinergic reaction can be detected. This dosage may be repeated whenever necessary. The maximal dose for any one patient should be 4 mL (40 mg). Because of its brief effect, ENLON should not be given prior to the administration of curare, tubocurarine, gallamine triethiodide or dimethyl-tubocurarine: it should be used at the time when its effect is needed. When given to counteract curare overdosage, the effect of each dose on the respiration should be carefully observed before it is repeated, and assisted ventilation should always be employed.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Edrophonium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Edrophonium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indication
- Myasthenia gravis (diagnosis)
### Dosage
- The intravenous testing dose of ENLON in children weighing up to 75 lbs is 0.1 mL (1 mg); above this weight, the dose is 0.2 mL (2 mg). If there is no response after 45 seconds, it may be titrated up to 0.5 mL (5 mg) in children under 75 lbs, given in increments of 0.1 mL (1 mg) every 30 to 45 seconds and up to 1 mL (10 mg) in heavier children. In infants, the recommended dose is 0.05 mL (0.5 mg). Because of technical difficulty with intravenous injection in children, the intramuscular route may be used. In children weighing up to 75 lbs, 0.2 mL (2 mg) is injected intramuscularly. In children weighing more than 75 lbs, 0.5 mL (5 mg) is injected intramuscularly. All signs which would appear with the intravenous test appears with the intramuscular test except that there is a delay of two to ten minutes before a reaction is noted.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Edrophonium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Edrophonium in pediatric patients.
# Contraindications
- Known hypersensitivity to anticholinesterase agents; intestinal and urinary obstructions of mechanical type.
# Warnings
- Whenever anticholinesterase drugs are used for testing, a syringe containing 1 mg of atropine sulfate should be immediately available to be given in aliquots intravenously to counteract severe cholinergic reactions which may occur in the hypersensitive individual, whether he is normal or myasthenic. ENLON should be used with caution in patients with bronchial asthma or cardiac dysrhythmias. The transient bradycardia which sometimes occurs can be relieved by atropine sulfate. Isolated instances of cardiac and respiratory arrest following administration of ENLON have been reported. It is postulated that these are vagotonic effects.
- Contains sodium sulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
- The safety of ENLON during pregnancy or lactation in humans has not been established. Therefore, use of ENLON in women who may become pregnant requires weighing the drug’s potential benefits against its possible hazards to mother and child.
### Precautions
- Patients may develop “anticholinesterase insensitivity” for brief or prolonged periods. During these periods the patients should be carefully monitored and may need respiratory assistance. Dosages of anticholinesterase drugs should be reduced or withheld until patients again become sensitive to them.
# Adverse Reactions
## Clinical Trials Experience
- Careful observation should be made for severe cholinergic reactions in the hyperreactive individual. The myasthenic patient in crisis who is being tested with ENLON should be observed for bradycardia or cardiac standstill and cholinergic reactions if an overdose is given.
- The following reactions common to anticholinesterase agents may occur, although not all of these reactions have been reported with the administration of ENLON, probably because of its short duration of action and limited indications:
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Edrophonium in the drug label.
# Drug Interactions
- Care should be given when administering this drug to patients with symptoms of myasthenic weakness who are also on anticholinesterase drugs. Since symptoms of anticholinesterase overdose (cholinergic crisis) may mimic underdosage (myasthenic weakness), their condition may be worsened by the use of this drug.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- The safety of ENLON during pregnancy or lactation in humans has not been established. Therefore, use of ENLON in women who may become pregnant requires weighing the drug’s potential benefits against its possible hazards to mother and child.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Edrophonium in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Edrophonium during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Edrophonium with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Edrophonium with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Edrophonium with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Edrophonium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Edrophonium with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Edrophonium in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Edrophonium in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Edrophonium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Edrophonium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Intramuscular
### Monitoring
There is limited information regarding Monitoring of Edrophonium in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Edrophonium in the drug label.
# Overdosage
- With drugs of this type, muscarine-like symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions and bradycardia) often appear with overdosage (cholinergic crisis). An important complication that can arise is obstruction of the airway by bronchial secretions. These may be managed with suction (especially if tracheostomy has been performed) and by the use of atropine. Many experts have advocated a wide range of dosages of atropine (for ENLON, see atropine dosage below), but if there are copious secretions, up to 1.2 mg intravenously may be given initially and repeated every 20 minutes until secretions are controlled. Signs of atropine overdosage such as dry mouth, flush and tachycardia should be avoided as tenacious secretions and bronchial plugs may form. A total dose of atropine of 5 to 10 mg or even more may be required. The following steps should be taken in the management of overdosage of ENLON:
- Adequate respiratory exchange should be maintained by assuring an open airway and by the use of assisted respiration augmented by oxygen.
Cardiac function should be monitored until complete stabilization has been achieved
- Atropine sulfate in doses of 0.4 to 0.5 mg should be administered intravenously. This may be repeated every 3 to 10 minutes. Because of the short duration of action of ENLON the total dose required will seldom exceed 2 mg.
Pralidoxime chloride (a cholinesterase reactivator) may be given intravenously at the rate of 50 to 100 mg per minute; usually the total dose does not exceed 1000 mg. Extreme caution should be exercised in the use of pralidoxime chloride when the cholinergic symptoms are induced by double-bond phosphorous anticholinesterase drugs. 9
If convulsions occur or shock is present, appropriate measures should be instituted.
# Pharmacology
## Mechanism of Action
- ENLON is an anticholinesterase drug. Its pharmacologic action is due primarily to the inhibition or inactivation of acetylcholinesterase at sites of cholinergic transmission. Its effect is manifest within 30 to 60 seconds after injection and lasts an average of 10 minutes.
## Structure
- ENLON is a short and rapid-acting cholinergic drug. Chemically, edrophonium chloride is ethyl(m-hydroxyphenyl) dimethylammonium chloride and its structural formula is:
- Each mL contains, in a sterile solution, 10 mg edrophonium chloride compounded with 0.45% phenol as a preservative, and 0.2% sodium sulfite as an antioxidant, buffered with sodium citrate and citric acid, and pH adjusted to approximately 5.4.
ENLON is intended for IV and IM use.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Edrophonium in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Edrophonium in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Edrophonium in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Edrophonium in the drug label.
# How Supplied
- ENLON (edrophonium chloride injection, USP):
NDC 10019-873-15 15 mL vials
## Storage
- ENLON (edrophonium chloride injection, USP) should be stored at controlled room temperature 15º-30ºC (59º-86ºF)
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Edrophonium in the drug label.
# Precautions with Alcohol
- Alcohol-Edrophonium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Enlon®[1]
# Look-Alike Drug Names
There is limited information regarding Edrophonium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Edrophonium | |
da3819496c6c1febd6ad107be74b6ea3da75aabb | wikidoc | Rilpivirine | Rilpivirine
- Rifabutin Co-administration: For patients concomitantly receiving rifabutin, the Rilpivirine dose should be increased to 50 mg (two tablets of 25 mg each) once daily, taken with a meal. When rifabutin co-administration is stopped, the Rilpivirine dose should be decreased to 25 mg once daily, taken with a meal.
- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- the antimycobacterials rifampin, rifapentine
- proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
- the glucocorticoid systemic dexamethasone (more than a single dose)
- St John's wort (Hypericum perforatum)
- Caution should be given to prescribing Rilpivirine with drugs that may reduce the exposure of rilpivirine.
- In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Rilpivirine should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
## Depressive Disorders
- The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with Rilpivirine During the Phase 3 trials (N = 1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among Rilpivirine (n = 686) or efavirenz (n = 682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both Rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among Rilpivirine or efavirenz was 1% in each arm. Suicidal ideation was reported in 4 subjects in each arm while suicide attempt was reported in 2 subjects in the Rilpivirine arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to Rilpivirine and if so, to determine whether the risks of continued therapy outweigh the benefits.
## Hepatotoxicity
- Hepatic adverse events have been reported in patients receiving a rilpivirine containing regimen. Patients with underlying hepatitis B or hepatitis C, or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of Rilpivirine A few cases of hepatic toxicity have been reported in patients receiving a rilpivirine containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with Rilpivirine is recommended in patients with underlying hepatic disease such as hepatitis B or hepatitis C, or in patients with marked elevations in transaminases prior to treatment initiation. *Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.
## Fat Redistribution
- Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
## Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Rilpivirine During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution syndrome; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- The safety assessment is based on the Week 96 pooled data from 1368 patients in the Phase 3 controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1 infected adult patients, 686 of whom received Rilpivirine (25 mg once daily). The median duration of exposure for patients in the Rilpivirine arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRs occurred in the first 48 weeks of treatment. The proportion of subjects who discontinued treatment with Rilpivirine or efavirenz due to ADR, regardless of severity, was 2% and 4%, respectively. The most common ADRs leading to discontinuation were psychiatric disorders: 10 (1%) subjects in the Rilpivirine arm and 11 (2%) subjects in the efavirenz arm. Rash led to discontinuation in 1 (0.1%) subject in the Rilpivirine arm and 10 (1.5%) subjects in the efavirenz arm.
## Common Adverse Drug Reactions
- ADRs of at least moderate intensity (≥ Grade 2) reported in at least 2% of adult subjects are presented in Table 1. Selected treatment-emergent laboratory abnormalities are included in Table 2.
- No new ADR terms were identified in adult subjects in the Phase 3 TMC278-C209 and TMC278-C215 trials between 48 weeks and 96 weeks nor in the Phase 2b TMC278-C204 trial through 240 weeks. The incidence of adverse events in the Phase 2b TMC278-C204 trial was similar to the Phase 3 trials through 96 weeks.
## Less Common Adverse Drug Reactions
- Treatment-emergent ADRs of at least moderate intensity (≥ Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving Rilpivirine are listed below by System Organ Class. Some adverse events have been included because of investigator's assessment of potential causal relationship and were considered serious or have been reported in more than 1 subject treated with Rilpivirine.
- Gastrointestinal Disorders: diarrhea, abdominal discomfort
- Hepatobiliary Disorders: cholecystitis, cholelithiasis
- Metabolism and Nutrition Disorders: decreased appetite
- Nervous System Disorders: somnolence
- Psychiatric Disorders: sleep disorders, anxiety
- Renal and Urinary Disorders: glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis
## Laboratory Abnormalities in Treatment-Naïve Subjects
- The percentage of subjects treated with Rilpivirine or efavirenz in the Phase 3 trials with selected treatment-emergent clinical laboratory abnormalities (Grades 1 to 4), representing worst Grade toxicity are shown in Table 2.
- In the pooled Phase 3 trials, at Week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (-30.85; -7.37) nmol/L in the Rilpivirine group and of -0.6 (-13.29; 12.17) nmol/L in the efavirenz group. At Week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the Rilpivirine group (+18.4 ± 8.36 nmol/L) than in the efavirenz group (+54.1 ± 7.24 nmol/L). Mean values for both basal and ACTH-stimulated cortisol values at Week 96 were within the normal range. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency.
- In the pooled Phase 3 trials, an increase in serum creatinine was observed over the 96 weeks of treatment with Rilpivirine Most of this increase occurred within the first four weeks of treatment, with a mean change of 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL) observed after 96 weeks of treatment. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant and no subject discontinued treatment due to increases in serum creatinine. Serum creatinine increases occurred regardless of the background N(t)RTI regimen.
- Changes from baseline in total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides are presented in Table 3. The clinical benefit of these findings has not been demonstrated.
## Subjects Co-Infected with Hepatitis B and/or Hepatitis C Virus
- In subjects co-infected with hepatitis B or hepatitis C virus receiving Rilpivirine the incidence of hepatic enzyme elevation was higher than in subjects receiving Rilpivirine who were not co-infected. This observation was the same in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in co-infected subjects was comparable to that in subjects without co-infection.
- Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.
- Table 4 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of Rilpivirine and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with Rilpivirine are also included in Table 4.
In addition to the drugs included in Table 4, the interaction between Rilpivirine and the following drugs was evaluated in clinical studies and no dose adjustment is needed for either drug: acetaminophen, atorvastatin, chlorzoxazone, ethinylestradiol, norethindrone, raltegravir, sildenafil, telaprevir and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. No clinically relevant drug-drug interaction is expected when Rilpivirine is co-administered with maraviroc, ribavirin or the NRTIs abacavir, emtricitabine, lamivudine, stavudine and zidovudine.
- There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Rilpivirine should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
- Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to Rilpivirine an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
- The effect of Rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern).
- When supratherapeutic doses of 75 mg once daily and 300 mg once daily of Rilpivirine were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of Rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of Rilpivirine.
- The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.
## Absorption and Bioavailability
- After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4–5 hours. The absolute bioavailability of Rilpivirine is unknown.
## Effects of Food on Oral Absorption
- The exposure to rilpivirine was approximately 40% lower when Rilpivirine was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When Rilpivirine was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.
## Distribution
- Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.
## Metabolism
- In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 CYP3A system.
## Elimination
- The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine.
# Special Populations
## Hepatic Impairment
- Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Rilpivirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C).
## Hepatitis B and/or Hepatitis C Virus Co-infection
- Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine.
## Renal Impairment
- Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
## Gender
- No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women.
## Race
- Population pharmacokinetic analysis of rilpivirine in HIV-infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.
## Pediatric Patients
- The pharmacokinetics and dosing recommendations of rilpivirine in pediatric patients have not been established.
## Drug Interactions
- Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of Rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance. Co-administration of Rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Co-administration of Rilpivirine with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine and to the class of NNRTIs.
- Rilpivirine at a dose of 25 mg q.d. is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.
- Drug interaction studies were performed with Rilpivirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the Cmax, AUC, and Cmin values of rilpivirine are summarized in Table 6 (effect of other drugs on Rilpivirine). The effect of co-administration of Rilpivirine on the Cmax, AUC, and Cmin values of other drugs are summarized in Table 7 (effect of Rilpivirine on other drugs).
- The evidence of efficacy of Rilpivirine is based on the analyses of 48- and 96-week data from 2 randomized, double-blinded, active controlled, Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve adults. Antiretroviral treatment-naïve HIV-1 infected subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA ≥ 5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI RAMs. The Phase 3 trials were identical in design, with the exception of the background regimen (BR). In TMC278-C209, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278-C215, randomization was also stratified by N(t)RTI BR.
- In the pooled analysis for TMC278-C209 and TMC278-C215, demographics and baseline characteristics were balanced between the Rilpivirine arm and the efavirenz arm. Table 9 displays selected demographic and baseline disease characteristics of the subjects in the Rilpivirine and efavirenz arms.
Week 96 efficacy outcomes for subjects treated with Rilpivirine 25 mg once daily from the pooled analysis are shown in Table 10. The incidence of virologic failure was higher in the Rilpivirine arm than the efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment.
At Week 96, the mean CD4+ cell count increase from baseline was 228 cells/mm3 for Rilpivirine-treated subjects and 219 cells/mm3 for efavirenz-treated subjects in the pooled analysis of the TMC278-C209 and TMC278-C215 trials.
Study TMC278-C204 was a randomized, active-controlled, Phase 2b trial in antiretroviral treatment-naïve HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-finding part followed by a long-term, open-label part. After Week 96, subjects randomized to one of the 3 doses of Rilpivirine were switched to Rilpivirine 25 mg once daily. Subjects in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine.
Study TMC278-C204 enrolled 368 HIV-1-infected treatment-naïve adult subjects who had a plasma HIV-1 RNA ≥ 5000 copies/ml, previously received ≤ 2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI RAMs.
- At 96 weeks, the proportion of subjects with <50 HIV-1 RNA copies/ml receiving Rilpivirine 25 mg (N = 93) compared to subjects receiving efavirenz (N = 89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 cells/mm3 in subjects receiving Rilpivirine 25 mg and 160 cells/mm3 in subjects receiving efavirenz.
- At 240 weeks, 60% (56/93) of subjects who originally received 25 mg once daily achieved HIV RNA < 50 copies/mL compared to 57% (51/89) of subjects in the control group.
- Rilpivirine tablets are packaged in bottles in the following configuration: 25 mg tablets-bottles of 30 (NDC 59676-278-01). | Rilpivirine
- Rifabutin Co-administration: For patients concomitantly receiving rifabutin, the Rilpivirine dose should be increased to 50 mg (two tablets of 25 mg each) once daily, taken with a meal. When rifabutin co-administration is stopped, the Rilpivirine dose should be decreased to 25 mg once daily, taken with a meal.
- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- the antimycobacterials rifampin, rifapentine
- proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
- the glucocorticoid systemic dexamethasone (more than a single dose)
- St John's wort (Hypericum perforatum)
- Caution should be given to prescribing Rilpivirine with drugs that may reduce the exposure of rilpivirine.
- In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Rilpivirine should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
### Depressive Disorders
- The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with Rilpivirine During the Phase 3 trials (N = 1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among Rilpivirine (n = 686) or efavirenz (n = 682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both Rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among Rilpivirine or efavirenz was 1% in each arm. Suicidal ideation was reported in 4 subjects in each arm while suicide attempt was reported in 2 subjects in the Rilpivirine arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to Rilpivirine and if so, to determine whether the risks of continued therapy outweigh the benefits.
### Hepatotoxicity
- Hepatic adverse events have been reported in patients receiving a rilpivirine containing regimen. Patients with underlying hepatitis B or hepatitis C, or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of Rilpivirine A few cases of hepatic toxicity have been reported in patients receiving a rilpivirine containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with Rilpivirine is recommended in patients with underlying hepatic disease such as hepatitis B or hepatitis C, or in patients with marked elevations in transaminases prior to treatment initiation. *Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.
### Fat Redistribution
- Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
### Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Rilpivirine During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution syndrome; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- The safety assessment is based on the Week 96 pooled data from 1368 patients in the Phase 3 controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1 infected adult patients, 686 of whom received Rilpivirine (25 mg once daily). The median duration of exposure for patients in the Rilpivirine arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRs occurred in the first 48 weeks of treatment. The proportion of subjects who discontinued treatment with Rilpivirine or efavirenz due to ADR, regardless of severity, was 2% and 4%, respectively. The most common ADRs leading to discontinuation were psychiatric disorders: 10 (1%) subjects in the Rilpivirine arm and 11 (2%) subjects in the efavirenz arm. Rash led to discontinuation in 1 (0.1%) subject in the Rilpivirine arm and 10 (1.5%) subjects in the efavirenz arm.
### Common Adverse Drug Reactions
- ADRs of at least moderate intensity (≥ Grade 2) reported in at least 2% of adult subjects are presented in Table 1. Selected treatment-emergent laboratory abnormalities are included in Table 2.
- No new ADR terms were identified in adult subjects in the Phase 3 TMC278-C209 and TMC278-C215 trials between 48 weeks and 96 weeks nor in the Phase 2b TMC278-C204 trial through 240 weeks. The incidence of adverse events in the Phase 2b TMC278-C204 trial was similar to the Phase 3 trials through 96 weeks.
### Less Common Adverse Drug Reactions
- Treatment-emergent ADRs of at least moderate intensity (≥ Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving Rilpivirine are listed below by System Organ Class. Some adverse events have been included because of investigator's assessment of potential causal relationship and were considered serious or have been reported in more than 1 subject treated with Rilpivirine.
- Gastrointestinal Disorders: diarrhea, abdominal discomfort
- Hepatobiliary Disorders: cholecystitis, cholelithiasis
- Metabolism and Nutrition Disorders: decreased appetite
- Nervous System Disorders: somnolence
- Psychiatric Disorders: sleep disorders, anxiety
- Renal and Urinary Disorders: glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis
### Laboratory Abnormalities in Treatment-Naïve Subjects
- The percentage of subjects treated with Rilpivirine or efavirenz in the Phase 3 trials with selected treatment-emergent clinical laboratory abnormalities (Grades 1 to 4), representing worst Grade toxicity are shown in Table 2.
- In the pooled Phase 3 trials, at Week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (-30.85; -7.37) nmol/L in the Rilpivirine group and of -0.6 (-13.29; 12.17) nmol/L in the efavirenz group. At Week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the Rilpivirine group (+18.4 ± 8.36 nmol/L) than in the efavirenz group (+54.1 ± 7.24 nmol/L). Mean values for both basal and ACTH-stimulated cortisol values at Week 96 were within the normal range. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency.
- In the pooled Phase 3 trials, an increase in serum creatinine was observed over the 96 weeks of treatment with Rilpivirine Most of this increase occurred within the first four weeks of treatment, with a mean change of 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL) observed after 96 weeks of treatment. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant and no subject discontinued treatment due to increases in serum creatinine. Serum creatinine increases occurred regardless of the background N(t)RTI regimen.
- Changes from baseline in total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides are presented in Table 3. The clinical benefit of these findings has not been demonstrated.
### Subjects Co-Infected with Hepatitis B and/or Hepatitis C Virus
- In subjects co-infected with hepatitis B or hepatitis C virus receiving Rilpivirine the incidence of hepatic enzyme elevation was higher than in subjects receiving Rilpivirine who were not co-infected. This observation was the same in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in co-infected subjects was comparable to that in subjects without co-infection.
- Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.
- Table 4 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of Rilpivirine and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with Rilpivirine are also included in Table 4.
In addition to the drugs included in Table 4, the interaction between Rilpivirine and the following drugs was evaluated in clinical studies and no dose adjustment is needed for either drug: acetaminophen, atorvastatin, chlorzoxazone, ethinylestradiol, norethindrone, raltegravir, sildenafil, telaprevir and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. No clinically relevant drug-drug interaction is expected when Rilpivirine is co-administered with maraviroc, ribavirin or the NRTIs abacavir, emtricitabine, lamivudine, stavudine and zidovudine.
- There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Rilpivirine should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
- Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to Rilpivirine an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
- The effect of Rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern).
- When supratherapeutic doses of 75 mg once daily and 300 mg once daily of Rilpivirine were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of Rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of Rilpivirine.
- The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.
### Absorption and Bioavailability
- After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4–5 hours. The absolute bioavailability of Rilpivirine is unknown.
### Effects of Food on Oral Absorption
- The exposure to rilpivirine was approximately 40% lower when Rilpivirine was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When Rilpivirine was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.
### Distribution
- Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.
### Metabolism
- In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 CYP3A system.
### Elimination
- The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine.
## Special Populations
### Hepatic Impairment
- Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Rilpivirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C).
### Hepatitis B and/or Hepatitis C Virus Co-infection
- Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine.
### Renal Impairment
- Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
### Gender
- No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women.
### Race
- Population pharmacokinetic analysis of rilpivirine in HIV-infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.
### Pediatric Patients
- The pharmacokinetics and dosing recommendations of rilpivirine in pediatric patients have not been established.
### Drug Interactions
- Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of Rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance. Co-administration of Rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Co-administration of Rilpivirine with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine and to the class of NNRTIs.
- Rilpivirine at a dose of 25 mg q.d. is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.
- Drug interaction studies were performed with Rilpivirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the Cmax, AUC, and Cmin values of rilpivirine are summarized in Table 6 (effect of other drugs on Rilpivirine). The effect of co-administration of Rilpivirine on the Cmax, AUC, and Cmin values of other drugs are summarized in Table 7 (effect of Rilpivirine on other drugs).
- The evidence of efficacy of Rilpivirine is based on the analyses of 48- and 96-week data from 2 randomized, double-blinded, active controlled, Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve adults. Antiretroviral treatment-naïve HIV-1 infected subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA ≥ 5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI RAMs. The Phase 3 trials were identical in design, with the exception of the background regimen (BR). In TMC278-C209, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278-C215, randomization was also stratified by N(t)RTI BR.
- In the pooled analysis for TMC278-C209 and TMC278-C215, demographics and baseline characteristics were balanced between the Rilpivirine arm and the efavirenz arm. Table 9 displays selected demographic and baseline disease characteristics of the subjects in the Rilpivirine and efavirenz arms.
Week 96 efficacy outcomes for subjects treated with Rilpivirine 25 mg once daily from the pooled analysis are shown in Table 10. The incidence of virologic failure was higher in the Rilpivirine arm than the efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment.
At Week 96, the mean CD4+ cell count increase from baseline was 228 cells/mm3 for Rilpivirine-treated subjects and 219 cells/mm3 for efavirenz-treated subjects in the pooled analysis of the TMC278-C209 and TMC278-C215 trials.
Study TMC278-C204 was a randomized, active-controlled, Phase 2b trial in antiretroviral treatment-naïve HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-finding part [Rilpivirine doses blinded] followed by a long-term, open-label part. After Week 96, subjects randomized to one of the 3 doses of Rilpivirine were switched to Rilpivirine 25 mg once daily. Subjects in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine.
Study TMC278-C204 enrolled 368 HIV-1-infected treatment-naïve adult subjects who had a plasma HIV-1 RNA ≥ 5000 copies/ml, previously received ≤ 2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI RAMs.
- At 96 weeks, the proportion of subjects with <50 HIV-1 RNA copies/ml receiving Rilpivirine 25 mg (N = 93) compared to subjects receiving efavirenz (N = 89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 cells/mm3 in subjects receiving Rilpivirine 25 mg and 160 cells/mm3 in subjects receiving efavirenz.
- At 240 weeks, 60% (56/93) of subjects who originally received 25 mg once daily achieved HIV RNA < 50 copies/mL compared to 57% (51/89) of subjects in the control group.
- Rilpivirine tablets are packaged in bottles in the following configuration: 25 mg tablets-bottles of 30 (NDC 59676-278-01). | https://www.wikidoc.org/index.php/Edurant | |
a8c2ee0e538388769357dde9de66e0366742bb3a | wikidoc | Edward Bove | Edward Bove
Edward Bove is a Professor in the Department of Surgery at the University of Michigan School of Medicine, Michigan, United States. Dr. Bove is also the Head of the Section of Cardiac Surgery, the Director of the Division of Pediatric Cardiovascular Surgery, and the Co-Director of the Michigan Congenital Heart Center at the University of Michigan Health System in Ann Arbor, Michigan. He is well known for his contributions to the repair of congenital heart defects, most notably Hypoplastic Left Heart Syndrome.
Dr. Bove was born and raised in New York. He received his bachelor’s degree from the College of the Holy Cross in Worcester, Massachusetts in 1968, and his medical degree from Albany Medical College, Albany, New York in 1972. Dr. Bove performed his post-doctoral training at:
- Surgical Intern, University of Michigan, Ann Arbor, Michigan
- Resident in Surgery, University of Michigan, Ann Arbor, Michigan
- Thoracic Surgery Research Laboratory, University of Michigan, Ann Arbor, Michigan
- Chief Resident in Surgery, University of Michigan, Ann Arbor, Michigan
- Resident in Thoracic Surgery, University of Michigan, Ann Arbor, Michigan
- Senior Registrar, Thoracic Unit, The Hospital for Sick Children, London, England
Dr. Bove was an Assistant Professor of Surgery from 1980-1983 at the Health Science Center Syracuse. From 1983-1985, he was an Associate Professor of Surgery at the Health Science Center Syracuse. Dr. Bove became a Associate Professor of Surgery at the University of Michigan in 1985. In 1988, Dr. Bove was elevated to Professor of Surgery at the University of Michigan. In 1999, he was appointed head of the Section of Cardiac Surgery for the University.
Dr. Bove is considered one of the world's outstanding pediatric cardiac surgeons, and is particularly renowned for his work with the Hypoplastic Left Heart Syndrome.
Dr. Bove is also the author of 224 articles on the repair of congenital heart defects. He is board-certified in both General and Cardiac surgery.
Dr. Bove has received recognition for his work including being listed in Who's Who in Health and Medical Services and the Best Doctors in America. Dr. Bove is also on the board of the American Board of Thoracic Surgery.. More recently, Dr. Bove became one of the public faces of the University of Michigan Health System by being prominently featured in the System's new marketing campaign.
Dr. Bove is married and has two children, Christopher and Susan.
# Quotes
"Sadly, we lose some. It upsets me as much today as ever - just ask my wife. The high risk - it wears on you. Some days I'm as high as the top of the world, but other days I'm deflated lower than the curb on the road." | Edward Bove
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Edward Bove is a Professor in the Department of Surgery at the University of Michigan School of Medicine, Michigan, United States. Dr. Bove is also the Head of the Section of Cardiac Surgery, the Director of the Division of Pediatric Cardiovascular Surgery, and the Co-Director of the Michigan Congenital Heart Center at the University of Michigan Health System in Ann Arbor, Michigan. He is well known for his contributions to the repair of congenital heart defects, most notably Hypoplastic Left Heart Syndrome.
Dr. Bove was born and raised in New York. He received his bachelor’s degree from the College of the Holy Cross in Worcester, Massachusetts in 1968, and his medical degree from Albany Medical College, Albany, New York in 1972. Dr. Bove performed his post-doctoral training at:
- Surgical Intern, University of Michigan, Ann Arbor, Michigan
- Resident in Surgery, University of Michigan, Ann Arbor, Michigan
- Thoracic Surgery Research Laboratory, University of Michigan, Ann Arbor, Michigan
- Chief Resident in Surgery, University of Michigan, Ann Arbor, Michigan
- Resident in Thoracic Surgery, University of Michigan, Ann Arbor, Michigan
- Senior Registrar, Thoracic Unit, The Hospital for Sick Children, London, England
Dr. Bove was an Assistant Professor of Surgery from 1980-1983 at the Health Science Center Syracuse. From 1983-1985, he was an Associate Professor of Surgery at the Health Science Center Syracuse. Dr. Bove became a Associate Professor of Surgery at the University of Michigan in 1985. In 1988, Dr. Bove was elevated to Professor of Surgery at the University of Michigan. In 1999, he was appointed head of the Section of Cardiac Surgery for the University.
Dr. Bove is considered one of the world's outstanding pediatric cardiac surgeons, and is particularly renowned for his work with the Hypoplastic Left Heart Syndrome.[2]
Dr. Bove is also the author of 224 articles on the repair of congenital heart defects. [3] He is board-certified in both General and Cardiac surgery.
Dr. Bove has received recognition for his work including being listed in Who's Who in Health and Medical Services and the Best Doctors in America. Dr. Bove is also on the board of the American Board of Thoracic Surgery.[4]. More recently, Dr. Bove became one of the public faces of the University of Michigan Health System by being prominently featured in the System's new marketing campaign.
Dr. Bove is married and has two children, Christopher and Susan.
# Quotes
"Sadly, we lose some. It upsets me as much today as ever - just ask my wife. The high risk - it wears on you. Some days I'm as high as the top of the world, but other days I'm deflated lower than the curb on the road." [5]
# External links
- University Bio
- University Article focusing on Hypoplastic Left Heart Syndrome
- Additional University Bio
- Additional University Bio
- Appointed to an Endowed Chair
- Article regarding Dr. Bove
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Edward_Bove | |
8e16da2aae581130249549d55788c6c5e2538339 | wikidoc | Effect size | Effect size
In statistics, effect size is a measure of the strength of the relationship between two variables. In scientific experiments, it is often useful to know not only whether an experiment has a statistically significant effect, but also the size of any observed effects. In practical situations, effect sizes are helpful for making decisions. Effect size measures are the common currency of meta-analysis studies that summarize the findings from a specific area of research.
# Summary
The concept of effect size appears in everyday language. For example, a weight loss program may boast that it leads to an average weight loss of 30 pounds. In this case, 30 pounds is an indicator of the claimed effect size. Another example is that a tutoring program may claim that it raises school performance by one letter grade. This grade increase is the claimed effect size of the program.
An effect size is best explained through an example: if you had no previous contact with humans, and one day visited England, how many people would you need to see before you realize that, on average, men are taller than women there? The answer relates to the effect size of the difference in average height between men and women. The larger the effect size, the easier it is to see that men are taller. If the height difference were small, then it would require knowing the heights of many men and women to notice that (on average) men are taller than women. This example is demonstrated further below.
In inferential statistics, an effect size helps to determine whether a statistically significant difference is a difference of practical concern. In other words, given a sufficiently large sample size, it is always possible to show that there is a difference between two means being compared out to some decimal position. The effects size helps us to know whether the difference observed is a difference that matters. Effect size, along with N and critical alpha, and power in statistical hypothesis testing are related, and any one of these values can be determined given the others. In meta-analysis, effect sizes are used as a common measure that can be calculated for different studies and then combined into overall analyses.
# Types
## Pearson r correlation
Pearson's r correlation is one of the most widely used effect sizes. It can be used when the data are continuous or binary, thus the Pearson r is arguably the most versatile effect size. This was the first important effect size to be developed in statistics, and it was introduced by Karl Pearson. Pearson's r can vary in magnitude from -1 to 1, with -1 indicating a perfect negative relationship, 1 indicating a perfect positive relationship, and 0 indicating no relationship between two variables. Cohen (1988, 1992) gives the rules of thumb: small = 0.1; medium = 0.3; large = 0.5.
Another often used measure of the size of the relationship between two variables is the square of r, often referred to as "r-squared" or the coefficient of determination. It is a measure of the proportion of variance shared by the two variables and varies from 0 to 1. An r² of 0.21 would suggest that 21% of the variance is shared by these two variables.
## Cohen's d
Cohen's d is the appropriate effect size measure to use in the context of a t-test on means. d is defined as the difference between two means divided by the pooled standard deviation for those means. Thus, in the case where both samples are the same size,
Different people offer different advice regarding how to interpret the resultant effect size, but the most accepted opinion is that of Cohen (1992) where 0.2 is indicative of a small effect, 0.5 a medium and 0.8 a large effect size.
So, in the example above of visiting England and observing men and women's height, the data (from a 2004 UK representative sample of 2436 men and 3311 women ) is:
- Men: Mean Height = 1750 mm; Standard Deviation = 89.93 mm
- Women: Mean Height = 1612 mm; Standard Deviation = 69.05 mm
The effect size (using Cohen's d) would equal 1.72 (95% confidence intervals: 1.66 - 1.78). This is very large and you should have no problem in detecting that there is a consistent height difference, on average, between men and women.
One point worth noting, though, is that in some cases it may be wise to use a pooled standard deviation while in other cases it makes more sense to use just one of the standard deviations (e.g., pre-treatment standard deviation in a therapeutic trial). Either way, note that sample size and unequal sample size does not play a part in the calculation - points noted by Hedges.
## Hedges' ĝ
Hedges and Olkin (1985) noted that one could adjust effect size estimates by taking into account the sample size. The problem with Cohen's d is that the outcome is heavily influenced by the denominator in the equation. If one standard deviation is larger than the other then the denominator is weighted in that direction and the effect size is more conservative. However, surely it makes more sense to put stock in the larger sample size? Hedges' ĝ incorporates sample size by both computing a denominator which looks at the sample sizes of the respective standard deviations and also makes an adjustment to the overall effect size based on this sample size. The formula for Hedges' ĝ (as used by software such as the Effect Size Generator) is
\hat{g} = \frac{\bar{x}_1 - \bar{x}_2}{\sqrt{\frac{(n_1 - 1) SD_1^2 + (n_2 - 1) SD_2^2}{(N_\mathrm{total} - 2)}}} \times \bigg(1-\frac{3}{4(n_1+n_2)-9}\bigg).
In the above 'height' example, Hedges' ĝ effect size equals 1.76 (95% confidence intervals: 1.70 - 1.82). Notice how the large sample size has increased the effect size from Cohen's d? If, instead, the available data were from only 90 men and 80 women Hedges' ĝ would provide a more conservative estimate of effect size: 1.70 (with larger 95% confidence intervals: 1.35 - 2.05).
## Cohen's f^{2}
Cohen's f^{2} is the appropriate effect size measure to use in the context of an F-test for multiple correlation or multiple regression. The f^{2} effect size measure for multiple regression is defined as:
The f^{2} effect size measure for hierarchical multiple regression is defined as:
By convention, f^{2} effect sizes of 0.02, 0.15, and 0.35 are considered small, medium, and large, respectively (Cohen, 1988).
## φ, Cramer's φ, or Cramer's V
The best measure of association for the chi-square test is phi (or Cramer's phi or V). Phi is related to the point-biserial correlation coefficient and Cohen's d and estimates the extent of the relationship between two variables (2 x 2). Cramer's Phi may be used with variables having more than two levels.
Phi can be computed by finding the square root of the chi-square statistic divided by the sample size.
Similarly, Cramer's phi can be found through a slightly more complex formula that takes the number of rows or columns into account (k).
## Odds ratio
The odds ratio is another useful effect size. It is appropriate when both variables are binary. For example, consider a study on spelling. In a control group, two students pass the class for every one who fails, so the odds of passing are two to one (or more briefly 2/1 = 2). In the treatment group, six students pass for every one who fails, so the odds of passing are six to one (or 6/1 = 6). The effect size can be computed by noting that the odds of passing in the treatment group are three times higher than in the control group (because 6 divided by 2 is 3). Therefore, the odds ratio is 3. However, odds ratio statistics are on a different scale to Cohen's d. So, this '3' is not comparable to a Cohen's d of '3'. | Effect size
In statistics, effect size is a measure of the strength of the relationship between two variables. In scientific experiments, it is often useful to know not only whether an experiment has a statistically significant effect, but also the size of any observed effects. In practical situations, effect sizes are helpful for making decisions. Effect size measures are the common currency of meta-analysis studies that summarize the findings from a specific area of research.
# Summary
The concept of effect size appears in everyday language. For example, a weight loss program may boast that it leads to an average weight loss of 30 pounds. In this case, 30 pounds is an indicator of the claimed effect size. Another example is that a tutoring program may claim that it raises school performance by one letter grade. This grade increase is the claimed effect size of the program.
An effect size is best explained through an example: if you had no previous contact with humans, and one day visited England, how many people would you need to see before you realize that, on average, men are taller than women there? The answer relates to the effect size of the difference in average height between men and women. The larger the effect size, the easier it is to see that men are taller. If the height difference were small, then it would require knowing the heights of many men and women to notice that (on average) men are taller than women. This example is demonstrated further below.
In inferential statistics, an effect size helps to determine whether a statistically significant difference is a difference of practical concern. In other words, given a sufficiently large sample size, it is always possible to show that there is a difference between two means being compared out to some decimal position. The effects size helps us to know whether the difference observed is a difference that matters. Effect size, along with N and critical alpha, and power in statistical hypothesis testing are related, and any one of these values can be determined given the others. In meta-analysis, effect sizes are used as a common measure that can be calculated for different studies and then combined into overall analyses.
# Types
## Pearson r correlation
Pearson's r correlation is one of the most widely used effect sizes. It can be used when the data are continuous or binary, thus the Pearson r is arguably the most versatile effect size. This was the first important effect size to be developed in statistics, and it was introduced by Karl Pearson. Pearson's r can vary in magnitude from -1 to 1, with -1 indicating a perfect negative relationship, 1 indicating a perfect positive relationship, and 0 indicating no relationship between two variables. Cohen (1988, 1992) gives the rules of thumb: small = 0.1; medium = 0.3; large = 0.5.
Another often used measure of the size of the relationship between two variables is the square of r, often referred to as "r-squared" or the coefficient of determination. It is a measure of the proportion of variance shared by the two variables and varies from 0 to 1. An r² of 0.21 would suggest that 21% of the variance is shared by these two variables.
## Cohen's d
Cohen's d is the appropriate effect size measure to use in the context of a t-test on means. d is defined as the difference between two means divided by the pooled standard deviation for those means. Thus, in the case where both samples are the same size,
Different people offer different advice regarding how to interpret the resultant effect size, but the most accepted opinion is that of Cohen (1992) where 0.2 is indicative of a small effect, 0.5 a medium and 0.8 a large effect size.
So, in the example above of visiting England and observing men and women's height, the data (from a 2004 UK representative sample of 2436 men and 3311 women [1]) is:
- Men: Mean Height = 1750 mm; Standard Deviation = 89.93 mm
- Women: Mean Height = 1612 mm; Standard Deviation = 69.05 mm
The effect size (using Cohen's d) would equal 1.72 (95% confidence intervals: 1.66 - 1.78). This is very large and you should have no problem in detecting that there is a consistent height difference, on average, between men and women.
One point worth noting, though, is that in some cases it may be wise to use a pooled standard deviation while in other cases it makes more sense to use just one of the standard deviations (e.g., pre-treatment standard deviation in a therapeutic trial). Either way, note that sample size and unequal sample size does not play a part in the calculation - points noted by Hedges.
## Hedges' ĝ
Hedges and Olkin (1985) noted that one could adjust effect size estimates by taking into account the sample size. The problem with Cohen's d is that the outcome is heavily influenced by the denominator in the equation. If one standard deviation is larger than the other then the denominator is weighted in that direction and the effect size is more conservative. However, surely it makes more sense to put stock in the larger sample size? Hedges' ĝ incorporates sample size by both computing a denominator which looks at the sample sizes of the respective standard deviations and also makes an adjustment to the overall effect size based on this sample size. The formula for Hedges' ĝ (as used by software such as the Effect Size Generator) is
<math>\hat{g} = \frac{\bar{x}_1 - \bar{x}_2}{\sqrt{\frac{(n_1 - 1) SD_1^2 + (n_2 - 1) SD_2^2}{(N_\mathrm{total} - 2)}}} \times \bigg(1-\frac{3}{4(n_1+n_2)-9}\bigg).</math>
In the above 'height' example, Hedges' ĝ effect size equals 1.76 (95% confidence intervals: 1.70 - 1.82). Notice how the large sample size has increased the effect size from Cohen's d? If, instead, the available data were from only 90 men and 80 women Hedges' ĝ would provide a more conservative estimate of effect size: 1.70 (with larger 95% confidence intervals: 1.35 - 2.05).
## Cohen's <math>f^{2}</math>
Cohen's <math>f^{2}</math> is the appropriate effect size measure to use in the context of an F-test for multiple correlation or multiple regression. The <math>f^{2}</math> effect size measure for multiple regression is defined as:
The <math>f^{2}</math> effect size measure for hierarchical multiple regression is defined as:
By convention, <math>f^{2}</math> effect sizes of 0.02, 0.15, and 0.35 are considered small, medium, and large, respectively (Cohen, 1988).
## φ, Cramer's φ, or Cramer's V
The best measure of association for the chi-square test is phi (or Cramer's phi or V). Phi is related to the point-biserial correlation coefficient and Cohen's d and estimates the extent of the relationship between two variables (2 x 2).[1] Cramer's Phi may be used with variables having more than two levels.
Phi can be computed by finding the square root of the chi-square statistic divided by the sample size.
Similarly, Cramer's phi can be found through a slightly more complex formula that takes the number of rows or columns into account (k).
## Odds ratio
The odds ratio is another useful effect size. It is appropriate when both variables are binary. For example, consider a study on spelling. In a control group, two students pass the class for every one who fails, so the odds of passing are two to one (or more briefly 2/1 = 2). In the treatment group, six students pass for every one who fails, so the odds of passing are six to one (or 6/1 = 6). The effect size can be computed by noting that the odds of passing in the treatment group are three times higher than in the control group (because 6 divided by 2 is 3). Therefore, the odds ratio is 3. However, odds ratio statistics are on a different scale to Cohen's d. So, this '3' is not comparable to a Cohen's d of '3'. | https://www.wikidoc.org/index.php/Effect_size | |
ef07d1f3a49dd7bbbf0f93649774a025c919f544 | wikidoc | Venlafaxine | Venlafaxine
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# Black Box Warning
# Overview
Venlafaxine is an antidepressive agents that is FDA approved for the treatment of major depressive disorder, generalized anxiety disorder, social anxiety disorder, panic disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, sweating, weight loss, constipation, loss of appetite, nausea, xerostomia, asthenia, dizziness, dream disorder, headache, insomnia, somnolence, tremor, blurred vision, feeling nervous, abnormal ejaculation, erectile dysfunction, orgasm disorder.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Effexor XR (venlafaxine hydrochloride) extended-release capsules are indicated for the treatment of major depressive disorder.
- The efficacy of Effexor XR in the treatment of major depressive disorder was established in 8- and 12-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see Clinical Trials).
- A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
- The efficacy of Effexor (immediate release) in the treatment of major depressive disorder in adult inpatients meeting diagnostic criteria for major depressive disorder with melancholia was established in a 4-week controlled trial (see Clinical Trials). The safety and efficacy of Effexor XR in hospitalized depressed patients have not been adequately studied.
- The efficacy of Effexor XR in maintaining a response in major depressive disorder for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor (immediate release) in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see Clinical Trials). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Dosing Information
- For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of Effexor XR in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for Effexor XR has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140 to 180 mg/day.
- It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for Effexor (immediate release), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of Effexor XR are needed for more severely depressed patients is unknown; however, the experience with Effexor XR doses higher than 225 mg/day is very limited.
- Effexor XR is indicated for the treatment of Generalized Anxiety Disorder (GAD) as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
- The efficacy of Effexor XR in the treatment of GAD was established in 8-week and 6-month placebo-controlled trials in adult outpatients diagnosed with GAD according to DSM-IV criteria (see Clinical Trials).
- Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance.
- Although the effectiveness of Effexor XR has been demonstrated in 6-month clinical trials in patients with GAD, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Dosing Information
- For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Generalized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in GAD was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days.
- Effexor XR is indicated for the treatment of Social Anxiety Disorder, also known as Social Phobia, as defined in DSM-IV (300.23).
- Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
- The efficacy of Effexor XR in the treatment of Social Anxiety Disorder was established in four 12-week and one 6-month placebo-controlled trials in adult outpatients with Social Anxiety Disorder (DSM-IV) (see Clinical Trials).
- Although the effectiveness of Effexor XR has been demonstrated in a 6-month clinical trial in patients with Social Anxiety Disorder, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Dosing Information
- The recommended dose is 75 mg/day, administered in a single dose. There was no evidence that higher doses confer any additional benefit.
- Effexor XR is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.
- Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, ie, a discrete period of intense fear or discomfort, in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) derealization (feelings of unreality) or depersonalization (being detached from oneself); 10) fear of losing control; 11) fear of dying; 12) paresthesias (numbness or tingling sensations); 13) chills or hot flushes.
- The efficacy of Effexor XR in the treatment of panic disorder was established in two 12-week placebo-controlled trials in adult outpatients with panic disorder (DSM-IV). The efficacy of Effexor XR in prolonging time to relapse in panic disorder among responders following 12 weeks of open-label acute treatment was demonstrated in a placebo-controlled study (see CLINICAL PHARMACOLOGY, Clinical Trials). Nevertheless, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Dosing Information
- It is recommended that initial single doses of 37.5 mg/day of Effexor XR be used for 7 days. In clinical trials establishing the efficacy of Effexor XR in outpatients with panic disorder, initial doses of 37.5 mg/day for 7 days were followed by doses of 75 mg/day and subsequent weekly dose increases of 75 mg/day to a maximum dose of 225 mg/day. Although a dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies, certain patients not responding to 75 mg/day may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 7 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by:
- Class of Recommendation: Adult, Class IIb
- Strength of Evidence: Adult, Category C
- Dosing Information
- Dosage
### Non–Guideline-Supported Use
- Obsessive-compulsive disorder
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Venlafaxine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
# Contraindications
- Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation.
- The use of MAOIs intended to treat psychiatric disorders with Effexor XR or within 7 days of stopping treatment with Effexor XR is contraindicated because of an increased risk of serotonin syndrome. The use of Effexor XR within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
- Starting Effexor XR in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.
# Warnings
Clinical Worsening and Suicide Risk
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
- If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder
- A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor XR is not approved for use in treating bipolar depression.
Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Effexor XR, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- The concomitant use of Effexor XR with MAOIs intended to treat psychiatric disorders is contraindicated. Effexor XR should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking Effexor XR. Effexor XR should be discontinued before initiating treatment with the MAOI.
- If concomitant use of Effexor XR with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
- Treatment with Effexor XR and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma
- The pupillary dilation that occurs following use of many antidepressant drugs including Effexor XR may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Sustained Hypertension
- Effexor XR treatment is associated with sustained hypertension (defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits (see Table 2).
- An analysis for patients in Effexor (immediate release) studies meeting criteria for sustained hypertension revealed a dose-dependent increase in the incidence of sustained hypertension for Effexor (immediate release) (see Table 3).
- An insufficient number of patients received mean doses of Effexor XR over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.
- In premarketing major depressive disorder studies, 0.7% (5/705) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up to 6 months). In premarketing Social Anxiety Disorder studies up to 6 months, 0.6% (5/771) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were modest (1–24 mm Hg, SDBP). *In premarketing panic disorder studies up to 12 weeks, 0.5% (5/1001) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were in a modest range (7 to 19 mm Hg, SDBP).
- Sustained increases of SDBP could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered.
Elevations in Systolic and Diastolic Blood Pressure
- In placebo-controlled premarketing studies, there were changes in mean blood pressure (see Table 4 for mean changes in supine systolic and supine diastolic blood pressure). Across most indications, a dose-related increase in supine systolic and diastolic blood pressure was evident in Effexor XR-treated patients.
- Across all clinical trials in MDD, GAD, Social Anxiety Disorder and panic disorder, 1.4% of patients in the Effexor XR-treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure with blood pressure ≥105 mm Hg compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Effexor XR-treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure with blood pressure ≥180 mm Hg compared to 0.3% of patients in the placebo groups.
### PRECAUTIONS
General
Discontinuation of Treatment with Effexor XR
- Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder, and Social Anxiety Disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.
- During marketing of Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
- Patients should be monitored for these symptoms when discontinuing treatment with Effexor XR. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
Insomnia and Nervousness
- Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with Effexor XR (venlafaxine hydrochloride) extended-release capsules than with placebo in pooled analyses of short-term major depressive disorder, GAD, Social Anxiety Disorder, and panic disorder studies, as shown in Table 5.
- Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with Effexor XR in major depressive disorder studies.
- In GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively, of the patients treated with Effexor XR up to 8 weeks and 2% and 0.7%, respectively, of the patients treated with Effexor XR up to 6 months.
- In Social Anxiety Disorder trials, insomnia and nervousness led to drug discontinuation in 2% and 1%, respectively, of the patients treated with Effexor XR up to 12 weeks and 2% and 3% respectively, of the patients treated with Effexor XR up to 6 months.
- In panic disorder trials, insomnia and nervousness led to drug discontinuation in 1% and 0.1%, respectively, of the patients treated with Effexor XR up to 12 weeks.
Changes in Weight
Adult Patients
- A loss of 5% or more of body weight occurred in 7% of Effexor XR-treated and 2% of placebo-treated patients in the short-term placebo-controlled major depressive disorder trials. The discontinuation rate for weight loss associated with Effexor XR was 0.1% in major depressive disorder studies. In placebo-controlled GAD studies, a loss of 7% or more of body weight occurred in 3% of Effexor XR patients and 1% of placebo patients who received treatment for up to 6 months. The discontinuation rate for weight loss was 0.3% for patients receiving Effexor XR in GAD studies for up to eight weeks. In placebo-controlled Social Anxiety Disorder trials, 4% of the Effexor XR-treated and 1% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 6 months of treatment. None of the patients receiving Effexor XR in Social Anxiety Disorder studies discontinued for weight loss. In placebo-controlled panic disorder trials, 3% of the Effexor XR-treated and 2% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 12 weeks of treatment. None of the patients receiving Effexor XR in panic disorder studies discontinued for weight loss.
- The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor XR and weight loss agents is not recommended. Effexor XR is not indicated for weight loss alone or in combination with other products.
Pediatric Patients
- Weight loss has been observed in pediatric patients (ages 6–17) receiving Effexor XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated patients; p<0.001). In a 16-week, double-blind, placebo-controlled, flexible dose outpatient trial for Social Anxiety Disorder, Effexor XR-treated patients lost an average of 0.75 kg (n = 137), while placebo-treated patients gained an average of 0.76 kg (n = 148). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in the Social Anxiety Disorder study (47% of Effexor XR-treated patients vs. 14% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia.
- The risks associated with longer-term Effexor XR use were assessed in an open-label MDD study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (≥12 years old).
Changes in Height
Pediatric Patients
- During the eight-week, placebo-controlled GAD studies, Effexor XR-treated patients (ages 6–17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). During the 16-week, placebo-controlled Social Anxiety Disorder study, both the Effexor XR-treated (n = 109) and the placebo-treated (n = 112) patients each grew an average of 1.0 cm. In the six-month, open-label MDD study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (≥12 years old).
Changes in Appetite
Adult Patients
- Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (4%) in the pool of short-term, double-blind, placebo-controlled major depressive disorder studies. The discontinuation rate for anorexia associated with Effexor XR was 1.0% in major depressive disorder studies. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled GAD studies. The discontinuation rate for anorexia was 0.9% for patients receiving Effexor XR for up to 8 weeks in GAD studies. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (17%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled Social Anxiety Disorder studies. The discontinuation rate for anorexia was 0.6% for patients receiving Effexor XR for up to 12 weeks in Social Anxiety Disorder studies; no patients discontinued for anorexia between week 12 and month 6. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (3%) in the pool of short-term, double-blind, placebo-controlled panic disorder studies. The discontinuation rate for anorexia was 0.4% for patients receiving Effexor XR for up to 12 weeks in panic disorder studies.
Pediatric Patients
- Decreased appetite has been observed in pediatric patients receiving Effexor XR. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6-17 treated with Effexor XR for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving Effexor XR discontinued for anorexia or weight loss. In the placebo-controlled trial for Social Anxiety Disorder, 22% and 3% of patients aged 8-17 treated for up to 16 weeks with Effexor XR and placebo, respectively, reported treatment-emergent anorexia (decreased appetite). The discontinuation rates for anorexia were 0.7% and 0.0% for patients receiving Effexor XR and placebo, respectively; the discontinuation rates for weight loss were 0.7% for patients receiving either Effexor XR or placebo.
Activation of Mania/Hypomania
- During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of Effexor XR-treated patients and no placebo patients. In premarketing GAD studies, no Effexor XR-treated patients and 0.2% of placebo-treated patients experienced mania or hypomania. In premarketing Social Anxiety Disorder studies, 0.2% Effexor XR-treated patients and no placebo-treated patients experienced mania or hypomania. In premarketing panic disorder studies, 0.1% of Effexor XR-treated patients and no placebo-treated patients experienced mania or hypomania. In all premarketing major depressive disorder trials with Effexor (immediate release), mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with no placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, Effexor XR should be used cautiously in patients with a history of mania.
Hyponatremia
- Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Effexor XR. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of Effexor XR should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
- Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Seizures
- During premarketing experience, no seizures occurred among 705 Effexor XR-treated patients in the major depressive disorder studies, among 1381 Effexor XR-treated patients in GAD studies, or among 819 Effexor XR-treated patients in Social Anxiety Disorder studies. In panic disorder studies, 1 seizure occurred among 1,001 Effexor XR-treated patients. In all premarketing major depressive disorder trials with Effexor (immediate release), seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Effexor XR, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures.
Abnormal Bleeding
- SSRIs and SNRIs, including Effexor XR, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.
- Patients should be cautioned about the risk of bleeding associated with the concomitant use of Effexor XR and NSAIDs, aspirin, or other drugs that affect coagulation.
Serum Cholesterol Elevation
- Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials. Measurement of serum cholesterol levels should be considered during long-term treatment.
Interstitial Lung Disease and Eosinophilic Pneumonia
- Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered.
Use in Patients With Concomitant Illness
- Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor XR to patients with diseases or conditions that could affect hemodynamic responses or metabolism.
- Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine's premarketing testing. The electrocardiograms were analyzed for 275 patients who received Effexor XR and 220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in major depressive disorder, for 610 patients who received Effexor XR and 298 patients who received placebo in 8-week double-blind, placebo-controlled trials in GAD, for 593 patients who received Effexor XR and 534 patients who received placebo in 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder, and for 661 patients who received Effexor XR and 395 patients who received placebo in three 10- to 12-week double-blind, placebo-controlled trials in panic disorder. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in major depressive disorder studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). The mean change from baseline in QTc interval for Effexor XR-treated patients in the GAD studies did not differ significantly from that with placebo. The mean change from baseline in QTc interval for Effexor XR-treated patients in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 3.4 msec for Effexor XR and decrease of 1.6 msec for placebo). The mean change from baseline in QTc interval for Effexor XR-treated patients in the panic disorder studies was increased relative to that for placebo-treated patients (increase of 1.5 msec for Effexor XR and decrease of 0.7 msec for placebo).
- In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients in the major depressive disorder studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the GAD studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for Effexor XR and no change for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for Effexor XR and no change for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the panic disorder studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for Effexor XR and a mean decrease of less than 1 beat per minute for placebo).
- In a flexible-dose study, with Effexor (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group.
- As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (e.g., patients with hyperthyroidism, heart failure, or recent myocardial infarction).
- Evaluation of the electrocardiograms for 769 patients who received Effexor (immediate release) in 4- to 6-week double-blind, placebo-controlled trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo.
- In patients with renal impairment (GFR = 10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary. Effexor XR, like all drugs effective in the treatment of major depressive disorder, should be used with caution in such patients.
Clinical Worsening and Suicide Risk
- Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Interference with Cognitive and Motor Performance
- Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely affect their ability to engage in such activities.
Concomitant Medication
- Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions.
- Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Effexor XR and triptans, tramadol, tryptophan supplements or other serotonergic agents.
- Patients should be advised that taking Effexor XR can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
- Patients should be cautioned about the concomitant use of Effexor XR and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding).
Alcohol
- Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine.
Allergic Reactions
- Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.
Pregnancy
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Nursing
- Patients should be advised to notify their physician if they are breast-feeding an infant.
Laboratory Tests
- There are no specific laboratory tests recommended.
# Adverse Reactions
## Clinical Trials Experience
- The information included in the Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR subsection is based on data from a pool of three 8- and 12-week controlled clinical trials in major depressive disorder (includes two U.S. trials and one European trial), on data up to 8 weeks from a pool of five controlled clinical trials in GAD with Effexor XR®, on data up to 12 weeks from a pool of five controlled clinical trials in Social Anxiety Disorder, and on data up to 12 weeks from a pool of four controlled clinical trials in panic disorder. Information on additional adverse events associated with Effexor XR in the entire development program for the formulation and with Effexor (immediate release) is included in the Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR subsection.
- Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR
Adverse Events Associated with Discontinuation of Treatment
- Approximately 11% of the 357 patients who received Effexor XR (venlafaxine hydrochloride) extended-release capsules in placebo-controlled clinical trials for major depressive disorder discontinued treatment due to an adverse experience, compared with 6% of the 285 placebo-treated patients in those studies. Approximately 18% of the 1381 patients who received Effexor XR capsules in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. Approximately 15% of the 819 patients who received Effexor XR capsules in placebo-controlled clinical trials for Social Anxiety Disorder discontinued treatment due to an adverse experience, compared with 5% of the 695 placebo-treated patients in those studies. Approximately 7% of the 1,001 patients who received Effexor XR capsules in placebo-controlled clinical trials for panic disorder discontinued treatment due to an adverse experience, compared with 6% of the 662 placebo-treated patients in those studies. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the Effexor XR-treated patients at a rate at least twice that of placebo for any indication) are shown in Table 6.
- Adverse Events Occurring at an Incidence of 2% or More Among Effexor XR-Treated Patients
- Tables 7, 8, 9, and 10 enumerate the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of major depressive disorder (up to 12 weeks; dose range of 75 to 225 mg/day), of GAD (up to 8 weeks; dose range of 37.5 to 225 mg/day), of Social Anxiety Disorder (up to 12 weeks; dose range of 75 to 225 mg/day), and of panic disorder (up to 12 weeks; dose range of 37.5 to 225 mg/day), respectively, in 2% or more of patients treated with Effexor XR (venlafaxine hydrochloride) where the incidence in patients treated with Effexor XR was greater than the incidence for the respective placebo-treated patients. The table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.
- The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.
- Commonly Observed Adverse Events from Tables 7, 8, 9, and 10:
Major Depressive Disorder
- Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the major depressive disorder indication (Table 7): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. In the two U.S. placebo-controlled trials, the following additional events occurred in at least 5% of Effexor XR-treated patients (n = 192) and at a rate at least twice that of the placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women, and libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complaints (insomnia, nervousness, and tremor), problems of special senses (abnormal vision), cardiovascular effects (hypertension and vasodilatation), and yawning.
Generalized Anxiety Disorder
- Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the GAD indication (Table 8): Abnormalities of sexual function (abnormal ejaculation and impotence), gastrointestinal complaints (nausea, dry mouth, anorexia, and constipation), problems of special senses (abnormal vision), and sweating.
Social Anxiety Disorder
- Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for the 5 placebo-controlled trials for the Social Anxiety Disorder indication (Table 9): Asthenia, gastrointestinal complaints (anorexia, constipation, dry mouth, nausea), CNS complaints (insomnia, libido decreased, nervousness, somnolence, tremor), abnormalities of sexual function (abnormal ejaculation, impotence), yawn, and sweating.
- In the 6-month trial, the following adverse events occurred twice as often in the 150–225 mg/day Effexor XR group compared to the 75 mg/day Effexor XR group and placebo: vasodilation, libido decreased, tremor, yawn, abnormal vision, and impotence.
Panic Disorder
- Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for 4 placebo-controlled trials for the panic disorder indication (Table 10): gastrointestinal complaints (anorexia, constipation, dry mouth), CNS complaints (somnolence, tremor), abnormalities of sexual function (abnormal ejaculation), and sweating.
Vital Sign Changes
- Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled major depressive disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Effexor XR treatment for up to 8 weeks in premarketing placebo-controlled GAD trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 3 beats per minute, compared with an increase of 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 1 beat per minute, compared with a decrease of less than 1 beat per minute for placebo. (See the Sustained Hypertension and Elevations in Systolic and Diastolic Blood Pressure sections of WARNINGS for effects on blood pressure.)
- In a flexible-dose study, with Effexor (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo.
Laboratory Changes
Serum Cholesterol
- Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Effexor XR treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL, respectively, for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo.
- Patients treated with Effexor (immediate release) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation).
Serum Triglycerides
- Effexor XR treatment for up to 12 weeks in pooled premarketing Social Anxiety Disorder trials was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 8.2 mg/dL, compared with a mean final increase of 0.4 mg/dL for placebo. Effexor XR treatment for up to 6 months in a premarketing Social Anxiety Disorder trial was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 11.8 mg/dL, compared with a mean final on-therapy increase of 1.8 mg/dL for placebo.
- Effexor XR treatment for up to 12 weeks in pooled premarketing Panic Disorder trials was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 5.9 mg/dL, compared with a mean final increase of 0.9 mg/dL for placebo. Effexor XR treatment for up to 6 months in a premarketing Panic Disorder trial was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 9.3 mg/dL, compared with a mean final on-therapy decrease of 0.3 mg/dL for placebo.
ECG Changes
- In a flexible-dose study, with Effexor (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo.
- Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR
- During its premarketing assessment, multiple doses of Effexor XR were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies, 819 patients in Phase 3 Social Anxiety Disorder studies, and 1314 patients in Phase 3 panic disorder studies. In addition, in premarketing assessment of Effexor, multiple doses were administered to 2897 patients in Phase 2 to Phase 3 studies for major depressive disorder. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
- In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 7212 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Tables 7, 8, 9, and 10 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it.
- Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
- Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis, granuloma.
- Cardiovascular system - Frequent: migraine, tachycardia; Infrequent: angina pectoris, arrhythmia, bradycardia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), postural hypotension, syncope; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, hematoma, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneous hemorrhage, myocardial infarct, pallor, sinus arrhythmia, thrombophlebitis.
- Digestive system - Frequent: increased appetite; Infrequent: bruxism, colitis, dysphagia, tongue edema, eructation, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: abdominal distension, biliary pain, cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis, hematemesis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, liver tenderness, parotitis, periodontitis, proctitis, rectal disorder, salivary gland enlargement, increased salivation, soft stools, tongue discoloration.
- Endocrine system - Rare: galactorrhoea, goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis.
- Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura, thrombocytopenia.
- Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipidemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia.
- Musculoskeletal system - Infrequent: arthritis, arthrosis, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: bone pain, pathological fracture, muscle cramp, muscle spasms, musculoskeletal stiffness, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture.
- Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia, thinking abnormal, trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor, suicidal ideation; Rare: abnormal/changed behavior, adjustment disorder, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, energy increased, facial paralysis, abnormal gait, Guillain-Barre Syndrome, homicidal ideation, hyperchlorhydria, hypokinesia, hysteria, impulse control difficulties, motion sickness, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, torticollis.
- Respiratory system - Frequent: cough increased, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea.
- Skin and appendages - Frequent: pruritus; Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, maculopapular rash, psoriasis, urticaria; Rare: brittle nails, erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, miliaria, petechial rash, pruritic rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin hypertrophy, skin striae, sweating decreased.
- Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion; Infrequent: conjunctivitis, diplopia, dry eyes, eye pain, otitis media, parosmia, photophobia, taste loss; Rare: blepharitis, cataract, chromatopsia, conjunctival edema, corneal lesion, deafness, exophthalmos, eye hemorrhage, angle-closure glaucoma, retinal hemorrhage, subconjunctival hemorrhage, hyperacusis, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis, visual field defect.
- Urogenital system - Frequent: albuminuria, urination impaired; Infrequent: amenorrhea,- cystitis, dysuria, hematuria, kidney calculus, kidney pain, leukorrhea,- menorrhagia,- metrorrhagia,- nocturia, breast pain, polyuria, pyuria, prostatic disorder (prostatitis, enlarged prostate, and prostate irritability,- urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage,- vaginitis*; Rare: abortion,- anuria, breast discharge, breast engorgement, balanitis,- breast enlargement, endometriosis,- female lactation,- fibrocystic breast, calcium crystalluria, cervicitis,- orchitis,- ovarian cyst,- bladder pain, prolonged erection,- gynecomastia (male),- hypomenorrhea,- kidney function abnormal, mastitis, menopause,- pyelonephritis, oliguria, salpingitis,- urolithiasis, uterine hemorrhage,- uterine spasm,- vaginal dryness.*
- Based on the number of men and women as appropriate.
### DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
- Effexor XR (venlafaxine hydrochloride) extended-release capsules is not a controlled substance.
Physical and Psychological Dependence
- In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.
- Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.
- Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION).
- While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (eg, development of tolerance, incrementation of dose, drug-seeking behavior).
## Postmarketing Experience
- Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly).
Drug Interactions
- There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy.
# Drug Interactions
As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.
Alcohol
A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine.
Cimetidine
- Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.
Diazepam
- Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam.
Haloperidol
- Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown.
Lithium
- The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below).
Drugs Highly Bound to Plasma Proteins
- Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.
Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Effexor XR is initiated or discontinued.
Drugs that Inhibit Cytochrome P450 Isoenzymes
CYP2D6 Inhibitors
- In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers (see Metabolism and Excretion under CLINICAL PHARMACOLOGY). Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor.
Ketoconazole
- A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O-desmethylvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively.
- Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM (range in PMs -38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMs and 53% in PMs (range in PMs 4% to 134%).
- Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.
Drugs Metabolized by Cytochrome P450 Isoenzymes
CYP2D6
- In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan.
Imipramine
- Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC's increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown.
Metoprolol
- Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30–40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine.
- Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol.
- Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure.
Risperidone
- Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone).
CYP3A4
- Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine.
Indinavir
- In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown.
CYP1A2
- Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate.
CYP2C9
- Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide.
CYP2C19
- Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above).
Monoamine Oxidase Inhibitors
- See CONTRAINDICATIONS, WARNINGS, and ADMINISTRATION and MONITORING.
CNS-Active Drugs
- The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required.
Serotonergic Drugs
Triptans
- There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Effexor XR with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).
Drug-Laboratory Test Interactions
- False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.
Electroconvulsive Therapy
- There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic Effects - Pregnancy Category C
- Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Non-teratogenic Effects
- Neonates exposed to Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION).
Treatment of Pregnant Women During the Third Trimester
- Neonates exposed to Effexor XR, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Venlafaxine in women who are pregnant.
### Labor and Delivery
- The effect of venlafaxine on labor and delivery in humans is unknown.
### Nursing Mothers
- Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients.
- Anyone considering the use of Effexor XR in a child or adolescent must balance the potential risks with the clinical need.
- Although no studies have been designed to primarily assess Effexor XR's impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height (see PRECAUTIONS, General, Changes in Height and Changes in Weight ). Should the decision be made to treat a pediatric patient with Effexor XR, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration.
- In the studies conducted in pediatric patients (ages 6–17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation).
### Geriatic Use
Approximately 4% (14/357), 6% (77/1381), 1% (10/819), and 2% (16/1001) of Effexor XR-treated patients in placebo-controlled premarketing major depressive disorder, GAD, Social Anxiety Disorder trials, and panic disorder trials, respectively, were 65 years of age or over. Of 2,897 Effexor-treated (immediate release) patients in premarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor XR have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).
- The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION).
- No dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, or panic disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.
### Gender
- There is no FDA guidance on the use of Venlafaxine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Venlafaxine with respect to specific racial populations.
### Renal Impairment
- Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% to 50%. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients.
### Hepatic Impairment
- Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Venlafaxine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Venlafaxine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Effexor XR should be administered in a single dose with food either in the morning or in the evening at approximately the same time each day. Each capsule should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water, or it may be administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water to ensure complete swallowing of the pellets.
Initial Treatment
Major Depressive Disorder
- For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of Effexor XR in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for Effexor XR has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140 to 180 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY).
- It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for Effexor (immediate release), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of Effexor XR are needed for more severely depressed patients is unknown; however, the experience with Effexor XR doses higher than 225 mg/day is very limited. (See PRECAUTIONS-General-Use in Patients with Concomitant Illness.)
Generalized Anxiety Disorder
- For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Generalized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in GAD was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.)
Social Anxiety Disorder (Social Phobia)
- The recommended dose is 75 mg/day, administered in a single dose. There was no evidence that higher doses confer any additional benefit. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.)
Panic Disorder
- It is recommended that initial single doses of 37.5 mg/day of Effexor XR be used for 7 days. In clinical trials establishing the efficacy of Effexor XR in outpatients with panic disorder, initial doses of 37.5 mg/day for 7 days were followed by doses of 75 mg/day and subsequent weekly dose increases of 75 mg/day to a maximum dose of 225 mg/day. Although a dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies, certain patients not responding to 75 mg/day may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 7 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.)
- Switching Patients from Effexor Tablets
- Depressed patients who are currently being treated at a therapeutic dose with Effexor (immediate release) may be switched to Effexor XR at the nearest equivalent dose (mg/day), eg, 37.5 mg venlafaxine two-times-a-day to 75 mg Effexor XR once daily. However, individual dosage adjustments may be necessary.
- Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
- At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Effexor XR. Conversely, at least 7 days should be allowed after stopping Effexor XR before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).
- Use of Effexor XR With Other MAOls, Such as Linezolid or Methylene Blue
- Do not start Effexor XR in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).
- In some cases, a patient already receiving therapy with Effexor XR may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Effexor XR should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Effexor XR may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).
- The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Effexor XR is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
Special Populations
- Treatment of Pregnant Women During the Third Trimester
- Neonates exposed to Effexor XR, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Patients with Hepatic Impairment
- Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients.
Patients with Renal Impairment
- Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% to 50%. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients.
Elderly Patients
- No dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, or panic disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.
Maintenance Treatment
- There is no body of evidence available from controlled trials to indicate how long patients with major depressive disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, or panic disorder, should be treated with Effexor XR.
- It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see Clinical Trials under CLINICAL PHARMACOLOGY). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
- In patients with Generalized Anxiety Disorder, Effexor XR has been shown to be effective in 6-month clinical trials. The need for continuing medication in patients with GAD who improve with Effexor XR treatment should be periodically reassessed.
- In patients with Social Anxiety Disorder, Effexor XR has been shown to be effective in a 6-month clinical trial. The need for continuing medication in patients with Social Anxiety Disorder who improve with Effexor XR treatment should be periodically reassessed.
- In a study of panic disorder in which patients responding during 12 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day), patients continuing Effexor XR experienced a significantly longer time to relapse than patients randomized to placebo. The need for continuing medication in patients with panic disorder who improve with Effexor XR treatment should be periodically reassessed.
Discontinuing Effexor XR
- Symptoms associated with discontinuation of Effexor XR, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. In clinical trials with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at 1 week intervals. Individualization of tapering may be necessary.
### Monitoring
There is limited information regarding Monitoring of Venlafaxine in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Venlafaxine in the drug label.
# Overdosage
Human Experience
- Among the patients included in the premarketing evaluation of Effexor XR, there were 2 reports of acute overdosage with Effexor XR in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of Effexor XR and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of Effexor XR. This patient reported paresthesia of all four limbs but recovered without sequelae.
- There were 2 reports of acute overdose with Effexor XR in GAD trials. One patient took a combination of 0.75 g of Effexor XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of Effexor XR. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. These symptoms resolved over the next week.
- There were no reports of acute overdose with Effexor XR in Social Anxiety Disorder trials.
- There were 2 reports of acute overdose with Effexor XR in panic disorder trials. One patient took 0.675 g of Effexor XR once, and the other patient took 0.45 g of Effexor XR for 2 days. No signs or symptoms were associated with either overdose, and no actions were taken to treat them.
- Among the patients included in the premarketing evaluation with Effexor (immediate release), there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients.
- In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported.
- Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
Management of Overdosage
- Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.
- Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.
- Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known.
- In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference® (PDR).
# Pharmacology
## Mechanism of Action
## Structure
- Effexor XR is an extended-release capsule for oral administration that contains venlafaxine hydrochloride, a structurally novel antidepressant. It is designated (R/S)-1- cyclohexanol hydrochloride or (±)-1--p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below.
- Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43.
- Effexor XR is formulated as an extended-release capsule for once-a-day oral administration. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.
## Pharmacodynamics
- The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity.
## Pharmacokinetics
- Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively).
Absorption
- Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%.
- Administration of Effexor XR (150 mg q24 hours) generally resulted in lower Cmax (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than for Effexor (immediate release) . When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Effexor XR, therefore, provides a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet.
- Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM vs PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule.
Metabolism and Excretion
- Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 (“extensive metabolizers”). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent.
- Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion.
Special Populations
Age and Gender
- A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary.
Extensive/Poor Metabolizers
- Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups.
Liver Disease
- In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects.
- In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2–3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted.
- Dosage adjustment is necessary in these hepatically impaired patients.
Renal Disease
- In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR=10 to 70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR=10 to 70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56% compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats.
Mutagenesis
- Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow.
Impairment of Fertility
- Reproduction and fertility studies of venlafaxine in rats showed no adverse effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose of 225 mg/day on a mg/m2 basis.
- However, reduced fertility was observed in a study in which male and female rats were treated with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, prior to and during mating and gestation. This occurred at an ODV exposure (AUC) approximately 2 to 3 times that associated with a human venlafaxine dose of 225 mg/day.
# Clinical Studies
Major Depressive Disorder
- The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for major depressive disorder was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depressive disorder.
- A 12-week study utilizing Effexor XR doses in a range 75 to 150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing Effexor XR doses in a range 75 to 225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of Effexor XR over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the MADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and the CGI Global Improvement item. In both studies, Effexor XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score.
- A 4-week study of inpatients meeting DSM-III-R criteria for major depressive disorder with melancholia utilizing Effexor (immediate release) in a range of 150 to 375 mg/day (t.i.d. schedule) demonstrated superiority of Effexor over placebo. The mean dose in completers was 350 mg/day.
- Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.
- In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo.
- In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved during an initial 26 weeks of treatment on Effexor (immediate release) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.
Generalized Anxiety Disorder
- The efficacy of Effexor XR capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies, one 6-month, placebo-controlled, fixed-dose study, and one 6-month, placebo-controlled, flexible-dose study in adult outpatients meeting DSM-IV criteria for GAD.
- One 8-week study evaluating Effexor XR doses of 75, 150, and 225 mg/day, and placebo showed that the 225 mg/day dose was more effective than placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. While there was also evidence for superiority over placebo for the 75 and 150 mg/day doses, these doses were not as consistently effective as the highest dose. A second 8-week study evaluating Effexor XR doses of 75 and 150 mg/day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg/day dose was more consistently effective than the 150 mg/day dose. A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg/day dose range utilized in these two studies.
- Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg/day and the other evaluating Effexor XR doses of 75 to 225 mg/day, showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher doses.
- Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.
Social Anxiety Disorder (Social Phobia)
- The efficacy of Effexor XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study in adult outpatients meeting DSM-IV criteria for Social Anxiety Disorder. Patients received doses in a range of 75 to 225 mg/day. Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). In these five trials, Effexor XR was significantly more effective than placebo on change from baseline to endpoint on the LSAS total score. There was no evidence for any greater effectiveness of the 150 to 225 mg/day group compared to the 75 mg/day group in the 6-month study.
- Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.
Panic Disorder
- The efficacy of Effexor XR capsules as a treatment for panic disorder was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for panic disorder, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg/day in one study and 75 or 225 mg/day in the other study.
- Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of patients rated as responders (much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two trials, Effexor XR was significantly more effective than placebo in all three variables.
- In the two 12-week studies described above, one evaluating Effexor XR doses of 75 and 150 mg/day and the other evaluating Effexor XR doses of 75 and 225 mg/day, efficacy was established for each dose. A dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies.
- Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.
- In a longer-term study, adult outpatients meeting DSM-IV criteria for panic disorder who had responded during a 12-week open phase with Effexor XR (75 to 225 mg/day) were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the randomized phase following the 12-week open-label period, patients receiving continued Effexor XR experienced a significantly longer time to relapse.
# How Supplied
Effexor XR (venlafaxine hydrochloride) extended-release capsules are available as follows:
- 37.5 mg, grey cap/peach body with W and "Effexor XR" on the cap and "37.5" on the body.
- NDC 0008-0837-20, bottle of 15 capsules in unit of use package.
- NDC 0008-0837-21, bottle of 30 capsules in unit of use package.
- NDC 0008-0837-22, bottle of 90 capsules in unit of use package.
- NDC 0008-0837-03, carton of 10 Redipak ® blister strips of 10 capsules each.
- 75 mg, peach cap and body with W and "Effexor XR" on the cap and "75" on the body.
- NDC 0008-0833-20, bottle of 15 capsules in unit of use package.
- NDC 0008-0833-21, bottle of 30 capsules in unit of use package.
- NDC 0008-0833-22, bottle of 90 capsules in unit of use package.
- NDC 0008-0833-03, carton of 10 Redipak ® blister strips of 10 capsules each.
- 150 mg, dark orange cap and body with W and "Effexor XR" on the cap and "150" on the body.
- NDC 0008-0836-20, bottle of 15 capsules in unit of use package.
- NDC 0008-0836-21, bottle of 30 capsules in unit of use package.
- NDC 0008-0836-22, bottle of 90 capsules in unit of use package.
- NDC 0008-0836-03, carton of 10 Redipak ® blister strips of 10 capsules each.
## Storage
- Store at controlled room temperature, 20° to 25°C (68° to 77°F).
- The unit of use package is intended to be dispensed as a unit.
- The appearance of these capsules is a trademark of Wyeth Pharmaceuticals.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor XR and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for Effexor XR. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
- Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Effexor XR.
# Precautions with Alcohol
- Alcohol-Venlafaxine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Venlafaxine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
# Disclaimer
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# Black Box Warning
# Overview
Venlafaxine is an antidepressive agents that is FDA approved for the treatment of major depressive disorder, generalized anxiety disorder, social anxiety disorder, panic disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, sweating, weight loss, constipation, loss of appetite, nausea, xerostomia, asthenia, dizziness, dream disorder, headache, insomnia, somnolence, tremor, blurred vision, feeling nervous, abnormal ejaculation, erectile dysfunction, orgasm disorder.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Effexor XR (venlafaxine hydrochloride) extended-release capsules are indicated for the treatment of major depressive disorder.
- The efficacy of Effexor XR in the treatment of major depressive disorder was established in 8- and 12-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see Clinical Trials).
- A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
- The efficacy of Effexor (immediate release) in the treatment of major depressive disorder in adult inpatients meeting diagnostic criteria for major depressive disorder with melancholia was established in a 4-week controlled trial (see Clinical Trials). The safety and efficacy of Effexor XR in hospitalized depressed patients have not been adequately studied.
- The efficacy of Effexor XR in maintaining a response in major depressive disorder for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor (immediate release) in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see Clinical Trials). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Dosing Information
- For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of Effexor XR in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for Effexor XR has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140 to 180 mg/day.
- It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for Effexor (immediate release), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of Effexor XR are needed for more severely depressed patients is unknown; however, the experience with Effexor XR doses higher than 225 mg/day is very limited.
- Effexor XR is indicated for the treatment of Generalized Anxiety Disorder (GAD) as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
- The efficacy of Effexor XR in the treatment of GAD was established in 8-week and 6-month placebo-controlled trials in adult outpatients diagnosed with GAD according to DSM-IV criteria (see Clinical Trials).
- Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance.
- Although the effectiveness of Effexor XR has been demonstrated in 6-month clinical trials in patients with GAD, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Dosing Information
- For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Generalized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in GAD was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days.
- Effexor XR is indicated for the treatment of Social Anxiety Disorder, also known as Social Phobia, as defined in DSM-IV (300.23).
- Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
- The efficacy of Effexor XR in the treatment of Social Anxiety Disorder was established in four 12-week and one 6-month placebo-controlled trials in adult outpatients with Social Anxiety Disorder (DSM-IV) (see Clinical Trials).
- Although the effectiveness of Effexor XR has been demonstrated in a 6-month clinical trial in patients with Social Anxiety Disorder, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Dosing Information
- The recommended dose is 75 mg/day, administered in a single dose. There was no evidence that higher doses confer any additional benefit.
- Effexor XR is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.
- Panic disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, ie, a discrete period of intense fear or discomfort, in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, lightheaded, or faint; 9) derealization (feelings of unreality) or depersonalization (being detached from oneself); 10) fear of losing control; 11) fear of dying; 12) paresthesias (numbness or tingling sensations); 13) chills or hot flushes.
- The efficacy of Effexor XR in the treatment of panic disorder was established in two 12-week placebo-controlled trials in adult outpatients with panic disorder (DSM-IV). The efficacy of Effexor XR in prolonging time to relapse in panic disorder among responders following 12 weeks of open-label acute treatment was demonstrated in a placebo-controlled study (see CLINICAL PHARMACOLOGY, Clinical Trials). Nevertheless, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Dosing Information
- It is recommended that initial single doses of 37.5 mg/day of Effexor XR be used for 7 days. In clinical trials establishing the efficacy of Effexor XR in outpatients with panic disorder, initial doses of 37.5 mg/day for 7 days were followed by doses of 75 mg/day and subsequent weekly dose increases of 75 mg/day to a maximum dose of 225 mg/day. Although a dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies, certain patients not responding to 75 mg/day may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 7 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by:
- Class of Recommendation: Adult, Class IIb
- Strength of Evidence: Adult, Category C
- Dosing Information
- Dosage
### Non–Guideline-Supported Use
- Obsessive-compulsive disorder
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Venlafaxine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
# Contraindications
- Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation.
- The use of MAOIs intended to treat psychiatric disorders with Effexor XR or within 7 days of stopping treatment with Effexor XR is contraindicated because of an increased risk of serotonin syndrome. The use of Effexor XR within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
- Starting Effexor XR in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.
# Warnings
Clinical Worsening and Suicide Risk
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
- If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder
- A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor XR is not approved for use in treating bipolar depression.
Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Effexor XR, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- The concomitant use of Effexor XR with MAOIs intended to treat psychiatric disorders is contraindicated. Effexor XR should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking Effexor XR. Effexor XR should be discontinued before initiating treatment with the MAOI.
- If concomitant use of Effexor XR with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
- Treatment with Effexor XR and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma
- The pupillary dilation that occurs following use of many antidepressant drugs including Effexor XR may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Sustained Hypertension
- Effexor XR treatment is associated with sustained hypertension (defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits (see Table 2).
- An analysis for patients in Effexor (immediate release) studies meeting criteria for sustained hypertension revealed a dose-dependent increase in the incidence of sustained hypertension for Effexor (immediate release) (see Table 3).
- An insufficient number of patients received mean doses of Effexor XR over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.
- In premarketing major depressive disorder studies, 0.7% (5/705) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up to 6 months). In premarketing Social Anxiety Disorder studies up to 6 months, 0.6% (5/771) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were modest (1–24 mm Hg, SDBP). *In premarketing panic disorder studies up to 12 weeks, 0.5% (5/1001) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were in a modest range (7 to 19 mm Hg, SDBP).
- Sustained increases of SDBP could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered.
Elevations in Systolic and Diastolic Blood Pressure
- In placebo-controlled premarketing studies, there were changes in mean blood pressure (see Table 4 for mean changes in supine systolic and supine diastolic blood pressure). Across most indications, a dose-related increase in supine systolic and diastolic blood pressure was evident in Effexor XR-treated patients.
- Across all clinical trials in MDD, GAD, Social Anxiety Disorder and panic disorder, 1.4% of patients in the Effexor XR-treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure with blood pressure ≥105 mm Hg compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Effexor XR-treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure with blood pressure ≥180 mm Hg compared to 0.3% of patients in the placebo groups.
### PRECAUTIONS
General
Discontinuation of Treatment with Effexor XR
- Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder, and Social Anxiety Disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.
- During marketing of Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
- Patients should be monitored for these symptoms when discontinuing treatment with Effexor XR. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
Insomnia and Nervousness
- Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with Effexor XR (venlafaxine hydrochloride) extended-release capsules than with placebo in pooled analyses of short-term major depressive disorder, GAD, Social Anxiety Disorder, and panic disorder studies, as shown in Table 5.
- Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with Effexor XR in major depressive disorder studies.
- In GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively, of the patients treated with Effexor XR up to 8 weeks and 2% and 0.7%, respectively, of the patients treated with Effexor XR up to 6 months.
- In Social Anxiety Disorder trials, insomnia and nervousness led to drug discontinuation in 2% and 1%, respectively, of the patients treated with Effexor XR up to 12 weeks and 2% and 3% respectively, of the patients treated with Effexor XR up to 6 months.
- In panic disorder trials, insomnia and nervousness led to drug discontinuation in 1% and 0.1%, respectively, of the patients treated with Effexor XR up to 12 weeks.
Changes in Weight
Adult Patients
- A loss of 5% or more of body weight occurred in 7% of Effexor XR-treated and 2% of placebo-treated patients in the short-term placebo-controlled major depressive disorder trials. The discontinuation rate for weight loss associated with Effexor XR was 0.1% in major depressive disorder studies. In placebo-controlled GAD studies, a loss of 7% or more of body weight occurred in 3% of Effexor XR patients and 1% of placebo patients who received treatment for up to 6 months. The discontinuation rate for weight loss was 0.3% for patients receiving Effexor XR in GAD studies for up to eight weeks. In placebo-controlled Social Anxiety Disorder trials, 4% of the Effexor XR-treated and 1% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 6 months of treatment. None of the patients receiving Effexor XR in Social Anxiety Disorder studies discontinued for weight loss. In placebo-controlled panic disorder trials, 3% of the Effexor XR-treated and 2% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 12 weeks of treatment. None of the patients receiving Effexor XR in panic disorder studies discontinued for weight loss.
- The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor XR and weight loss agents is not recommended. Effexor XR is not indicated for weight loss alone or in combination with other products.
Pediatric Patients
- Weight loss has been observed in pediatric patients (ages 6–17) receiving Effexor XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated patients; p<0.001). In a 16-week, double-blind, placebo-controlled, flexible dose outpatient trial for Social Anxiety Disorder, Effexor XR-treated patients lost an average of 0.75 kg (n = 137), while placebo-treated patients gained an average of 0.76 kg (n = 148). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in the Social Anxiety Disorder study (47% of Effexor XR-treated patients vs. 14% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia.
- The risks associated with longer-term Effexor XR use were assessed in an open-label MDD study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (≥12 years old).
Changes in Height
Pediatric Patients
- During the eight-week, placebo-controlled GAD studies, Effexor XR-treated patients (ages 6–17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). During the 16-week, placebo-controlled Social Anxiety Disorder study, both the Effexor XR-treated (n = 109) and the placebo-treated (n = 112) patients each grew an average of 1.0 cm. In the six-month, open-label MDD study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (≥12 years old).
Changes in Appetite
Adult Patients
- Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (4%) in the pool of short-term, double-blind, placebo-controlled major depressive disorder studies. The discontinuation rate for anorexia associated with Effexor XR was 1.0% in major depressive disorder studies. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled GAD studies. The discontinuation rate for anorexia was 0.9% for patients receiving Effexor XR for up to 8 weeks in GAD studies. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (17%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled Social Anxiety Disorder studies. The discontinuation rate for anorexia was 0.6% for patients receiving Effexor XR for up to 12 weeks in Social Anxiety Disorder studies; no patients discontinued for anorexia between week 12 and month 6. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (3%) in the pool of short-term, double-blind, placebo-controlled panic disorder studies. The discontinuation rate for anorexia was 0.4% for patients receiving Effexor XR for up to 12 weeks in panic disorder studies.
Pediatric Patients
- Decreased appetite has been observed in pediatric patients receiving Effexor XR. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6-17 treated with Effexor XR for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving Effexor XR discontinued for anorexia or weight loss. In the placebo-controlled trial for Social Anxiety Disorder, 22% and 3% of patients aged 8-17 treated for up to 16 weeks with Effexor XR and placebo, respectively, reported treatment-emergent anorexia (decreased appetite). The discontinuation rates for anorexia were 0.7% and 0.0% for patients receiving Effexor XR and placebo, respectively; the discontinuation rates for weight loss were 0.7% for patients receiving either Effexor XR or placebo.
Activation of Mania/Hypomania
- During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of Effexor XR-treated patients and no placebo patients. In premarketing GAD studies, no Effexor XR-treated patients and 0.2% of placebo-treated patients experienced mania or hypomania. In premarketing Social Anxiety Disorder studies, 0.2% Effexor XR-treated patients and no placebo-treated patients experienced mania or hypomania. In premarketing panic disorder studies, 0.1% of Effexor XR-treated patients and no placebo-treated patients experienced mania or hypomania. In all premarketing major depressive disorder trials with Effexor (immediate release), mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with no placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, Effexor XR should be used cautiously in patients with a history of mania.
Hyponatremia
- Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Effexor XR. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of Effexor XR should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
- Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Seizures
- During premarketing experience, no seizures occurred among 705 Effexor XR-treated patients in the major depressive disorder studies, among 1381 Effexor XR-treated patients in GAD studies, or among 819 Effexor XR-treated patients in Social Anxiety Disorder studies. In panic disorder studies, 1 seizure occurred among 1,001 Effexor XR-treated patients. In all premarketing major depressive disorder trials with Effexor (immediate release), seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Effexor XR, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures.
Abnormal Bleeding
- SSRIs and SNRIs, including Effexor XR, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.
- Patients should be cautioned about the risk of bleeding associated with the concomitant use of Effexor XR and NSAIDs, aspirin, or other drugs that affect coagulation.
Serum Cholesterol Elevation
- Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials. Measurement of serum cholesterol levels should be considered during long-term treatment.
Interstitial Lung Disease and Eosinophilic Pneumonia
- Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered.
Use in Patients With Concomitant Illness
- Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor XR to patients with diseases or conditions that could affect hemodynamic responses or metabolism.
- Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine's premarketing testing. The electrocardiograms were analyzed for 275 patients who received Effexor XR and 220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in major depressive disorder, for 610 patients who received Effexor XR and 298 patients who received placebo in 8-week double-blind, placebo-controlled trials in GAD, for 593 patients who received Effexor XR and 534 patients who received placebo in 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder, and for 661 patients who received Effexor XR and 395 patients who received placebo in three 10- to 12-week double-blind, placebo-controlled trials in panic disorder. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in major depressive disorder studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). The mean change from baseline in QTc interval for Effexor XR-treated patients in the GAD studies did not differ significantly from that with placebo. The mean change from baseline in QTc interval for Effexor XR-treated patients in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 3.4 msec for Effexor XR and decrease of 1.6 msec for placebo). The mean change from baseline in QTc interval for Effexor XR-treated patients in the panic disorder studies was increased relative to that for placebo-treated patients (increase of 1.5 msec for Effexor XR and decrease of 0.7 msec for placebo).
- In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients in the major depressive disorder studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the GAD studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for Effexor XR and no change for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for Effexor XR and no change for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the panic disorder studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for Effexor XR and a mean decrease of less than 1 beat per minute for placebo).
- In a flexible-dose study, with Effexor (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group.
- As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (e.g., patients with hyperthyroidism, heart failure, or recent myocardial infarction).
- Evaluation of the electrocardiograms for 769 patients who received Effexor (immediate release) in 4- to 6-week double-blind, placebo-controlled trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo.
- In patients with renal impairment (GFR = 10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary. Effexor XR, like all drugs effective in the treatment of major depressive disorder, should be used with caution in such patients.
Clinical Worsening and Suicide Risk
- Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Interference with Cognitive and Motor Performance
- Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely affect their ability to engage in such activities.
Concomitant Medication
- Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions.
- Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Effexor XR and triptans, tramadol, tryptophan supplements or other serotonergic agents.
- Patients should be advised that taking Effexor XR can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
- Patients should be cautioned about the concomitant use of Effexor XR and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding).
Alcohol
- Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine.
Allergic Reactions
- Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.
Pregnancy
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Nursing
- Patients should be advised to notify their physician if they are breast-feeding an infant.
Laboratory Tests
- There are no specific laboratory tests recommended.
# Adverse Reactions
## Clinical Trials Experience
- The information included in the Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR subsection is based on data from a pool of three 8- and 12-week controlled clinical trials in major depressive disorder (includes two U.S. trials and one European trial), on data up to 8 weeks from a pool of five controlled clinical trials in GAD with Effexor XR®, on data up to 12 weeks from a pool of five controlled clinical trials in Social Anxiety Disorder, and on data up to 12 weeks from a pool of four controlled clinical trials in panic disorder. Information on additional adverse events associated with Effexor XR in the entire development program for the formulation and with Effexor (immediate release) is included in the Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR subsection.
- Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR
Adverse Events Associated with Discontinuation of Treatment
- Approximately 11% of the 357 patients who received Effexor XR (venlafaxine hydrochloride) extended-release capsules in placebo-controlled clinical trials for major depressive disorder discontinued treatment due to an adverse experience, compared with 6% of the 285 placebo-treated patients in those studies. Approximately 18% of the 1381 patients who received Effexor XR capsules in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. Approximately 15% of the 819 patients who received Effexor XR capsules in placebo-controlled clinical trials for Social Anxiety Disorder discontinued treatment due to an adverse experience, compared with 5% of the 695 placebo-treated patients in those studies. Approximately 7% of the 1,001 patients who received Effexor XR capsules in placebo-controlled clinical trials for panic disorder discontinued treatment due to an adverse experience, compared with 6% of the 662 placebo-treated patients in those studies. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the Effexor XR-treated patients at a rate at least twice that of placebo for any indication) are shown in Table 6.
- Adverse Events Occurring at an Incidence of 2% or More Among Effexor XR-Treated Patients
- Tables 7, 8, 9, and 10 enumerate the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of major depressive disorder (up to 12 weeks; dose range of 75 to 225 mg/day), of GAD (up to 8 weeks; dose range of 37.5 to 225 mg/day), of Social Anxiety Disorder (up to 12 weeks; dose range of 75 to 225 mg/day), and of panic disorder (up to 12 weeks; dose range of 37.5 to 225 mg/day), respectively, in 2% or more of patients treated with Effexor XR (venlafaxine hydrochloride) where the incidence in patients treated with Effexor XR was greater than the incidence for the respective placebo-treated patients. The table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.
- The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.
- Commonly Observed Adverse Events from Tables 7, 8, 9, and 10:
Major Depressive Disorder
- Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the major depressive disorder indication (Table 7): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. In the two U.S. placebo-controlled trials, the following additional events occurred in at least 5% of Effexor XR-treated patients (n = 192) and at a rate at least twice that of the placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women, and libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complaints (insomnia, nervousness, and tremor), problems of special senses (abnormal vision), cardiovascular effects (hypertension and vasodilatation), and yawning.
Generalized Anxiety Disorder
- Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the GAD indication (Table 8): Abnormalities of sexual function (abnormal ejaculation and impotence), gastrointestinal complaints (nausea, dry mouth, anorexia, and constipation), problems of special senses (abnormal vision), and sweating.
Social Anxiety Disorder
- Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for the 5 placebo-controlled trials for the Social Anxiety Disorder indication (Table 9): Asthenia, gastrointestinal complaints (anorexia, constipation, dry mouth, nausea), CNS complaints (insomnia, libido decreased, nervousness, somnolence, tremor), abnormalities of sexual function (abnormal ejaculation, impotence), yawn, and sweating.
- In the 6-month trial, the following adverse events occurred twice as often in the 150–225 mg/day Effexor XR group compared to the 75 mg/day Effexor XR group and placebo: vasodilation, libido decreased, tremor, yawn, abnormal vision, and impotence.
Panic Disorder
- Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for 4 placebo-controlled trials for the panic disorder indication (Table 10): gastrointestinal complaints (anorexia, constipation, dry mouth), CNS complaints (somnolence, tremor), abnormalities of sexual function (abnormal ejaculation), and sweating.
Vital Sign Changes
- Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled major depressive disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Effexor XR treatment for up to 8 weeks in premarketing placebo-controlled GAD trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 3 beats per minute, compared with an increase of 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 1 beat per minute, compared with a decrease of less than 1 beat per minute for placebo. (See the Sustained Hypertension and Elevations in Systolic and Diastolic Blood Pressure sections of WARNINGS for effects on blood pressure.)
- In a flexible-dose study, with Effexor (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo.
Laboratory Changes
Serum Cholesterol
- Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Effexor XR treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL, respectively, for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo.
- Patients treated with Effexor (immediate release) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation).
Serum Triglycerides
- Effexor XR treatment for up to 12 weeks in pooled premarketing Social Anxiety Disorder trials was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 8.2 mg/dL, compared with a mean final increase of 0.4 mg/dL for placebo. Effexor XR treatment for up to 6 months in a premarketing Social Anxiety Disorder trial was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 11.8 mg/dL, compared with a mean final on-therapy increase of 1.8 mg/dL for placebo.
- Effexor XR treatment for up to 12 weeks in pooled premarketing Panic Disorder trials was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 5.9 mg/dL, compared with a mean final increase of 0.9 mg/dL for placebo. Effexor XR treatment for up to 6 months in a premarketing Panic Disorder trial was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 9.3 mg/dL, compared with a mean final on-therapy decrease of 0.3 mg/dL for placebo.
ECG Changes
- In a flexible-dose study, with Effexor (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo.
- Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR
- During its premarketing assessment, multiple doses of Effexor XR were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies, 819 patients in Phase 3 Social Anxiety Disorder studies, and 1314 patients in Phase 3 panic disorder studies. In addition, in premarketing assessment of Effexor, multiple doses were administered to 2897 patients in Phase 2 to Phase 3 studies for major depressive disorder. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
- In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 7212 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Tables 7, 8, 9, and 10 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it.
- Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
- Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis, granuloma.
- Cardiovascular system - Frequent: migraine, tachycardia; Infrequent: angina pectoris, arrhythmia, bradycardia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), postural hypotension, syncope; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, hematoma, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneous hemorrhage, myocardial infarct, pallor, sinus arrhythmia, thrombophlebitis.
- Digestive system - Frequent: increased appetite; Infrequent: bruxism, colitis, dysphagia, tongue edema, eructation, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: abdominal distension, biliary pain, cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis, hematemesis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, liver tenderness, parotitis, periodontitis, proctitis, rectal disorder, salivary gland enlargement, increased salivation, soft stools, tongue discoloration.
- Endocrine system - Rare: galactorrhoea, goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis.
- Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura, thrombocytopenia.
- Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipidemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia.
- Musculoskeletal system - Infrequent: arthritis, arthrosis, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: bone pain, pathological fracture, muscle cramp, muscle spasms, musculoskeletal stiffness, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture.
- Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia, thinking abnormal, trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor, suicidal ideation; Rare: abnormal/changed behavior, adjustment disorder, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, energy increased, facial paralysis, abnormal gait, Guillain-Barre Syndrome, homicidal ideation, hyperchlorhydria, hypokinesia, hysteria, impulse control difficulties, motion sickness, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, torticollis.
- Respiratory system - Frequent: cough increased, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea.
- Skin and appendages - Frequent: pruritus; Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, maculopapular rash, psoriasis, urticaria; Rare: brittle nails, erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, miliaria, petechial rash, pruritic rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin hypertrophy, skin striae, sweating decreased.
- Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion; Infrequent: conjunctivitis, diplopia, dry eyes, eye pain, otitis media, parosmia, photophobia, taste loss; Rare: blepharitis, cataract, chromatopsia, conjunctival edema, corneal lesion, deafness, exophthalmos, eye hemorrhage, angle-closure glaucoma, retinal hemorrhage, subconjunctival hemorrhage, hyperacusis, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis, visual field defect.
- Urogenital system - Frequent: albuminuria, urination impaired; Infrequent: amenorrhea,* cystitis, dysuria, hematuria, kidney calculus, kidney pain, leukorrhea,* menorrhagia,* metrorrhagia,* nocturia, breast pain, polyuria, pyuria, prostatic disorder (prostatitis, enlarged prostate, and prostate irritability,* urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage,* vaginitis*; Rare: abortion,* anuria, breast discharge, breast engorgement, balanitis,* breast enlargement, endometriosis,* female lactation,* fibrocystic breast, calcium crystalluria, cervicitis,* orchitis,* ovarian cyst,* bladder pain, prolonged erection,* gynecomastia (male),* hypomenorrhea,* kidney function abnormal, mastitis, menopause,* pyelonephritis, oliguria, salpingitis,* urolithiasis, uterine hemorrhage,* uterine spasm,* vaginal dryness.*
- Based on the number of men and women as appropriate.
### DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
- Effexor XR (venlafaxine hydrochloride) extended-release capsules is not a controlled substance.
Physical and Psychological Dependence
- In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.
- Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.
- Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION).
- While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (eg, development of tolerance, incrementation of dose, drug-seeking behavior).
## Postmarketing Experience
- Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly).
Drug Interactions
- There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy.
# Drug Interactions
As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.
Alcohol
A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine.
Cimetidine
- Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.
Diazepam
- Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam.
Haloperidol
- Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown.
Lithium
- The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below).
Drugs Highly Bound to Plasma Proteins
- Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.
Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Effexor XR is initiated or discontinued.
Drugs that Inhibit Cytochrome P450 Isoenzymes
CYP2D6 Inhibitors
- In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers (see Metabolism and Excretion under CLINICAL PHARMACOLOGY). Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor.
Ketoconazole
- A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O-desmethylvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively.
- Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM (range in PMs -38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMs and 53% in PMs (range in PMs 4% to 134%).
- Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.
Drugs Metabolized by Cytochrome P450 Isoenzymes
CYP2D6
- In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan.
Imipramine
- Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC's increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown.
Metoprolol
- Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30–40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine.
- Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol.
- Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure.
Risperidone
- Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone).
CYP3A4
- Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine.
Indinavir
- In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown.
CYP1A2
- Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate.
CYP2C9
- Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide.
CYP2C19
- Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above).
Monoamine Oxidase Inhibitors
- See CONTRAINDICATIONS, WARNINGS, and ADMINISTRATION and MONITORING.
CNS-Active Drugs
- The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required.
Serotonergic Drugs
Triptans
- There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Effexor XR with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).
Drug-Laboratory Test Interactions
- False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.
Electroconvulsive Therapy
- There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic Effects - Pregnancy Category C
- Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Non-teratogenic Effects
- Neonates exposed to Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions-CNS-Active Drugs). When treating a pregnant woman with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION).
Treatment of Pregnant Women During the Third Trimester
- Neonates exposed to Effexor XR, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Venlafaxine in women who are pregnant.
### Labor and Delivery
- The effect of venlafaxine on labor and delivery in humans is unknown.
### Nursing Mothers
- Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients.
- Anyone considering the use of Effexor XR in a child or adolescent must balance the potential risks with the clinical need.
- Although no studies have been designed to primarily assess Effexor XR's impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height (see PRECAUTIONS, General, Changes in Height and Changes in Weight ). Should the decision be made to treat a pediatric patient with Effexor XR, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration.
- In the studies conducted in pediatric patients (ages 6–17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation).
### Geriatic Use
Approximately 4% (14/357), 6% (77/1381), 1% (10/819), and 2% (16/1001) of Effexor XR-treated patients in placebo-controlled premarketing major depressive disorder, GAD, Social Anxiety Disorder trials, and panic disorder trials, respectively, were 65 years of age or over. Of 2,897 Effexor-treated (immediate release) patients in premarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor XR have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).
- The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION).
- No dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, or panic disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.
### Gender
- There is no FDA guidance on the use of Venlafaxine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Venlafaxine with respect to specific racial populations.
### Renal Impairment
- Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% to 50%. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients.
### Hepatic Impairment
- Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Venlafaxine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Venlafaxine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Effexor XR should be administered in a single dose with food either in the morning or in the evening at approximately the same time each day. Each capsule should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water, or it may be administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water to ensure complete swallowing of the pellets.
Initial Treatment
Major Depressive Disorder
- For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of Effexor XR in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for Effexor XR has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140 to 180 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY).
- It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for Effexor (immediate release), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of Effexor XR are needed for more severely depressed patients is unknown; however, the experience with Effexor XR doses higher than 225 mg/day is very limited. (See PRECAUTIONS-General-Use in Patients with Concomitant Illness.)
Generalized Anxiety Disorder
- For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Generalized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in GAD was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.)
Social Anxiety Disorder (Social Phobia)
- The recommended dose is 75 mg/day, administered in a single dose. There was no evidence that higher doses confer any additional benefit. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.)
Panic Disorder
- It is recommended that initial single doses of 37.5 mg/day of Effexor XR be used for 7 days. In clinical trials establishing the efficacy of Effexor XR in outpatients with panic disorder, initial doses of 37.5 mg/day for 7 days were followed by doses of 75 mg/day and subsequent weekly dose increases of 75 mg/day to a maximum dose of 225 mg/day. Although a dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies, certain patients not responding to 75 mg/day may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 7 days. (See the Use in Patients with Concomitant Illness section of PRECAUTIONS.)
- Switching Patients from Effexor Tablets
- Depressed patients who are currently being treated at a therapeutic dose with Effexor (immediate release) may be switched to Effexor XR at the nearest equivalent dose (mg/day), eg, 37.5 mg venlafaxine two-times-a-day to 75 mg Effexor XR once daily. However, individual dosage adjustments may be necessary.
- Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
- At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Effexor XR. Conversely, at least 7 days should be allowed after stopping Effexor XR before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).
- Use of Effexor XR With Other MAOls, Such as Linezolid or Methylene Blue
- Do not start Effexor XR in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).
- In some cases, a patient already receiving therapy with Effexor XR may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Effexor XR should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Effexor XR may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).
- The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Effexor XR is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
Special Populations
- Treatment of Pregnant Women During the Third Trimester
- Neonates exposed to Effexor XR, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Patients with Hepatic Impairment
- Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients.
Patients with Renal Impairment
- Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared with normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% to 50%. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients.
Elderly Patients
- No dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, or panic disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.
Maintenance Treatment
- There is no body of evidence available from controlled trials to indicate how long patients with major depressive disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, or panic disorder, should be treated with Effexor XR.
- It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see Clinical Trials under CLINICAL PHARMACOLOGY). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
- In patients with Generalized Anxiety Disorder, Effexor XR has been shown to be effective in 6-month clinical trials. The need for continuing medication in patients with GAD who improve with Effexor XR treatment should be periodically reassessed.
- In patients with Social Anxiety Disorder, Effexor XR has been shown to be effective in a 6-month clinical trial. The need for continuing medication in patients with Social Anxiety Disorder who improve with Effexor XR treatment should be periodically reassessed.
- In a study of panic disorder in which patients responding during 12 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day), patients continuing Effexor XR experienced a significantly longer time to relapse than patients randomized to placebo. The need for continuing medication in patients with panic disorder who improve with Effexor XR treatment should be periodically reassessed.
Discontinuing Effexor XR
- Symptoms associated with discontinuation of Effexor XR, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. In clinical trials with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at 1 week intervals. Individualization of tapering may be necessary.
### Monitoring
There is limited information regarding Monitoring of Venlafaxine in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Venlafaxine in the drug label.
# Overdosage
Human Experience
- Among the patients included in the premarketing evaluation of Effexor XR, there were 2 reports of acute overdosage with Effexor XR in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of Effexor XR and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of Effexor XR. This patient reported paresthesia of all four limbs but recovered without sequelae.
- There were 2 reports of acute overdose with Effexor XR in GAD trials. One patient took a combination of 0.75 g of Effexor XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of Effexor XR. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. These symptoms resolved over the next week.
- There were no reports of acute overdose with Effexor XR in Social Anxiety Disorder trials.
- There were 2 reports of acute overdose with Effexor XR in panic disorder trials. One patient took 0.675 g of Effexor XR once, and the other patient took 0.45 g of Effexor XR for 2 days. No signs or symptoms were associated with either overdose, and no actions were taken to treat them.
- Among the patients included in the premarketing evaluation with Effexor (immediate release), there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients.
- In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported.
- Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
Management of Overdosage
- Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.
- Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.
- Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known.
- In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference® (PDR).
# Pharmacology
## Mechanism of Action
-
## Structure
- Effexor XR is an extended-release capsule for oral administration that contains venlafaxine hydrochloride, a structurally novel antidepressant. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below.
- Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43.
- Effexor XR is formulated as an extended-release capsule for once-a-day oral administration. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.
## Pharmacodynamics
- The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity.
## Pharmacokinetics
- Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively).
Absorption
- Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%.
- Administration of Effexor XR (150 mg q24 hours) generally resulted in lower Cmax (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than for Effexor (immediate release) [Cmax's for immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax's were 2 hours for venlafaxine and 3 hours for ODV]. When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Effexor XR, therefore, provides a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet.
- Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM vs PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule.
Metabolism and Excretion
- Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 (“extensive metabolizers”). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent.
- Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion.
Special Populations
Age and Gender
- A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary.
Extensive/Poor Metabolizers
- Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups.
Liver Disease
- In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects.
- In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2–3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted.
- Dosage adjustment is necessary in these hepatically impaired patients.
Renal Disease
- In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR=10 to 70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR=10 to 70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56% compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats.
Mutagenesis
- Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow.
Impairment of Fertility
- Reproduction and fertility studies of venlafaxine in rats showed no adverse effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose of 225 mg/day on a mg/m2 basis.
- However, reduced fertility was observed in a study in which male and female rats were treated with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, prior to and during mating and gestation. This occurred at an ODV exposure (AUC) approximately 2 to 3 times that associated with a human venlafaxine dose of 225 mg/day.
# Clinical Studies
Major Depressive Disorder
- The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for major depressive disorder was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depressive disorder.
- A 12-week study utilizing Effexor XR doses in a range 75 to 150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing Effexor XR doses in a range 75 to 225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of Effexor XR over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the MADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and the CGI Global Improvement item. In both studies, Effexor XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score.
- A 4-week study of inpatients meeting DSM-III-R criteria for major depressive disorder with melancholia utilizing Effexor (immediate release) in a range of 150 to 375 mg/day (t.i.d. schedule) demonstrated superiority of Effexor over placebo. The mean dose in completers was 350 mg/day.
- Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.
- In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo.
- In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10, and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (immediate release) [100 to 200 mg/day, on a b.i.d. schedule] were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.
Generalized Anxiety Disorder
- The efficacy of Effexor XR capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies, one 6-month, placebo-controlled, fixed-dose study, and one 6-month, placebo-controlled, flexible-dose study in adult outpatients meeting DSM-IV criteria for GAD.
- One 8-week study evaluating Effexor XR doses of 75, 150, and 225 mg/day, and placebo showed that the 225 mg/day dose was more effective than placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. While there was also evidence for superiority over placebo for the 75 and 150 mg/day doses, these doses were not as consistently effective as the highest dose. A second 8-week study evaluating Effexor XR doses of 75 and 150 mg/day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg/day dose was more consistently effective than the 150 mg/day dose. A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg/day dose range utilized in these two studies.
- Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg/day and the other evaluating Effexor XR doses of 75 to 225 mg/day, showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher doses.
- Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.
Social Anxiety Disorder (Social Phobia)
- The efficacy of Effexor XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study in adult outpatients meeting DSM-IV criteria for Social Anxiety Disorder. Patients received doses in a range of 75 to 225 mg/day. Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). In these five trials, Effexor XR was significantly more effective than placebo on change from baseline to endpoint on the LSAS total score. There was no evidence for any greater effectiveness of the 150 to 225 mg/day group compared to the 75 mg/day group in the 6-month study.
- Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.
Panic Disorder
- The efficacy of Effexor XR capsules as a treatment for panic disorder was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for panic disorder, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg/day in one study and 75 or 225 mg/day in the other study.
- Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of patients rated as responders (much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two trials, Effexor XR was significantly more effective than placebo in all three variables.
- In the two 12-week studies described above, one evaluating Effexor XR doses of 75 and 150 mg/day and the other evaluating Effexor XR doses of 75 and 225 mg/day, efficacy was established for each dose. A dose-response relationship for effectiveness in patients with panic disorder was not clearly established in fixed-dose studies.
- Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.
- In a longer-term study, adult outpatients meeting DSM-IV criteria for panic disorder who had responded during a 12-week open phase with Effexor XR (75 to 225 mg/day) were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the randomized phase following the 12-week open-label period, patients receiving continued Effexor XR experienced a significantly longer time to relapse.
# How Supplied
Effexor XR (venlafaxine hydrochloride) extended-release capsules are available as follows:
- 37.5 mg, grey cap/peach body with W and "Effexor XR" on the cap and "37.5" on the body.
- NDC 0008-0837-20, bottle of 15 capsules in unit of use package.
- NDC 0008-0837-21, bottle of 30 capsules in unit of use package.
- NDC 0008-0837-22, bottle of 90 capsules in unit of use package.
- NDC 0008-0837-03, carton of 10 Redipak ® blister strips of 10 capsules each.
- 75 mg, peach cap and body with W and "Effexor XR" on the cap and "75" on the body.
- NDC 0008-0833-20, bottle of 15 capsules in unit of use package.
- NDC 0008-0833-21, bottle of 30 capsules in unit of use package.
- NDC 0008-0833-22, bottle of 90 capsules in unit of use package.
- NDC 0008-0833-03, carton of 10 Redipak ® blister strips of 10 capsules each.
- 150 mg, dark orange cap and body with W and "Effexor XR" on the cap and "150" on the body.
- NDC 0008-0836-20, bottle of 15 capsules in unit of use package.
- NDC 0008-0836-21, bottle of 30 capsules in unit of use package.
- NDC 0008-0836-22, bottle of 90 capsules in unit of use package.
- NDC 0008-0836-03, carton of 10 Redipak ® blister strips of 10 capsules each.
## Storage
- Store at controlled room temperature, 20° to 25°C (68° to 77°F).
- The unit of use package is intended to be dispensed as a unit.
- The appearance of these capsules is a trademark of Wyeth Pharmaceuticals.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor XR and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for Effexor XR. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
- Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Effexor XR.
# Precautions with Alcohol
- Alcohol-Venlafaxine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Effexor | |
f52ccca792572b35a38d95d6d3544fb66136185d | wikidoc | Egg allergy | Egg allergy
# Overview
Egg allergy is a type of food allergy. It is a hypersensitivity to dietary substances from the yolk or whites of eggs, causing an overreaction of the immune system which may lead to severe physical symptoms for millions of people around the world.
Egg allergy appears mainly, but not exclusively, in children. In fact, it is the second most common food allergy in children. (The most common is cows' milk allergy.) It is usually treated with an exclusion diet and vigilant avoidance of foods that may be contaminated with egg. The most severe food allergy reaction is called anaphylaxis and is an emergency situation requiring immediate attention and treatment with epinephrine. The Asthma and Allergy Foundation of America estimates that most children outgrow egg allergy by the age of five, but some people remain allergic for a lifetime.
# Antigens
Most people who are allergic to hen's eggs have antibodies which react to one of four proteins in the egg white: ovomucoid, ovalbumin, ovotransferrin, and lysozyme; ovomucoid, also called Gal d 1, is the most common target of immune system attack. The egg yolk contains several potential antigens: livetin, apovitillin, and phosvitin.
A person who reacts only to a protein in the egg yolk may be able to easily tolerate egg whites, and vice versa. Some people will be allergic to proteins in both the egg white and the egg yolk. Egg yolk allergies may be somewhat more common in adults. A small number of people who are allergic to eggs will develop an allergy to chicken or other poultry meats.
# Diagnosis
Diagnosis is generally made through a combination of skin prick testing or blood testing and detailed records of all foods and drink the person regularly ingests.
# Treatment
There is currently no cure for egg allergy.
Most people who are allergic to eggs avoid eating any form of egg or egg component. For people with more serious allergic reactions to eggs, such as urticaria (hives), inflammation, and/or anaphylaxis, doctors suggest carrying an EpiPen for use in emergency. Certain food companies also produce egg substitutes, artificial brands of egg mix or batter, which have the same cooking properties of natural eggs but are free of allergens, allowing safe consumption by those whom are allergic.
# Prognosis
In a study presented at the 2007 American Academy of Allergy, Asthma, and Immunology (AAAAI) meeting, 50% of patients outgrew egg allergy by age 17. Of those patients who outgrew it, 45% did so by age 5. Children who outgrew the allergy tended to have peak IgE levels at around age one, which then decline.
# Vaccine hazard
The flu vaccine is typically made using chicken embryo, and as a result the final vaccine does contain egg proteins. Egg-allergic individuals may react to egg protein(s) in the vaccine (or to gelatin or neomycin if they are allergic to that). If an individual is unable to take the vaccine, vaccinating all other members of their family can help protect them from the flu (see Herd immunity).
Different brands and even individual batches of flu vaccine do vary in their egg protein content. Allergists formerly used skin testing with flu vaccine to predict if receiving the flu shot might be safe, but the results of this type of testing are totally unpredictive and this type of testing should be abandoned. Instead, the age-appropriate immunization material containing the lowest amount of egg proteins should be chosen, then a 1/10 dose should be given followed by a 30-minute observation period in a medical setting fully equipped to treat any possible reaction. Ovalbumin is usually used as a marker for the egg proteins. Vaccines available as recently as 2010 in the US contained up to 21 µg of ovalbumin per 0.5 mL dose. In 2011 the ovalbumin content varies from less than 5.0 µg/dose down to less than 0.05 µg/dose, depending on the brand. One study done on 83 egg allergic patients resulted in a lack of serious reactions at doses of ovalbumin ranging from 0.10 µg to 0.60 µg. Thus so some brands available in the US in 2011 are probably safe for most egg allergic patients (administered with caution), but others may not be. For reference modern MMR vaccine (which is generally accepted now to be well tolerated by egg allergic patients, but which is still given with caution) was shown in a 2009 study reported in the BMJ to contain 0.0005 to 0.0010 µg/dose (0.5 to 1.0 ng/dose).
Egg proteins can also be found in yellow fever vaccine and MMR vaccine. The quantity of egg protein in a dose of MMR vaccine is approximately 40 picograms (much lower than in influenza vaccine, which contains approximately 0.02-1.0 micrograms), and this is believed to be associated with a much lower risk.
# Cooking without eggs
In cooking, eggs are multifunctional: they may act as an emulsifier to reduce oil/water separation (mayonnaise), a binder (water binding and particle adhesion, as in meatloaf), or an aerator (cakes, especially angel food). Some commercial egg replacers can substitute for particular functions potato starch and tapioca for water binding, whey protein for aeration or particle binding, or soy lecithin for emulsification). For home use, one-half cup of applesauce can replace one egg in some baking recipes.
Most people find it necessary to strictly avoid any item containing eggs, including:
- Albumin
- Apovitellin
- Cholesterol-free egg substitute (e.g. Eggbeaters)
- Dried egg solids, dried egg
- Egg, egg white, egg yolk
- Egg wash
- Eggnog
- Fat substitutes (some)
- Globulin
- Livetin
- Lysozyme
- Mayonnaise
- Meringue or meringue powder
- Ovalbumin
- Ovoglobulin
- Ovomucin
- Ovomucoid
- Ovotransferrin
- Ovovitelia
- Ovovitellin
- Powdered eggs
- Silici albuminate
- Simplesse
- Trailblazer
- Vitellin
- Whole egg
Ingredients that sometimes include egg are:
- Artificial flavoring
- Lecithin
- Natural flavoring
- Nougat
# Egg white intolerance
Egg whites, which are potent histamine liberators, also provoke a nonallergic response in some people. In this situation, proteins in egg white directly trigger the release of histamine from mast cells on contact. Because this mechanism is classified as a pharmacological reaction, or "pseudoallergy", the condition is considered a food intolerance instead of a true IgE-based allergic reaction.
The response is usually localized, typically in the gastrointestinal tract. Symptoms may include abdominal pain, diarrhea, or any symptoms of histamine release. If sufficiently strong, it can result in an anaphylactoid reaction, which is clinically indistinguishable from true anaphylaxis.
Some people with this condition tolerate small quantities of egg whites. They are more often able to tolerate well-cooked eggs, such as found in cake or dried egg-based pasta, than loosely cooked eggs, such as fried eggs or meringues, or uncooked eggs.
# Notable people allergic to eggs
Famous people allergic to eggs include:
- Elizabeth Bird, wife of Alfred Bird, who invented the famous egg-free Bird's Custard, the original version of what is known generically as custard powder today.
- NFL player Drew Brees
- Zooey Deschanel
- Seal
- Jason Mantzoukas
- Former Serbian Prime Minister and war criminal Nikola Šainović | Egg allergy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Egg allergy is a type of food allergy. It is a hypersensitivity to dietary substances from the yolk or whites of eggs, causing an overreaction of the immune system which may lead to severe physical symptoms for millions of people around the world.[1]
Egg allergy appears mainly, but not exclusively, in children. In fact, it is the second most common food allergy in children.[2] (The most common is cows' milk allergy.) It is usually treated with an exclusion diet and vigilant avoidance of foods that may be contaminated with egg. The most severe food allergy reaction is called anaphylaxis[3] and is an emergency situation requiring immediate attention and treatment with epinephrine. The Asthma and Allergy Foundation of America estimates that most children outgrow egg allergy by the age of five, but some people remain allergic for a lifetime.[4]
# Antigens
Most people who are allergic to hen's eggs have antibodies which react to one of four proteins in the egg white:[5] ovomucoid, ovalbumin, ovotransferrin, and lysozyme; ovomucoid, also called Gal d 1, is the most common target of immune system attack.[5] The egg yolk contains several potential antigens: livetin, apovitillin, and phosvitin.
A person who reacts only to a protein in the egg yolk may be able to easily tolerate egg whites, and vice versa. Some people will be allergic to proteins in both the egg white and the egg yolk. Egg yolk allergies may be somewhat more common in adults.[5] A small number of people who are allergic to eggs will develop an allergy to chicken or other poultry meats.[5]
# Diagnosis
Diagnosis is generally made through a combination of skin prick testing or blood testing and detailed records of all foods and drink the person regularly ingests.
# Treatment
There is currently no cure for egg allergy.
Most people who are allergic to eggs avoid eating any form of egg or egg component. For people with more serious allergic reactions to eggs, such as urticaria (hives), inflammation, and/or anaphylaxis, doctors suggest carrying an EpiPen for use in emergency. Certain food companies also produce egg substitutes, artificial brands of egg mix or batter, which have the same cooking properties of natural eggs but are free of allergens, allowing safe consumption by those whom are allergic.
# Prognosis
In a study presented at the 2007 American Academy of Allergy, Asthma, and Immunology (AAAAI) meeting, 50% of patients outgrew egg allergy by age 17. Of those patients who outgrew it, 45% did so by age 5. Children who outgrew the allergy tended to have peak IgE levels at around age one, which then decline.[6]
# Vaccine hazard
The flu vaccine is typically made using chicken embryo, and as a result the final vaccine does contain egg proteins. Egg-allergic individuals may react to egg protein(s) in the vaccine (or to gelatin or neomycin if they are allergic to that). If an individual is unable to take the vaccine, vaccinating all other members of their family can help protect them from the flu (see Herd immunity).
Different brands and even individual batches of flu vaccine do vary in their egg protein content. Allergists formerly used skin testing with flu vaccine to predict if receiving the flu shot might be safe, but the results of this type of testing are totally unpredictive and this type of testing should be abandoned. Instead, the age-appropriate immunization material containing the lowest amount of egg proteins should be chosen, then a 1/10 dose should be given followed by a 30-minute observation period in a medical setting fully equipped to treat any possible reaction. Ovalbumin is usually used as a marker for the egg proteins. Vaccines available as recently as 2010 in the US contained up to 21 µg of ovalbumin per 0.5 mL dose. In 2011 the ovalbumin content varies from less than 5.0 µg/dose down to less than 0.05 µg/dose, depending on the brand. One study done on 83 egg allergic patients resulted in a lack of serious reactions at doses of ovalbumin ranging from 0.10 µg to 0.60 µg. Thus so some brands available in the US in 2011 are probably safe for most egg allergic patients (administered with caution), but others may not be. For reference modern MMR vaccine (which is generally accepted now to be well tolerated by egg allergic patients, but which is still given with caution) was shown in a 2009 study reported in the BMJ to contain 0.0005 to 0.0010 µg/dose (0.5 to 1.0 ng/dose).[7][full citation needed]
Egg proteins can also be found in yellow fever vaccine and MMR vaccine.[8] The quantity of egg protein in a dose of MMR vaccine is approximately 40 picograms (much lower than in influenza vaccine, which contains approximately 0.02-1.0 micrograms), and this is believed to be associated with a much lower risk.[9]
# Cooking without eggs
In cooking, eggs are multifunctional: they may act as an emulsifier to reduce oil/water separation (mayonnaise), a binder (water binding and particle adhesion, as in meatloaf), or an aerator (cakes, especially angel food). Some commercial egg replacers can substitute for particular functions potato starch and tapioca for water binding, whey protein for aeration or particle binding, or soy lecithin for emulsification). For home use, one-half cup of applesauce can replace one egg in some baking recipes.[citation needed]
Most people find it necessary to strictly avoid any item containing eggs, including:[10]
- Albumin
- Apovitellin
- Cholesterol-free egg substitute (e.g. Eggbeaters)
- Dried egg solids, dried egg
- Egg, egg white, egg yolk
- Egg wash
- Eggnog
- Fat substitutes (some)
- Globulin
- Livetin
- Lysozyme
- Mayonnaise
- Meringue or meringue powder
- Ovalbumin
- Ovoglobulin
- Ovomucin
- Ovomucoid
- Ovotransferrin
- Ovovitelia
- Ovovitellin
- Powdered eggs
- Silici albuminate
- Simplesse
- Trailblazer
- Vitellin
- Whole egg
Ingredients that sometimes include egg are:
- Artificial flavoring
- Lecithin
- Natural flavoring
- Nougat
# Egg white intolerance
Egg whites, which are potent histamine liberators, also provoke a nonallergic response in some people. In this situation, proteins in egg white directly trigger the release of histamine from mast cells on contact.[11][12] Because this mechanism is classified as a pharmacological reaction, or "pseudoallergy",[11] the condition is considered a food intolerance instead of a true IgE-based allergic reaction.
The response is usually localized, typically in the gastrointestinal tract.[11] Symptoms may include abdominal pain, diarrhea, or any symptoms of histamine release. If sufficiently strong, it can result in an anaphylactoid reaction, which is clinically indistinguishable from true anaphylaxis.[12]
Some people with this condition tolerate small quantities of egg whites.[13] They are more often able to tolerate well-cooked eggs, such as found in cake or dried egg-based pasta, than loosely cooked eggs, such as fried eggs or meringues, or uncooked eggs.[13]
# Notable people allergic to eggs
Famous people allergic to eggs include:
- Elizabeth Bird, wife of Alfred Bird, who invented the famous egg-free Bird's Custard, the original version of what is known generically as custard powder today.[citation needed]
- NFL player Drew Brees [14]
- Zooey Deschanel [15]
- Seal [16]
- Jason Mantzoukas [17]
- Former Serbian Prime Minister and war criminal Nikola Šainović [18] | https://www.wikidoc.org/index.php/Egg_allergy | |
646efb30b752988a38c005798bd0be7434685f48 | wikidoc | Egocentrism | Egocentrism
In psychology, egocentrism is defined as
a) the incomplete differentiation of the self and the world, including other people and
b) the tendency to perceive, understand and interpret the world in terms of the self. The term derives from the Greek egô, meaning "I". An egocentric person has no theory of mind, cannot "put himself in other people's shoes," and believes everyone sees what he sees (or that what he sees in some way exceeds what others see.)
It appears that this is shown mostly in younger children. They are unable to separate their own beliefs, thoughts and ideas from others. For example, if a child sees that there is candy in a box, he assumes that someone else walking into the room also knows that there is candy in that box. He reasons that "since I know it, you should too". As stated previously this may be rooted in the limitations in the child's theory of mind skills. However, it does not mean that children are unable to put their selves in someone else's shoes. As far as feelings are concerned, it is shown that children exhibit empathy early on and are able to cooperate with others and be aware of their needs and wants.
Jean Piaget (1896-1980) claimed that young children are egocentric. This does not mean that they are selfish, but that they do not have the mental ability to understand that other people may have different opinions and beliefs from themselves. Piaget did a test to investigate egocentrism called the mountains study. He put children in front of a simple plaster mountain range and then asked them to pick from four pictures the view that he, Piaget, would see. Younger children picked the picture of the view they themselves saw.
However the Mountains Study has been criticized for judging children's visual spatial awareness, rather than egocentrism. A follow up study involving police dolls showed that even young children were able to correctly say what the interviewer would see. It is thought that Piaget overestimated the levels of egocentrism in children.
Egocentrism is the child's inability to see other people's view points. The child at this stage of cognitive development assumes that their view of the world is the same as other peoples, e.g. a little girl covers her eyes and says 'mummy you can't see me now, can you?' | Egocentrism
In psychology, egocentrism is defined as
a) the incomplete differentiation of the self and the world, including other people and
b) the tendency to perceive, understand and interpret the world in terms of the self. The term derives from the Greek egô, meaning "I". An egocentric person has no theory of mind, cannot "put himself in other people's shoes," and believes everyone sees what he sees (or that what he sees in some way exceeds what others see.)
It appears that this is shown mostly in younger children. They are unable to separate their own beliefs, thoughts and ideas from others. For example, if a child sees that there is candy in a box, he assumes that someone else walking into the room also knows that there is candy in that box. He reasons that "since I know it, you should too". As stated previously this may be rooted in the limitations in the child's theory of mind skills. However, it does not mean that children are unable to put their selves in someone else's shoes. As far as feelings are concerned, it is shown that children exhibit empathy early on and are able to cooperate with others and be aware of their needs and wants.
Jean Piaget (1896-1980) claimed that young children are egocentric. This does not mean that they are selfish, but that they do not have the mental ability to understand that other people may have different opinions and beliefs from themselves. Piaget did a test to investigate egocentrism called the mountains study. He put children in front of a simple plaster mountain range and then asked them to pick from four pictures the view that he, Piaget, would see. Younger children picked the picture of the view they themselves saw.
However the Mountains Study has been criticized for judging children's visual spatial awareness, rather than egocentrism. A follow up study involving police dolls showed that even young children were able to correctly say what the interviewer would see. It is thought that Piaget overestimated the levels of egocentrism in children.
Egocentrism is the child's inability to see other people's view points. The child at this stage of cognitive development assumes that their view of the world is the same as other peoples, e.g. a little girl covers her eyes and says 'mummy you can't see me now, can you?' | https://www.wikidoc.org/index.php/Egocentrism | |
3203e1cc500db6406a05468adeb3fd780e4b0271 | wikidoc | Idursulfase | Idursulfase
# Disclaimer
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# Black Box Warning
# Overview
Idursulfase is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme that is FDA approved for the treatment of Hunter syndrome (Mucopolysaccharidosis II, MPS II). There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, pruritus, musculoskeletal pain, urticaria, diarrhea, cough, pyrexia, rash, vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ELAPRASE is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). ELAPRASE has been shown to improve walking capacity in patients 5 years and older.
- In patients 16 months to 5 years of age, no data are available to demonstrate improvement in disease-related symptoms or long term clinical outcome; however, treatment with ELAPRASE has reduced spleen volume similarly to that of adults and children 5 years of age and older.
- The safety and efficacy of ELAPRASE have not been established in pediatric patients less than 16 months of age
### Dosage
- The recommended dosage regimen of ELAPRASE is 0.5 mg per kg of body weight administered once weekly as an intravenous infusion.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
### DOSAGE FORMS AND STRENGTHS
- Injection: 6 mg/3 mL (2 mg/mL) in single-use vials
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idursulfase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idursulfase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- ELAPRASE is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). ELAPRASE has been shown to improve walking capacity in patients 5 years and older.
- In patients 16 months to 5 years of age, no data are available to demonstrate improvement in disease-related symptoms or long term clinical outcome; however, treatment with ELAPRASE has reduced spleen volume similarly to that of adults and children 5 years of age and older.
- The safety and efficacy of ELAPRASE have not been established in pediatric patients less than 16 months of age
### Dosage
- The recommended dosage regimen of ELAPRASE is 0.5 mg per kg of body weight administered once weekly as an intravenous infusion.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idursulfase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idursulfase in pediatric patients.
# Contraindications
- None
# Warnings
### Hypersensitivity Reactions Including Anaphylaxis
- Serious hypersensitivity reactions, including anaphylaxis, have occurred during and up to 24 hours after infusion. Some of these reactions were life-threatening and included respiratory distress, hypoxia, hypotension, urticaria, and angioedema of the throat or tongue, regardless of duration of the course of treatment.
- If anaphylactic or other acute reactions occur, immediately discontinue the infusion of ELAPRASE and initiate appropriate medical treatment. When severe reactions have occurred during clinical trials, subsequent infusions were managed with antihistamine and/or corticosteroids prior to or during infusions, a slower rate of ELAPRASE infusion, and/or early discontinuation of the ELAPRASE infusion.
- In clinical trials with ELAPRASE, 16 of 108 (15%) patients experienced hypersensitivity reactions during 26 of 8,274 infusions (0.3%) that involved adverse events in at least two of the following three body systems: cutaneous, respiratory, or cardiovascular. Of these 16 patients, 11 experienced anaphylactic reactions during 19 of 8,274 infusions (0.2%) with symptoms of bronchospasm, cyanosis, dyspnea, erythema, edema (facial and peripheral), flushing, rash, respiratory distress, urticaria, vomiting, and wheezing.
- In postmarketing reports, patients receiving ELAPRASE experienced anaphylactic reactions up to several years after initiating treatment. Some patients were reported to have repeated anaphylactic events over a two- to four-month time period. Medical management included treatment with antihistamines, inhaled beta-adrenergic agonists, corticosteroids, oxygen, and vasopressors. Treatment was discontinued for some patients, while others continued treatment with premedication and a slower infusion rate.
- Due to the potential for severe reactions, appropriate medical support should be readily available when ELAPRASE is administered. Observe patients closely for an appropriate period of time after administration of ELAPRASE, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials and postmarketing reports. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur.
- In the clinical trial of Hunter syndrome patients aged 7 years and younger, patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations experienced a higher incidence of hypersensitivity reactions, serious adverse reactions and anti-idursulfase antibody development than Hunter syndrome patients with missense mutations. Eleven of 15 (73%) patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations and five of 12 (42%) patients with missense mutations experienced hypersensitivity reactions. Nine of 15 (60%) patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations and two of 12 (17%) patients with missense mutations had serious adverse reactions. All 15 patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations developed anti-idursulfase (ELAPRASE) antibodies, compared to only 3 patients with missense mutations (Table 2). Thirteen patients with these mutations developed neutralizing antibodies, which interfere with ELAPRASE uptake into the cell or ELAPRASE enzyme activity, compared to only one patient with missense mutation.
- Patients with compromised respiratory function or acute febrile or respiratory illness at the time of ELAPRASE infusion may be at higher risk of life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the patient's clinical status prior to administration of ELAPRASE and consider delaying the ELAPRASE infusion. One patient with a tracheostomy, severe airway disease and acute febrile illness experienced respiratory distress, hypoxia, cyanosis, and seizure with a loss of consciousness during ELAPRASE infusion.
- Caution should be exercised when administering ELAPRASE to patients susceptible to fluid overload, or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions. Appropriate medical support and monitoring measures should be readily available during ELAPRASE infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The following serious adverse reactions are described below and elsewhere in the labeling:
- Hypersensitivity Reactions Including Anaphylaxis
- In clinical trials, the most common adverse reactions (>10%) following ELAPRASE treatment were hypersensitivity reactions, and included rash, urticaria, pruritus, flushing, pyrexia, and headache. Most hypersensitivity reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, with or without administering additional treatments including antihistamines, corticosteroids or both prior to or during infusions.
- In clinical trials, the most frequent serious adverse reactions following ELAPRASE treatment were hypoxic episodes. Other notable serious adverse reactions that occurred in the ELAPRASE-treated patients but not in the placebo-treated patients included one case each of: cardiac arrhythmia, pulmonary embolism, cyanosis, respiratory failure, infection, and arthralgia.
- A 53-week, double-blind, placebo-controlled clinical trial of ELAPRASE was conducted in 96 male patients with Hunter syndrome, ages 5-31 years old. Of the 96 patients, 83% were White, non-Hispanic. Patients were randomized to three treatment groups, each with 32 patients: ELAPRASE 0.5 mg/kg once weekly, ELAPRASE 0.5 mg/kg every other week, or placebo. Hypersensitivity reactions were reported in 69% (22 of 32) of patients who received once-weekly treatment of ELAPRASE.
- Table 1 summarizes the adverse reactions that occurred in at least 9% of patients (≥3 patients) in the ELAPRASE 0.5 mg/kg once weekly group and with a higher incidence than in the placebo group.
- Additional adverse reactions that occurred in at least 9% of patients (≥3 patients) in the ELAPRASE 0.5 mg/kg every other week group and with a higher incidence than in the placebo group included: rash (19%), flushing (16%), fatigue (13%), tachycardia (9%), and chills (9%).
- An open-label extension trial was conducted in patients who completed the placebo-controlled trial. Ninety-four of the 96 patients who were enrolled in the placebo-controlled trial consented to participate in the extension trial. All 94 patients received ELAPRASE 0.5 mg/kg once weekly for 24 months. No new serious adverse reactions were reported. Approximately half (53%) of patients experienced hypersensitivity reactions during the 24-month extension trial. In addition to the adverse reactions listed in Table 1, common hypersensitivity reactions occurring in at least 5% of patients (≥ 5 patients) in the extension trial included: rash (23%), pyrexia (9%), flushing (7%), erythema (7%), nausea (5%), dizziness (5%), vomiting (5%), and hypotension (5%).
- A 53-week, open-label, single-arm, safety trial of once weekly ELAPRASE 0.5 mg/kg treatment was conducted in patients with Hunter syndrome, ages 16 months to 4 years old (n=20) and ages 5 to 7.5 years old (n=8) at enrollment. Patients experienced similar adverse reactions as those observed in clinical trials in patients 5 years and older, with the most common adverse reactions following ELAPRASE treatment being hypersensitivity reactions (57%). A higher incidence of the following common hypersensitivity reactions were reported in this younger age group: pyrexia (36%), rash (32%) and vomiting (14%). The most common serious adverse reactions occurring in at least 10% of patients (≥ 3 patients) included: bronchopneumonia/pneumonia (18%), ear infection (11%), and pyrexia (11%).
- Twenty-seven patients had results of genotype analysis: 15 patients had complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations and 12 patients had missense mutations.
- Safety results demonstrated that patients with complete gene deletion, large gene rearrangement, nonsense, frameshift, or splice site mutations are more likely to experience hypersensitivity reactions and have serious adverse reactions following ELAPRASE administration, compared to patients with missense mutations. Table 2 summarizes these findings.
- As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials in patients 5 years and older, 63 of the 64 patients treated with ELAPRASE 0.5 mg/kg once weekly or placebo for 53 weeks, followed by ELAPRASE 0.5 mg/kg once weekly in the extension trial, had immunogenicity data available for analysis. Of the 63 patients, 32 (51%) patients tested positive for anti-idursulfase IgG antibodies (Ab) at least one time (Table 2). Of the 32 Ab-positive patients, 23 (72%) tested positive for Ab at three or more different time points (persistent Ab). The incidence of hypersensitivity reactions was higher in patients who tested positive for Ab than those who tested negative.
- Thirteen of 32 (41%) Ab-positive patients also tested positive for antibodies that neutralize idursulfase uptake into cells (uptake neutralizing antibodies, uptake NAb) or enzymatic activity (activity NAb) at least one time, and 8 (25%) of Ab-positive patients had persistent NAb. There was no clear relationship between the presence of either Ab or NAb and therapeutic response.
- In the clinical trial in patients 7 years and younger, 19 of 28 (68%) patients treated with ELAPRASE 0.5 mg/kg once weekly tested Ab-positive. Of the 19 Ab-positive patients, 16 (84%) tested positive for Ab at three or more different time points (persistent Ab). In addition, 15 of 19 (79%) Ab-positive patients tested positive for NAb, with 14 of 15 (93%) NAb-positive patients having persistent NAb.
- All 15 patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations tested positive for Ab (Table 2). Of these 15 patients, neutralizing antibodies were observed in 13 (87%) patients. The NAbs in these patients developed earlier (most reported to be positive at Week 9 rather than at Week 27, as reported in clinical trials in patients older than 5 years of age) and were associated with higher titers and greater in vitro neutralizing activity than in patients older than 5 years of age. The presence of Ab was associated with reduced systemic idursulfase exposure.
- The immunogenicity data reflect the percentage of patients whose test results were positive for antibodies to idursulfase in specific assays, and are highly dependent on the sensitivity and specificity of these assays. The observed incidence of positive antibody in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to idursulfase with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of ELAPRASE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- In post-marketing experience, late-emergent symptoms and signs of anaphylactic reactions have occurred up to 24 hours after initial treatment and recovery from an initial anaphylactic reaction. In addition, patients experienced repeated anaphylaxis over a two- to four-month period, up to several years after initiating ELAPRASE treatment.
- A seven year-old male patient with Hunter syndrome, who received ELAPRASE at twice the recommended dosage (1 mg/kg weekly) for 1.5 years, experienced two anaphylactic events after 4.5 years of treatment. Treatment has been withdrawn.
- Serious adverse reactions that resulted in death included cardiorespiratory arrest, respiratory failure, respiratory distress, cardiac failure, and pneumonia.
# Drug Interactions
There is limited information regarding Idursulfase Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratogenicity studies have not been conducted with ELAPRASE. A pre- and postnatal development study in rats showed no evidence of adverse effects on pre- and postnatal development at intravenous doses up to 12.5 mg/kg, administered twice weekly (about 4 times the recommended human weekly dose of 0.5 mg/kg based on body surface area). There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Idursulfase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Idursulfase during labor and delivery.
### Nursing Mothers
- ELAPRASE was excreted in breast milk of lactating rats at a concentration higher (4 to 5-fold) than that of the plasma. It is not known whether ELAPRASE is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ELAPRASE is administered to a nursing woman.
### Pediatric Use
- Clinical trials with ELAPRASE were conducted in 96 patients with Hunter syndrome, ages 5 to 31 years old, with the majority of the patients in the pediatric age group (median age 15 years old). In addition, an open-label, uncontrolled clinical trial was conducted in 28 patients with Hunter syndrome, ages 16 months to 7.5 years old. Patients 16 months to 5 years of age demonstrated reduction in spleen volume that was similar to that of adults and children 5 years and older. However, there are no data to support improvement in disease-related symptoms or long term clinical outcome in patients 16 months to 5 years of age.
The safety and effectiveness of ELAPRASE have not been established in pediatric patients less than 16 months of age.
### Geriatic Use
- Clinical studies of ELAPRASE did not include patients older than 31 years of age. It is not known whether older patients respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Idursulfase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Idursulfase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Idursulfase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Idursulfase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Idursulfase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Idursulfase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Prepare and use ELAPRASE according to the following steps using aseptic technique:
- Determine the total volume of ELAPRASE to be administered and the number of vials needed based on the patient's weight and the recommended dose of 0.5 mg/kg.
- Round up to the next whole vial to determine the total number of vials needed. Remove the required number of vials from the refrigerator to allow them to reach room temperature.
- Before withdrawing the ELAPRASE solution from the vial, visually inspect each vial for particulate matter and discoloration. The ELAPRASE solution should be clear to slightly opalescent and colorless. Do not use if the solution is discolored or if there is particulate matter in the solution. Do not shake the ELAPRASE solution.
- Withdraw the calculated volume of ELAPRASE from the appropriate number of vials.
- Add the calculated volume of ELAPRASE solution to a 100 mL bag of 0.9% Sodium Chloride Injection, USP for intravenous infusion.
- Mix gently. Do not shake the solution.
- Administer the diluted ELAPRASE solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 micrometer (µm) in-line filter.
- The total volume of infusion should be administered over a period of 3 hours, which may be gradually reduced to 1 hour if no hypersensitivity reactions are observed. Patients may require longer infusion times if hypersensitivity reactions occur; however, infusion times should not exceed 8 hours. The initial infusion rate should be 8 mL per hour for the first 15 minutes. If the infusion is well tolerated, the rate of infusion may be increased by 8 mL per hour increments every 15 minutes. The infusion rate should not exceed 100 mL per hour. The infusion rate may be slowed, temporarily stopped, or discontinued for that visit in the event of hypersensitivity reactions. ELAPRASE should not be infused with other products in the infusion tubing.
- ELAPRASE does not contain preservatives; therefore, after dilution with saline, the infusion bags should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2°C to 8°C (36°F to 46 °F) for up to 24 hours. Other than during infusion, do not store the diluted ELAPRASE solution at room temperature. Any unused product or waste material should be discarded and disposed of in accordance with local requirements.
### Monitoring
Caution should be exercised when administering ELAPRASE to patients susceptible to fluid overload, or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions. Appropriate medical support and monitoring measures should be readily available during ELAPRASE infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient
# IV Compatibility
There is limited information regarding IV Compatibility of Idursulfase in the drug label.
# Overdosage
- One patient with Hunter syndrome, who received ELAPRASE at twice the recommended dosage for one and a half years, experienced two anaphylactic reactions over a 3-month period 4.5 years after initiating ELAPRASE treatment.
# Pharmacology
## Mechanism of Action
- Hunter syndrome (Mucopolysaccharidosis II, MPS II) is an X-linked recessive disease caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. This enzyme cleaves the terminal 2-O-sulfate moieties from the glycosaminoglycans (GAG) dermatan sulfate and heparan sulfate. Due to the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome, GAG progressively accumulate in the lysosomes of a variety of cells, leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction.
- ELAPRASE is intended to provide exogenous enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow binding of the enzyme to the M6P receptors on the cell surface, leading to cellular internalization of the enzyme, targeting to intracellular lysosomes and subsequent catabolism of accumulated GAG.
## Structure
- ELAPRASE is a formulation of idursulfase, a purified form of human iduronate-2-sulfatase, a lysosomal enzyme. Idursulfase is produced by recombinant DNA technology in a human cell line. Idursulfase is an enzyme that hydrolyzes the 2-sulfate esters of terminal iduronate sulfate residues from the glycosaminoglycans dermatan sulfate and heparan sulfate in the lysosomes of various cell types.
- Idursulfase is a 525-amino acid glycoprotein with a molecular weight of approximately 76 kilodaltons. The enzyme contains eight asparagine-linked glycosylation sites occupied by complex oligosaccharide structures. The enzyme activity of idursulfase is dependent on the post-translational modification of a specific cysteine to formylglycine. Idursulfase has a specific activity ranging from 46 to 74 units/mg of protein (one unit is defined as the amount of enzyme required to hydrolyze 1 µmole of heparin disaccharide substrate per hour under the specified assay conditions).
- ELAPRASE is administered as an intravenous infusion and supplied as a sterile, nonpyrogenic clear to slightly opalescent, colorless solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP. Each vial contains an extractable volume of 3 mL with an idursulfase concentration of 2 mg/mL at a pH of approximately 6. Each vial contains 6 mg idursulfase, sodium chloride (24 mg), sodium phosphate monobasic monohydrate (6.75 mg), sodium phosphate dibasic heptahydrate (2.97 mg), and polysorbate 20 (0.66 mg). ELAPRASE does not contain preservatives. Each vial is for single use only.
## Pharmacodynamics
- Decreases in urinary GAG levels were observed following treatment with ELAPRASE. The responsiveness of urinary GAG to dosage alterations of ELAPRASE is unknown, and the relationship of urinary GAG to other measures of clinical response has not been established. Patients who tested positive for anti-idursulfase antibodies (Ab) experienced a less pronounced decrease in urinary GAG levels
## Pharmacokinetics
- The pharmacokinetic characteristics of idursulfase were evaluated in 59 patients with Hunter syndrome. The serum concentration of idursulfase was quantified using an antigen-specific ELISA assay. The area under the concentration-time curve (AUC) increased in a greater than dose proportional manner as the dose increased from 0.15 mg/kg to 1.5 mg/kg following a single 1-hour infusion of ELAPRASE. The pharmacokinetic parameters at the recommended dose regimen (0.5 mg/kg ELAPRASE administered weekly as a 3-hour infusion) were determined at Week 1 and Week 27 in 10 patients 7.7 to 27 years of age (Table 3). There were no apparent differences in PK parameter values between Week 1 and Week 27 regardless of the antibody status in these patients.
- Idursulfase pharmacokinetics was evaluated in 27 patients with Hunter syndrome 16 months to 7.5 years of age who received ELAPRASE 0.5 mg/kg once weekly as a 3-hour infusion. The presence of anti-idursulfase antibody (Ab) was associated with a reduced systemic exposure of idursulfase. Eight of the 18 Ab-positive patients had no measurable idursulfase concentrations. An additional 9 Ab-positive patients had decreased Cmax, AUC, and t1/2 at Week 27 compared to Week 1 (Table 4). Idursulfase pharmacokinetics was similar between Week 1 and Week 27 in Ab-negative patients (Table 4).
- All patients with the complete gene deletion or large gene rearrangement genotype (n = 8) developed Ab at Week 27. Five of these eight patients had no measurable idursulfase concentrations at Week 27, and three had a lower systemic exposure at Week 27 compared to Week 1.
## Nonclinical Toxicology
- Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with ELAPRASE.
- ELAPRASE at intravenous doses up to 5 mg/kg administered twice weekly (about 1.6 times the recommended human weekly dose based on body surface area) had no effect on fertility and reproductive performance in male rats.
# Clinical Studies
- The safety and efficacy of ELAPRASE were evaluated in a 53-week, randomized, double-blind, placebo-controlled clinical trial of 96 patients with Hunter syndrome. The trial included patients with deficiency in iduronate-2-sulfatase enzyme activity and a percent predicted forced vital capacity (% predicted FVC) less than 80%. The age of patients ranged from 5 to 31 years. Patients received ELAPRASE 0.5 mg/kg once per week (n=32), ELAPRASE 0.5 mg/kg once every other week (n=32), or placebo (n=32).
- The primary efficacy outcome assessment was a two-component composite score based on the sum of the ranks of the change from baseline to Week 53 in distance walked in six minutes (6-minute walk test) and the ranks of the change in % predicted FVC. This two-component composite primary endpoint differed statistically significantly between the three groups, and the difference was greatest between the placebo group and the once weekly treatment group (once weekly ELAPRASE vs. placebo, p=0.0049).
- Examination of the individual components of the composite score showed that, in the adjusted analysis, the weekly ELAPRASE-treated group experienced a 35 meter greater mean increase in the distance walked in six minutes compared to placebo. The changes in %-predicted FVC were not statistically significant (Table 5).
- Pharmacodynamic assessments included urinary GAG levels and changes in liver and spleen size. Urinary GAG levels were elevated in all patients at baseline. Following 53 weeks of treatment, mean urinary GAG levels were reduced in the ELAPRASE once weekly group, although GAG levels still remained above the upper limit of normal in half of the ELAPRASE-treated patients. Urinary GAG levels remained elevated and essentially unchanged in the placebo group. Sustained reductions in both liver and spleen volumes were observed in the ELAPRASE once weekly group through Week 53 compared to placebo. There were essentially no changes in liver and spleen volumes in the placebo group.
- Patients who participated in the placebo-controlled trial were eligible to continue treatment in an open-label extension trial. During the extension trial, all patients received ELAPRASE 0.5mg/kg once weekly for 24 months.
- Patients who were treated with ELAPRASE once weekly and every other week in the placebo-controlled trial demonstrated improvement in distance walked in the 6-minute walk test for an additional 8 months of treatment in the extension trial. There was no change in mean %-predicted FVC in all Hunter syndrome patients after 6 months of treatment in the extension trial; however, a slight decrease in mean %-predicted FVC was demonstrated through to month 24 of the extension trial. The long-term effect of ELAPRASE on pulmonary function in Hunter syndrome patients is unclear.
- There were no further reductions in mean urinary GAG levels in patients initially treated with ELAPRASE once weekly; however, the patients treated with ELAPRASE every other week during the placebo-controlled trial experienced further reductions in mean urinary GAG levels after changing to a more frequent dosing regimen during the extension trial. The persistence of reduced urinary GAG levels did not correlate with the long term effect demonstrated by the 6-minute walk test distance or %-predicted FVC.
- A 53-week, open-label, multicenter, single-arm trial was conducted to assess the safety, pharmacokinetics, and pharmacodynamics of ELAPRASE 0.5 mg/kg once weekly in male Hunter syndrome patients aged 7 years and younger. Safety results demonstrated that patients with complete gene deletion or large gene rearrangement mutations are more likely to develop antibodies, including neutralizing antibodies, and to experience hypersensitivity reactions with ELAPRASE administration. In patients who remained antibody negative, the pharmacokinetic profile, reduction in urinary GAG excretion levels, and reduction in spleen volume were similar to those of adults and children 5 years and older. In patients who were persistently antibody positive, the presence of anti-idursulfase antibody was associated with reduced systemic exposure of idursulfase and a less pronounced decrease in urinary GAG levels
# How Supplied
- ELAPRASE is supplied as a sterile injection in a 5 mL Type I glass vial. The vials are closed with a butyl rubber stopper with fluororesin coating and an aluminum overseal with a blue flip-off plastic cap.
- Each carton contains a single vial NDC 54092-700-01
## Storage
- Store ELAPRASE vials in the carton at 2°C to 8°C (36°F to 46°F) to protect from light. Do not freeze or shake. Do not use ELAPRASE after the expiration date on the vial.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL - 6 mg/3 mL Vial Carton
elaprase®
(idursulfase)
injection
6 mg/3 mL
(2 mg/mL)
Single Use Vial,
Discard Unused Portion
Must be diluted for
intravenous infusion
Shire
Rx Only
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be advised that life-threatening anaphylactic reactions have occurred in some patients during and up to 24 hours after ELAPRASE therapy. Patients who have experienced anaphylactic reactions may require prolonged observation. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions.
- A Hunter Outcome Survey has been established in order to understand better the variability and progression of Hunter syndrome (MPS II) in the population as a whole, and to monitor and evaluate long-term treatment effects of ELAPRASE. Patients and their physicians are encouraged to participate in this program. For more information, call Shire Human Genetic Therapies, Inc. at 1-866-888-0660.
# Precautions with Alcohol
- Alcohol-Idursulfase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ELAPRASE®
# Look-Alike Drug Names
There is limited information regarding Idursulfase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Idursulfase
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Black Box Warning
# Overview
Idursulfase is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme that is FDA approved for the treatment of Hunter syndrome (Mucopolysaccharidosis II, MPS II). There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, pruritus, musculoskeletal pain, urticaria, diarrhea, cough, pyrexia, rash, vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ELAPRASE is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). ELAPRASE has been shown to improve walking capacity in patients 5 years and older.
- In patients 16 months to 5 years of age, no data are available to demonstrate improvement in disease-related symptoms or long term clinical outcome; however, treatment with ELAPRASE has reduced spleen volume similarly to that of adults and children 5 years of age and older.
- The safety and efficacy of ELAPRASE have not been established in pediatric patients less than 16 months of age
### Dosage
- The recommended dosage regimen of ELAPRASE is 0.5 mg per kg of body weight administered once weekly as an intravenous infusion.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
### DOSAGE FORMS AND STRENGTHS
- Injection: 6 mg/3 mL (2 mg/mL) in single-use vials
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idursulfase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idursulfase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- ELAPRASE is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). ELAPRASE has been shown to improve walking capacity in patients 5 years and older.
- In patients 16 months to 5 years of age, no data are available to demonstrate improvement in disease-related symptoms or long term clinical outcome; however, treatment with ELAPRASE has reduced spleen volume similarly to that of adults and children 5 years of age and older.
- The safety and efficacy of ELAPRASE have not been established in pediatric patients less than 16 months of age
### Dosage
- The recommended dosage regimen of ELAPRASE is 0.5 mg per kg of body weight administered once weekly as an intravenous infusion.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idursulfase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idursulfase in pediatric patients.
# Contraindications
- None
# Warnings
### Hypersensitivity Reactions Including Anaphylaxis
- Serious hypersensitivity reactions, including anaphylaxis, have occurred during and up to 24 hours after infusion. Some of these reactions were life-threatening and included respiratory distress, hypoxia, hypotension, urticaria, and angioedema of the throat or tongue, regardless of duration of the course of treatment.
- If anaphylactic or other acute reactions occur, immediately discontinue the infusion of ELAPRASE and initiate appropriate medical treatment. When severe reactions have occurred during clinical trials, subsequent infusions were managed with antihistamine and/or corticosteroids prior to or during infusions, a slower rate of ELAPRASE infusion, and/or early discontinuation of the ELAPRASE infusion.
- In clinical trials with ELAPRASE, 16 of 108 (15%) patients experienced hypersensitivity reactions during 26 of 8,274 infusions (0.3%) that involved adverse events in at least two of the following three body systems: cutaneous, respiratory, or cardiovascular. Of these 16 patients, 11 experienced anaphylactic reactions during 19 of 8,274 infusions (0.2%) with symptoms of bronchospasm, cyanosis, dyspnea, erythema, edema (facial and peripheral), flushing, rash, respiratory distress, urticaria, vomiting, and wheezing.
- In postmarketing reports, patients receiving ELAPRASE experienced anaphylactic reactions up to several years after initiating treatment. Some patients were reported to have repeated anaphylactic events over a two- to four-month time period. Medical management included treatment with antihistamines, inhaled beta-adrenergic agonists, corticosteroids, oxygen, and vasopressors. Treatment was discontinued for some patients, while others continued treatment with premedication and a slower infusion rate.
- Due to the potential for severe reactions, appropriate medical support should be readily available when ELAPRASE is administered. Observe patients closely for an appropriate period of time after administration of ELAPRASE, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials and postmarketing reports. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur.
- In the clinical trial of Hunter syndrome patients aged 7 years and younger, patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations experienced a higher incidence of hypersensitivity reactions, serious adverse reactions and anti-idursulfase antibody development than Hunter syndrome patients with missense mutations. Eleven of 15 (73%) patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations and five of 12 (42%) patients with missense mutations experienced hypersensitivity reactions. Nine of 15 (60%) patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations and two of 12 (17%) patients with missense mutations had serious adverse reactions. All 15 patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations developed anti-idursulfase (ELAPRASE) antibodies, compared to only 3 patients with missense mutations (Table 2). Thirteen patients with these mutations developed neutralizing antibodies, which interfere with ELAPRASE uptake into the cell or ELAPRASE enzyme activity, compared to only one patient with missense mutation.
- Patients with compromised respiratory function or acute febrile or respiratory illness at the time of ELAPRASE infusion may be at higher risk of life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the patient's clinical status prior to administration of ELAPRASE and consider delaying the ELAPRASE infusion. One patient with a tracheostomy, severe airway disease and acute febrile illness experienced respiratory distress, hypoxia, cyanosis, and seizure with a loss of consciousness during ELAPRASE infusion.
- Caution should be exercised when administering ELAPRASE to patients susceptible to fluid overload, or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions. Appropriate medical support and monitoring measures should be readily available during ELAPRASE infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The following serious adverse reactions are described below and elsewhere in the labeling:
- Hypersensitivity Reactions Including Anaphylaxis
- In clinical trials, the most common adverse reactions (>10%) following ELAPRASE treatment were hypersensitivity reactions, and included rash, urticaria, pruritus, flushing, pyrexia, and headache. Most hypersensitivity reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, with or without administering additional treatments including antihistamines, corticosteroids or both prior to or during infusions.
- In clinical trials, the most frequent serious adverse reactions following ELAPRASE treatment were hypoxic episodes. Other notable serious adverse reactions that occurred in the ELAPRASE-treated patients but not in the placebo-treated patients included one case each of: cardiac arrhythmia, pulmonary embolism, cyanosis, respiratory failure, infection, and arthralgia.
- A 53-week, double-blind, placebo-controlled clinical trial of ELAPRASE was conducted in 96 male patients with Hunter syndrome, ages 5-31 years old. Of the 96 patients, 83% were White, non-Hispanic. Patients were randomized to three treatment groups, each with 32 patients: ELAPRASE 0.5 mg/kg once weekly, ELAPRASE 0.5 mg/kg every other week, or placebo. Hypersensitivity reactions were reported in 69% (22 of 32) of patients who received once-weekly treatment of ELAPRASE.
- Table 1 summarizes the adverse reactions that occurred in at least 9% of patients (≥3 patients) in the ELAPRASE 0.5 mg/kg once weekly group and with a higher incidence than in the placebo group.
- Additional adverse reactions that occurred in at least 9% of patients (≥3 patients) in the ELAPRASE 0.5 mg/kg every other week group and with a higher incidence than in the placebo group included: rash (19%), flushing (16%), fatigue (13%), tachycardia (9%), and chills (9%).
- An open-label extension trial was conducted in patients who completed the placebo-controlled trial. Ninety-four of the 96 patients who were enrolled in the placebo-controlled trial consented to participate in the extension trial. All 94 patients received ELAPRASE 0.5 mg/kg once weekly for 24 months. No new serious adverse reactions were reported. Approximately half (53%) of patients experienced hypersensitivity reactions during the 24-month extension trial. In addition to the adverse reactions listed in Table 1, common hypersensitivity reactions occurring in at least 5% of patients (≥ 5 patients) in the extension trial included: rash (23%), pyrexia (9%), flushing (7%), erythema (7%), nausea (5%), dizziness (5%), vomiting (5%), and hypotension (5%).
- A 53-week, open-label, single-arm, safety trial of once weekly ELAPRASE 0.5 mg/kg treatment was conducted in patients with Hunter syndrome, ages 16 months to 4 years old (n=20) and ages 5 to 7.5 years old (n=8) at enrollment. Patients experienced similar adverse reactions as those observed in clinical trials in patients 5 years and older, with the most common adverse reactions following ELAPRASE treatment being hypersensitivity reactions (57%). A higher incidence of the following common hypersensitivity reactions were reported in this younger age group: pyrexia (36%), rash (32%) and vomiting (14%). The most common serious adverse reactions occurring in at least 10% of patients (≥ 3 patients) included: bronchopneumonia/pneumonia (18%), ear infection (11%), and pyrexia (11%).
- Twenty-seven patients had results of genotype analysis: 15 patients had complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations and 12 patients had missense mutations.
- Safety results demonstrated that patients with complete gene deletion, large gene rearrangement, nonsense, frameshift, or splice site mutations are more likely to experience hypersensitivity reactions and have serious adverse reactions following ELAPRASE administration, compared to patients with missense mutations. Table 2 summarizes these findings.
- As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials in patients 5 years and older, 63 of the 64 patients treated with ELAPRASE 0.5 mg/kg once weekly or placebo for 53 weeks, followed by ELAPRASE 0.5 mg/kg once weekly in the extension trial, had immunogenicity data available for analysis. Of the 63 patients, 32 (51%) patients tested positive for anti-idursulfase IgG antibodies (Ab) at least one time (Table 2). Of the 32 Ab-positive patients, 23 (72%) tested positive for Ab at three or more different time points (persistent Ab). The incidence of hypersensitivity reactions was higher in patients who tested positive for Ab than those who tested negative.
- Thirteen of 32 (41%) Ab-positive patients also tested positive for antibodies that neutralize idursulfase uptake into cells (uptake neutralizing antibodies, uptake NAb) or enzymatic activity (activity NAb) at least one time, and 8 (25%) of Ab-positive patients had persistent NAb. There was no clear relationship between the presence of either Ab or NAb and therapeutic response.
- In the clinical trial in patients 7 years and younger, 19 of 28 (68%) patients treated with ELAPRASE 0.5 mg/kg once weekly tested Ab-positive. Of the 19 Ab-positive patients, 16 (84%) tested positive for Ab at three or more different time points (persistent Ab). In addition, 15 of 19 (79%) Ab-positive patients tested positive for NAb, with 14 of 15 (93%) NAb-positive patients having persistent NAb.
- All 15 patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations tested positive for Ab (Table 2). Of these 15 patients, neutralizing antibodies were observed in 13 (87%) patients. The NAbs in these patients developed earlier (most reported to be positive at Week 9 rather than at Week 27, as reported in clinical trials in patients older than 5 years of age) and were associated with higher titers and greater in vitro neutralizing activity than in patients older than 5 years of age. The presence of Ab was associated with reduced systemic idursulfase exposure.
- The immunogenicity data reflect the percentage of patients whose test results were positive for antibodies to idursulfase in specific assays, and are highly dependent on the sensitivity and specificity of these assays. The observed incidence of positive antibody in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to idursulfase with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of ELAPRASE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- In post-marketing experience, late-emergent symptoms and signs of anaphylactic reactions have occurred up to 24 hours after initial treatment and recovery from an initial anaphylactic reaction. In addition, patients experienced repeated anaphylaxis over a two- to four-month period, up to several years after initiating ELAPRASE treatment.
- A seven year-old male patient with Hunter syndrome, who received ELAPRASE at twice the recommended dosage (1 mg/kg weekly) for 1.5 years, experienced two anaphylactic events after 4.5 years of treatment. Treatment has been withdrawn.
- Serious adverse reactions that resulted in death included cardiorespiratory arrest, respiratory failure, respiratory distress, cardiac failure, and pneumonia.
# Drug Interactions
There is limited information regarding Idursulfase Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratogenicity studies have not been conducted with ELAPRASE. A pre- and postnatal development study in rats showed no evidence of adverse effects on pre- and postnatal development at intravenous doses up to 12.5 mg/kg, administered twice weekly (about 4 times the recommended human weekly dose of 0.5 mg/kg based on body surface area). There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Idursulfase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Idursulfase during labor and delivery.
### Nursing Mothers
- ELAPRASE was excreted in breast milk of lactating rats at a concentration higher (4 to 5-fold) than that of the plasma. It is not known whether ELAPRASE is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ELAPRASE is administered to a nursing woman.
### Pediatric Use
- Clinical trials with ELAPRASE were conducted in 96 patients with Hunter syndrome, ages 5 to 31 years old, with the majority of the patients in the pediatric age group (median age 15 years old). In addition, an open-label, uncontrolled clinical trial was conducted in 28 patients with Hunter syndrome, ages 16 months to 7.5 years old. Patients 16 months to 5 years of age demonstrated reduction in spleen volume that was similar to that of adults and children 5 years and older. However, there are no data to support improvement in disease-related symptoms or long term clinical outcome in patients 16 months to 5 years of age.
The safety and effectiveness of ELAPRASE have not been established in pediatric patients less than 16 months of age.
### Geriatic Use
- Clinical studies of ELAPRASE did not include patients older than 31 years of age. It is not known whether older patients respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Idursulfase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Idursulfase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Idursulfase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Idursulfase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Idursulfase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Idursulfase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Prepare and use ELAPRASE according to the following steps using aseptic technique:
- Determine the total volume of ELAPRASE to be administered and the number of vials needed based on the patient's weight and the recommended dose of 0.5 mg/kg.
- Round up to the next whole vial to determine the total number of vials needed. Remove the required number of vials from the refrigerator to allow them to reach room temperature.
- Before withdrawing the ELAPRASE solution from the vial, visually inspect each vial for particulate matter and discoloration. The ELAPRASE solution should be clear to slightly opalescent and colorless. Do not use if the solution is discolored or if there is particulate matter in the solution. Do not shake the ELAPRASE solution.
- Withdraw the calculated volume of ELAPRASE from the appropriate number of vials.
- Add the calculated volume of ELAPRASE solution to a 100 mL bag of 0.9% Sodium Chloride Injection, USP for intravenous infusion.
- Mix gently. Do not shake the solution.
- Administer the diluted ELAPRASE solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 micrometer (µm) in-line filter.
- The total volume of infusion should be administered over a period of 3 hours, which may be gradually reduced to 1 hour if no hypersensitivity reactions are observed. Patients may require longer infusion times if hypersensitivity reactions occur; however, infusion times should not exceed 8 hours. The initial infusion rate should be 8 mL per hour for the first 15 minutes. If the infusion is well tolerated, the rate of infusion may be increased by 8 mL per hour increments every 15 minutes. The infusion rate should not exceed 100 mL per hour. The infusion rate may be slowed, temporarily stopped, or discontinued for that visit in the event of hypersensitivity reactions. ELAPRASE should not be infused with other products in the infusion tubing.
- ELAPRASE does not contain preservatives; therefore, after dilution with saline, the infusion bags should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2°C to 8°C (36°F to 46 °F) for up to 24 hours. Other than during infusion, do not store the diluted ELAPRASE solution at room temperature. Any unused product or waste material should be discarded and disposed of in accordance with local requirements.
### Monitoring
Caution should be exercised when administering ELAPRASE to patients susceptible to fluid overload, or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions. Appropriate medical support and monitoring measures should be readily available during ELAPRASE infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient
# IV Compatibility
There is limited information regarding IV Compatibility of Idursulfase in the drug label.
# Overdosage
- One patient with Hunter syndrome, who received ELAPRASE at twice the recommended dosage for one and a half years, experienced two anaphylactic reactions over a 3-month period 4.5 years after initiating ELAPRASE treatment.
# Pharmacology
## Mechanism of Action
- Hunter syndrome (Mucopolysaccharidosis II, MPS II) is an X-linked recessive disease caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. This enzyme cleaves the terminal 2-O-sulfate moieties from the glycosaminoglycans (GAG) dermatan sulfate and heparan sulfate. Due to the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome, GAG progressively accumulate in the lysosomes of a variety of cells, leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction.
- ELAPRASE is intended to provide exogenous enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow binding of the enzyme to the M6P receptors on the cell surface, leading to cellular internalization of the enzyme, targeting to intracellular lysosomes and subsequent catabolism of accumulated GAG.
## Structure
- ELAPRASE is a formulation of idursulfase, a purified form of human iduronate-2-sulfatase, a lysosomal enzyme. Idursulfase is produced by recombinant DNA technology in a human cell line. Idursulfase is an enzyme that hydrolyzes the 2-sulfate esters of terminal iduronate sulfate residues from the glycosaminoglycans dermatan sulfate and heparan sulfate in the lysosomes of various cell types.
- Idursulfase is a 525-amino acid glycoprotein with a molecular weight of approximately 76 kilodaltons. The enzyme contains eight asparagine-linked glycosylation sites occupied by complex oligosaccharide structures. The enzyme activity of idursulfase is dependent on the post-translational modification of a specific cysteine to formylglycine. Idursulfase has a specific activity ranging from 46 to 74 units/mg of protein (one unit is defined as the amount of enzyme required to hydrolyze 1 µmole of heparin disaccharide substrate per hour under the specified assay conditions).
- ELAPRASE is administered as an intravenous infusion and supplied as a sterile, nonpyrogenic clear to slightly opalescent, colorless solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP. Each vial contains an extractable volume of 3 mL with an idursulfase concentration of 2 mg/mL at a pH of approximately 6. Each vial contains 6 mg idursulfase, sodium chloride (24 mg), sodium phosphate monobasic monohydrate (6.75 mg), sodium phosphate dibasic heptahydrate (2.97 mg), and polysorbate 20 (0.66 mg). ELAPRASE does not contain preservatives. Each vial is for single use only.
## Pharmacodynamics
- Decreases in urinary GAG levels were observed following treatment with ELAPRASE. The responsiveness of urinary GAG to dosage alterations of ELAPRASE is unknown, and the relationship of urinary GAG to other measures of clinical response has not been established. Patients who tested positive for anti-idursulfase antibodies (Ab) experienced a less pronounced decrease in urinary GAG levels
## Pharmacokinetics
- The pharmacokinetic characteristics of idursulfase were evaluated in 59 patients with Hunter syndrome. The serum concentration of idursulfase was quantified using an antigen-specific ELISA assay. The area under the concentration-time curve (AUC) increased in a greater than dose proportional manner as the dose increased from 0.15 mg/kg to 1.5 mg/kg following a single 1-hour infusion of ELAPRASE. The pharmacokinetic parameters at the recommended dose regimen (0.5 mg/kg ELAPRASE administered weekly as a 3-hour infusion) were determined at Week 1 and Week 27 in 10 patients 7.7 to 27 years of age (Table 3). There were no apparent differences in PK parameter values between Week 1 and Week 27 regardless of the antibody status in these patients.
- Idursulfase pharmacokinetics was evaluated in 27 patients with Hunter syndrome 16 months to 7.5 years of age who received ELAPRASE 0.5 mg/kg once weekly as a 3-hour infusion. The presence of anti-idursulfase antibody (Ab) was associated with a reduced systemic exposure of idursulfase. Eight of the 18 Ab-positive patients had no measurable idursulfase concentrations. An additional 9 Ab-positive patients had decreased Cmax, AUC, and t1/2 at Week 27 compared to Week 1 (Table 4). Idursulfase pharmacokinetics was similar between Week 1 and Week 27 in Ab-negative patients (Table 4).
- All patients with the complete gene deletion or large gene rearrangement genotype (n = 8) developed Ab at Week 27. Five of these eight patients had no measurable idursulfase concentrations at Week 27, and three had a lower systemic exposure at Week 27 compared to Week 1.
## Nonclinical Toxicology
- Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with ELAPRASE.
- ELAPRASE at intravenous doses up to 5 mg/kg administered twice weekly (about 1.6 times the recommended human weekly dose based on body surface area) had no effect on fertility and reproductive performance in male rats.
# Clinical Studies
- The safety and efficacy of ELAPRASE were evaluated in a 53-week, randomized, double-blind, placebo-controlled clinical trial of 96 patients with Hunter syndrome. The trial included patients with deficiency in iduronate-2-sulfatase enzyme activity and a percent predicted forced vital capacity (% predicted FVC) less than 80%. The age of patients ranged from 5 to 31 years. Patients received ELAPRASE 0.5 mg/kg once per week (n=32), ELAPRASE 0.5 mg/kg once every other week (n=32), or placebo (n=32).
- The primary efficacy outcome assessment was a two-component composite score based on the sum of the ranks of the change from baseline to Week 53 in distance walked in six minutes (6-minute walk test) and the ranks of the change in % predicted FVC. This two-component composite primary endpoint differed statistically significantly between the three groups, and the difference was greatest between the placebo group and the once weekly treatment group (once weekly ELAPRASE vs. placebo, p=0.0049).
- Examination of the individual components of the composite score showed that, in the adjusted analysis, the weekly ELAPRASE-treated group experienced a 35 meter greater mean increase in the distance walked in six minutes compared to placebo. The changes in %-predicted FVC were not statistically significant (Table 5).
- Pharmacodynamic assessments included urinary GAG levels and changes in liver and spleen size. Urinary GAG levels were elevated in all patients at baseline. Following 53 weeks of treatment, mean urinary GAG levels were reduced in the ELAPRASE once weekly group, although GAG levels still remained above the upper limit of normal in half of the ELAPRASE-treated patients. Urinary GAG levels remained elevated and essentially unchanged in the placebo group. Sustained reductions in both liver and spleen volumes were observed in the ELAPRASE once weekly group through Week 53 compared to placebo. There were essentially no changes in liver and spleen volumes in the placebo group.
- Patients who participated in the placebo-controlled trial were eligible to continue treatment in an open-label extension trial. During the extension trial, all patients received ELAPRASE 0.5mg/kg once weekly for 24 months.
- Patients who were treated with ELAPRASE once weekly and every other week in the placebo-controlled trial demonstrated improvement in distance walked in the 6-minute walk test for an additional 8 months of treatment in the extension trial. There was no change in mean %-predicted FVC in all Hunter syndrome patients after 6 months of treatment in the extension trial; however, a slight decrease in mean %-predicted FVC was demonstrated through to month 24 of the extension trial. The long-term effect of ELAPRASE on pulmonary function in Hunter syndrome patients is unclear.
- There were no further reductions in mean urinary GAG levels in patients initially treated with ELAPRASE once weekly; however, the patients treated with ELAPRASE every other week during the placebo-controlled trial experienced further reductions in mean urinary GAG levels after changing to a more frequent dosing regimen during the extension trial. The persistence of reduced urinary GAG levels did not correlate with the long term effect demonstrated by the 6-minute walk test distance or %-predicted FVC.
- A 53-week, open-label, multicenter, single-arm trial was conducted to assess the safety, pharmacokinetics, and pharmacodynamics of ELAPRASE 0.5 mg/kg once weekly in male Hunter syndrome patients aged 7 years and younger. Safety results demonstrated that patients with complete gene deletion or large gene rearrangement mutations are more likely to develop antibodies, including neutralizing antibodies, and to experience hypersensitivity reactions with ELAPRASE administration. In patients who remained antibody negative, the pharmacokinetic profile, reduction in urinary GAG excretion levels, and reduction in spleen volume were similar to those of adults and children 5 years and older. In patients who were persistently antibody positive, the presence of anti-idursulfase antibody was associated with reduced systemic exposure of idursulfase and a less pronounced decrease in urinary GAG levels
# How Supplied
- ELAPRASE is supplied as a sterile injection in a 5 mL Type I glass vial. The vials are closed with a butyl rubber stopper with fluororesin coating and an aluminum overseal with a blue flip-off plastic cap.
- Each carton contains a single vial NDC 54092-700-01
## Storage
- Store ELAPRASE vials in the carton at 2°C to 8°C (36°F to 46°F) to protect from light. Do not freeze or shake. Do not use ELAPRASE after the expiration date on the vial.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL - 6 mg/3 mL Vial Carton
elaprase®
(idursulfase)
injection
6 mg/3 mL
(2 mg/mL)
Single Use Vial,
Discard Unused Portion
Must be diluted for
intravenous infusion
Shire
Rx Only
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be advised that life-threatening anaphylactic reactions have occurred in some patients during and up to 24 hours after ELAPRASE therapy. Patients who have experienced anaphylactic reactions may require prolonged observation. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions.
- A Hunter Outcome Survey has been established in order to understand better the variability and progression of Hunter syndrome (MPS II) in the population as a whole, and to monitor and evaluate long-term treatment effects of ELAPRASE. Patients and their physicians are encouraged to participate in this program. For more information, call Shire Human Genetic Therapies, Inc. at 1-866-888-0660.
# Precautions with Alcohol
- Alcohol-Idursulfase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ELAPRASE®[1]
# Look-Alike Drug Names
There is limited information regarding Idursulfase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Elaprase | |
e3b4998de75d79219833114a1001de7f9d92e1d4 | wikidoc | Resistivity | Resistivity
Electrical resistivity (also known as specific electrical resistance) is a measure of how strongly a material opposes the flow of electric current. A low resistivity indicates a material that readily allows the movement of electrical charge. The SI unit of electrical resistivity is the ohm metre.
# Definitions
The electrical resistivity ρ (rho) of a material is given by
where
Electrical resistivity can also be defined as
where
Finally, electrical resistivity is also defined as the inverse of the conductivity σ (sigma), of the material, or
# Table of resistivities
This table shows the resistivity and temperature coefficient of various materials at 20 °C (68 °F)
*The numbers in this column increase or decrease the significand portion of the resistivity. For example, at 30°C (303.15 K), the resistivity of silver is 1.65×10−8. This is calculated as Δρ = α ΔT ρo where ρo is the resistivity at 20°C and α is the temperature coefficient
# Temperature dependence
In general, electrical resistivity of metals increases with temperature, while the resistivity of semiconductors decreases with increasing temperature. In both cases, electron-phonon interactions can play a key role. At high temperatures, the resistance of a metal increases linearly with temperature. As the temperature of a metal is reduced, the temperature dependence of resistivity follows a power law function of temperature. Mathematically the temperature dependence of the resistivity ρ of a metal is given by the Bloch-Gruneissen formula :
where \rho(0) is the residual resistivity due to defect scattering, A is a constant that depends on the velocity of electrons at the fermi surface, the Debye radius and the number density of electrons in the metal. \Theta_R is the Debye temperature as obtained from resistivity measurements and matches very closely with the values of Debye temperature obtained from specific heat measurements. n is an integer that depends upon the nature of interaction:
- n=5 implies that the resistance is due to scattering of electrons by phonons (as it is for simple metals)
- n=3 implies that the resistance is due to s-d electron scattering (as is the case for transition metals)
- n=2 implies that the resistance is due to electron-electron interaction.
As the temperature of the metal is sufficiently reduced (so as to 'freeze' all the phonons), the resistivity usually reaches a
constant value, known as the residual resistivity. This value depends not only on the type of metal, but on its purity and thermal history. The value of the residual resistivity of a metal is decided by its impurity concentration. Some materials lose all electrical resistivity at sufficiently low temperatures, due to an effect known as superconductivity.
An even better approximation of the temperature dependence of the resistivity of a semiconductor is given by the Steinhart-Hart equation:
where A, B and C are the so-called Steinhart-Hart coefficients.
This equation is used to calibrate thermistors.
In non-crystalline semi-conductors, conduction can occur by charges quantum tunnelling from one localised site to another. This is known as variable range hopping and has the characteristic form of \rho = Ae^{T^{-1/n}}, where n=2,3,4 depending on the dimensionality of the system.
# Complex resistivity
When analyzing the response of materials to alternating electric fields, as is done in certain types of tomography, it is necessary to replace resistivity with a complex quantity called impeditivity, in analogy to electrical impedance. Impeditivity is the sum of a real component, the resistivity, and an imaginary component, the reactivity (reactance) .
# Sources
- ↑ Jump up to: 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 Serway, Raymond A. (1998). Principles of Physics (2nd ed ed.). Fort Worth, Texas; London: Saunders College Pub. pp. p602. ISBN 0-03-020457-7.CS1 maint: Extra text (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jump up to: 2.0 2.1 2.2 2.3 Griffiths, David (1999) . "7. Electrodynamics". In Alison Reeves (ed.). Introduction to Electrodynamics (3rd edition ed.). Upper Saddle River, New Jersey: Prentice Hall. p. 286. ISBN 0-13-805326-x Check |isbn= value: invalid character (help). OCLC 40251748. Check date values in: |accessdate= (help); |access-date= requires |url= (help)CS1 maint: Extra text: editors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 3.0 3.1 3.2 Giancoli, Douglas C. (1995). Physics: Principles with Applications (4th ed ed.). London: Prentice Hall. ISBN 0-13-102153-2.CS1 maint: Extra text (link) (see also Table of Resistivity)
- ↑ Ni,Fe,Cr alloy commonly used in heating elements.
- ↑ Jump up to: 5.0 5.1 5.2 The resistivity of semiconductors depends strongly on the presence of impurities in the material.
- Paul Tipler (2004). Physics for Scientists and Engineers: Electricity, Magnetism, Light, and Elementary Modern Physics (5th ed.). W. H. Freeman. ISBN 0-7167-0810-8. | Resistivity
Electrical resistivity (also known as specific electrical resistance) is a measure of how strongly a material opposes the flow of electric current. A low resistivity indicates a material that readily allows the movement of electrical charge. The SI unit of electrical resistivity is the ohm metre.
# Definitions
The electrical resistivity ρ (rho) of a material is given by
where
Electrical resistivity can also be defined as
where
Finally, electrical resistivity is also defined as the inverse of the conductivity σ (sigma), of the material, or
# Table of resistivities
This table shows the resistivity and temperature coefficient of various materials at 20 °C (68 °F)
Template:Disputed-section
*The numbers in this column increase or decrease the significand portion of the resistivity. For example, at 30°C (303.15 K), the resistivity of silver is 1.65×10−8. This is calculated as Δρ = α ΔT ρo where ρo is the resistivity at 20°C and α is the temperature coefficient
# Temperature dependence
In general, electrical resistivity of metals increases with temperature, while the resistivity of semiconductors decreases with increasing temperature. In both cases, electron-phonon interactions can play a key role. At high temperatures, the resistance of a metal increases linearly with temperature. As the temperature of a metal is reduced, the temperature dependence of resistivity follows a power law function of temperature. Mathematically the temperature dependence of the resistivity ρ of a metal is given by the Bloch-Gruneissen formula :
where <math>\rho(0)</math> is the residual resistivity due to defect scattering, A is a constant that depends on the velocity of electrons at the fermi surface, the Debye radius and the number density of electrons in the metal. <math>\Theta_R</math> is the Debye temperature as obtained from resistivity measurements and matches very closely with the values of Debye temperature obtained from specific heat measurements. n is an integer that depends upon the nature of interaction:
- n=5 implies that the resistance is due to scattering of electrons by phonons (as it is for simple metals)
- n=3 implies that the resistance is due to s-d electron scattering (as is the case for transition metals)
- n=2 implies that the resistance is due to electron-electron interaction.
As the temperature of the metal is sufficiently reduced (so as to 'freeze' all the phonons), the resistivity usually reaches a
constant value, known as the residual resistivity. This value depends not only on the type of metal, but on its purity and thermal history. The value of the residual resistivity of a metal is decided by its impurity concentration. Some materials lose all electrical resistivity at sufficiently low temperatures, due to an effect known as superconductivity.
An even better approximation of the temperature dependence of the resistivity of a semiconductor is given by the Steinhart-Hart equation:
where A, B and C are the so-called Steinhart-Hart coefficients.
This equation is used to calibrate thermistors.
In non-crystalline semi-conductors, conduction can occur by charges quantum tunnelling from one localised site to another. This is known as variable range hopping and has the characteristic form of <math>\rho = Ae^{T^{-1/n}}</math>, where n=2,3,4 depending on the dimensionality of the system.
# Complex resistivity
When analyzing the response of materials to alternating electric fields, as is done in certain types of tomography, it is necessary to replace resistivity with a complex quantity called impeditivity, in analogy to electrical impedance. Impeditivity is the sum of a real component, the resistivity, and an imaginary component, the reactivity (reactance) [1].
# Sources
- ↑ Jump up to: 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 Serway, Raymond A. (1998). Principles of Physics (2nd ed ed.). Fort Worth, Texas; London: Saunders College Pub. pp. p602. ISBN 0-03-020457-7.CS1 maint: Extra text (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jump up to: 2.0 2.1 2.2 2.3 Griffiths, David (1999) [1981]. "7. Electrodynamics". In Alison Reeves (ed.). Introduction to Electrodynamics (3rd edition ed.). Upper Saddle River, New Jersey: Prentice Hall. p. 286. ISBN 0-13-805326-x Check |isbn= value: invalid character (help). OCLC 40251748. Check date values in: |accessdate= (help); |access-date= requires |url= (help)CS1 maint: Extra text: editors list (link) CS1 maint: Extra text (link)
- ↑ Jump up to: 3.0 3.1 3.2 Giancoli, Douglas C. (1995). Physics: Principles with Applications (4th ed ed.). London: Prentice Hall. ISBN 0-13-102153-2.CS1 maint: Extra text (link) (see also Table of Resistivity)
- ↑ Ni,Fe,Cr alloy commonly used in heating elements.
- ↑ Jump up to: 5.0 5.1 5.2 The resistivity of semiconductors depends strongly on the presence of impurities in the material.
- Paul Tipler (2004). Physics for Scientists and Engineers: Electricity, Magnetism, Light, and Elementary Modern Physics (5th ed.). W. H. Freeman. ISBN 0-7167-0810-8. | https://www.wikidoc.org/index.php/Electrical_resistivity | |
645ee1d9cd1e7f3c3048a9605dbf14a08ce460dd | wikidoc | Oxaliplatin | Oxaliplatin
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# Black Box Warning
# Overview
Oxaliplatin is an Antineoplastic agent and platinum coordination complex that is FDA approved for the treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor, advanced colorectal cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Oxaliplatin, used in combination with infusional 5-fluorouracil/Leucovorin, is indicated for:
- adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.
- treatment of Colorectal canceradvanced colorectal cancer.
### Dosage
- Administer Oxaliplatin in combination with 5-fluorouracil/Leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):
- Day 1: Oxaliplatin 85 mg/m2 intravenous infusion in 250–500 mL 5% Dextrose injection, USP and Leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.
- Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.
- The administration of Oxaliplatin does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.
- For information on 5-fluorouracil and Leucovorin, see the respective package inserts.
- Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory test. Prolongation of infusion time for Oxaliplatin from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and Leucovorin do not need to be changed.
- Neuropathy and other toxicities were graded using the NCI CTC scale version 1.
- For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/Leucovorin regimen need not be altered.
- A dose reduction of Oxaliplatin to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 × 109/L and platelets ≥75 × 109/L.
- Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer
- Neuropathy was graded using a study-specific neurotoxicity scale. Other toxicities were graded by the NCI CTC, Version 2.0.
- For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/Leucovorin regimen need not be altered.
- A dose reduction of Oxaliplatin to 65 mg/m2 and 5-fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 × 109/L and platelets ≥75 × 109/L.
- Dose Modifications in Therapy for Patients with Renal Impairment
- In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin is 85 mg/m2. In patients with severe renal impairment, the initial recommended Oxaliplatin dose should be reduced to 65 mg/m2.
- Do not freeze and protect from light the concentrated solution.
A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.
- The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.
- After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature or up to 24 hours under refrigeration .
- After final dilution, protection from light is not required.
- Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.
- Needles or intravenous administration sets containing aluminum parts that may come in contact with Oxaliplatin should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.
### DOSAGE FORMS AND STRENGTHS
- Oxaliplatin is supplied in single-use vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxaliplatin in adult patients.
### Non–Guideline-Supported Use
- Breast Cancer
- Carcinoma of stomach, Advanced/metastatic
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Oxaliplatin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxaliplatin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxaliplatin in pediatric patients.
# Contraindications
- Oxaliplatin should not be administered to patients with a history of known allergy to Oxaliplatin or other platinum compounds
# Warnings
- Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to Oxaliplatin has been observed in 2–3% of colon cancer patients. These allergic reactions which can be fatal, can occur within minutes of administration and at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy. Rechallenge is contraindicated in these patients. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.
- Neuropathy
- Oxaliplatin is associated with two types of neuropathy:
- An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing.The symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed. The acute, reversible pattern of sensory neuropathy was observed in about 56% of study patients who received Oxaliplatin with 5-fluorouracil/Leucovorin. In any individual cycle acute neurotoxicity was observed in approximately 30% of patients. In adjuvant patients the median cycle of onset for grade 3 peripheral sensory neuropathy was 9 in the previously treated patients the median number of cycles administered on the Oxaliplatin with 5-fluorouracil/Leucovorin combination arm was 6.
- An acute syndrome of pharyngolaryngeal dysesthesia seen in 1–2% (grade 3/4) of patients previously untreated for advanced colorectal cancer, and the previously treated patients, is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of Oxaliplatin because cold temperature can exacerbate acute neurological symptoms.
- A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception). These forms of neuropathy occurred in 48% of the study patients receiving Oxaliplatin with 5-fluorouracil/Leucovorin. Persistent neuropathy can occur without any prior acute neuropathy event. The majority of the patients (80%) who developed grade 3 persistent neuropathy progressed from prior Grade 1 or 2 events. These symptoms may improve in some patients upon discontinuation of Oxaliplatin.
- In the adjuvant colon cancer trial, neuropathy was graded using a prelisted module derived from the Neuro-Sensory section of the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale, Version 1, as follows:
- Peripheral sensory neuropathy was reported in adjuvant patients treated with the Oxaliplatin combination with a frequency of 92% (all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral sensory neuropathy decreasing to 39% at 6 months follow-up (Grade 1=31%, Grade 2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 2=3%, Grade 3=1%).
- In the advanced colorectal cancer studies, neuropathy was graded using a study-specific neurotoxicity scale, which was different from the NCI CTC scale, Version 2.0
- Overall, neuropathy was reported in patients previously untreated for advanced colorectal cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (grade 3/4) events. Information regarding reversibility of neuropathy was not available from the trial for patients who had not been previously treated for colorectal cancer.
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging.
- Oxaliplatin has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any grade) and <1% (grade 3) with no grade 4 events in the Oxaliplatin plus infusional 5-fluorouracil/Leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5-fluorouracil/Leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the Oxaliplatin combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the Oxaliplatin plus 5-fluorouracil/Leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-fluorouracil/Leucovorin arm of unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, Oxaliplatin should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
- Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the Oxaliplatin combination arm than in the control arm. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases
- Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT,AST, bilirubin and creatinine) is recommended before each Oxaliplatin cycle.
- There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin plus 5-fluorouracil/Leucovorin while on anticoagulants. Patients receiving Oxaliplatin plus 5-fluorouracil/Leucovorin and requiring oral anticoagulants may require closer monitoring.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- More than 1100 patients with stage II or III colon cancer and more than 4,000 patients with advanced colorectal cancer have been treated in clinical studies with Oxaliplatin. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. The most common adverse reactions in previously untreated and treated patients were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea.
- One thousand one hundred and eight patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, have been treated in a clinical study with Oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin. The incidence of grade 3 or 4 adverse reactions was 70% on the Oxaliplatin combination arm, and 31% on the infusional 5-fluorouracil/Leucovorin arm. The adverse reactions in this trial are shown in the tables below. Discontinuation of treatment due to adverse reactions occurred in 15% of the patients receiving Oxaliplatin and infusional 5-fluorouracil/Leucovorin. Both 5-fluorouracil/Leucovorin and Oxaliplatin are associated with gastrointestinal or hematologic adverse reactions. When Oxaliplatin is administered in combination with infusional 5-fluorouracil/Leucovorin, the incidence of these events is increased.
- The incidence of death within 28 days of last treatment, regardless of causality, was 0.5% (n=6) in both the Oxaliplatin combination and infusional 5-fluorouracil/Leucovorin arms, respectively. Deaths within 60 days from initiation of therapy were 0.3% (n=3) in both the Oxaliplatin combination and infusional 5-fluorouracil/Leucovorin arms, respectively. On the Oxaliplatin combination arm, 3 deaths were due to sepsis/neutropenic sepsis, 2 from intracerebral bleeding and one from eosinophilic pneumonia. On the 5-fluorouracil/Leucovorin arm, one death was due to suicide, 2 from Steven-Johnson Syndrome (1 patient also had sepsis), 1 unknown cause, 1 anoxic cerebral infarction and 1 probable abdominal aorta rupture.
- The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial by body system and decreasing order of frequency in the Oxaliplatin and infusional 5-fluorouracil/Leucovorin arm for events with overall incidences ≥ 5% and for NCI grade 3/4 events with incidences ≥ 1%.
- The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial by body system and decreasing order of frequency in the Oxaliplatin and infusional 5-fluorouracil/Leucovorin arm for events with overall incidences ≥ 5% but with incidences <1% NCI grade 3/4 events.
- Although specific events can vary, the overall frequency of adverse reactions was similar in men and women and in patients <65 and ≥65 years. However, the following grade 3/4 events were more common in females: diarrhea, fatigue, granulocytopenia, nausea and vomiting. In patients ≥65 years old, the incidence of grade 3/4 diarrhea and granulocytopenia was higher than in younger patients. Insufficient subgroup sizes prevented analysis of safety by race. The following additional adverse reactions, were reported in ≥2% and <5% of the patients in the Oxaliplatin and infusional 5-fluorouracil/Leucovorin combination arm (listed in decreasing order of frequency): pain, leukopenia, weight decrease, coughing.
- The number of patients who developed secondary malignancies was similar; 62 in the Oxaliplatin combination arm and 68 in the infusional 5-fluorouracil/Leucovorin arm. An exploratory analysis showed that the number of deaths due to secondary malignancies was 1.96% in the Oxaliplatin combination arm and 0.98% in infusional 5-fluorouracil/Leucovorin arm. In addition, the number of cardiovascular deaths was 1.4% in the Oxaliplatin combination arm as compared to 0.7% in the infusional 5-fluorouracil/Leucovorin arm. Clinical significance of these findings is unknown.
- Two hundred and fifty-nine patients were treated in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm of the randomized trial in patients previously untreated for advanced colorectal cancer. The adverse reaction profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below.
- Both 5-fluorouracil and Oxaliplatin are associated with gastrointestinal and hematologic adverse reactions. When Oxaliplatin is administered in combination with 5-fluorouracil, the incidence of these events is increased.
- The incidence of death within 30 days of treatment in the previously untreated for advanced colorectal cancer study, regardless of causality, was 3% with the Oxaliplatin and 5-fluorouracil/Leucovorin combination, 5% with irinotecan plus 5-fluorouracil/Leucovorin, and 3% with Oxaliplatin plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the Oxaliplatin and 5-fluorouracil/Leucovorin combination, 5.1% with irinotecan plus 5-fluorouracil/Leucovorin, and 3.1% with Oxaliplatin plus irinotecan.
- The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study by body system and decreasing order of frequency in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm for events with overall incidences ≥5% and for grade 3/4 events with incidences ≥1%.
- The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study by body system and decreasing order of frequency in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm for events with overall incidences ≥5% but with incidences <1% NCI Grade 3/4 events.
- Adverse reactions were similar in men and women and in patients <65 and ≥65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope. The following additional adverse reactions, at least possibly related to treatment and potentially important, were reported in ≥2% and <5% of the patients in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm (listed in decreasing order of frequency): metabolic, pneumonitis, catheter infection, vertigo, prothrombin time, pulmonary, rectal bleeding, dysuria, nail changes, chest pain, rectal pain, syncope, hypertension, hypoxia, unknown infection, bone pain, pigmentation changes, and urticaria.
- Four hundred and fifty patients (about 150 receiving the combination of Oxaliplatin and 5-fluorouracil/Leucovorin) were studied in a randomized trial in patients with refractory and relapsed colorectal cancer. The adverse reaction profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below.
- Thirteen percent of patients in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm and 18% in the 5-fluorouracil/Leucovorin arm of the previously treated study had to discontinue treatment because of adverse effects related to gastrointestinal, or hematologic adverse reactions, or neuropathies. Both 5-fluorouracil and Oxaliplatin are associated with gastrointestinal and hematologic adverse reactions. When Oxaliplatin is administered in combination with 5-fluorouracil, the incidence of these events is increased.
- The incidence of death within 30 days of treatment in the previously treated study, regardless of causality, was 5% with the Oxaliplatin and 5-fluorouracil/Leucovorin combination, 8% with Oxaliplatin alone, and 7% with 5-fluorouracil/Leucovorin. Of the 7 deaths that occurred on the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm within 30 days of stopping treatment, 3 may have been treatment related, associated with gastrointestinal bleeding or dehydration.
- The following table provides adverse reactions reported in the previously treated study by body system and in decreasing order of frequency in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm for events with overall incidences ≥5% and for grade 3/4 events with incidences ≥1%. This table does not include hematologic and blood chemistry abnormalities; these are shown separately below.
- The following table provides adverse reactions reported in the previously treated study by body system and in decreasing order of frequency in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm for events with overall incidences ≥5% but with incidences <1% NCI Grade 3/4 events.
- Adverse reactions were similar in men and women and in patients <65 and ≥65 years, but older patients may have been more susceptible to dehydration, diarrhea, hypokalemia and fatigue. The following additional adverse reactions, at least possibly related to treatment and potentially important, were reported in ≥2% and <5% of the patients in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm (listed in decreasing order of frequency): anxiety, myalgia, erythematous rash, increased sweating, conjunctivitis, weight decrease, dry mouth, rectal hemorrhage, depression, ataxia, ascites, hemorrhoids, muscle weakness, nervousness, tachycardia, abnormal micturition frequency, dry skin, pruritus, hemoptysis, purpura, vaginal hemorrhage, melena, somnolence, pneumonia, proctitis, involuntary muscle contractions, intestinal obstruction, gingivitis, tenesmus, hot flashes, enlarged abdomen, urinary incontinence.
- The following tables list the hematologic changes occurring in ≥5% of patients, based on laboratory values and NCI grade, with the exception of those events occurring in adjuvant patients and anemia in the patients previously untreated for advanced colorectal cancer, respectively, which are based on AE reporting and NCI grade alone.
- Thrombocytopenia was frequently reported with the combination of Oxaliplatin and infusional 5-fluorouracil/Leucovorin. The incidence of all hemorrhagic events in the adjuvant and previously treated patients was higher on the Oxaliplatin combination arm compared to the infusional 5-fluorouracil/Leucovorin arm. These events included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant trial, two patients died from intracerebral hemorrhages.
- The incidence of Grade 3/4 thrombocytopenia was 2% in adjuvant patients with colon cancer. In patients treated for advanced colorectal cancer the incidence of Grade 3/4 thrombocytopenia was 3–5%, and the incidence of these events was greater for the combination of Oxaliplatin and 5-fluorouracil/Leucovorin over the irinotecan plus 5-fluorouracil/Leucovorin or 5-fluorouracil/Leucovorin control groups. Grade 3/4 gastrointestinal bleeding was reported in 0.2% of adjuvant patients receiving Oxaliplatin and 5-fluorouracil/Leucovorin. In the previously untreated patients, the incidence of epistaxis was 10% in the Oxaliplatin and 5-fluorouracil/Leucovorin arm, and 2% and 1%, respectively, in the irinotecan plus 5-fluorouracil/Leucovorin or irinotecan plus Oxaliplatin arms.
- Neutropenia was frequently observed with the combination of Oxaliplatin and 5-fluorouracil/Leucovorin, with Grade 3 and 4 events reported in 29% and 12% of adjuvant patients with colon cancer, respectively. In the adjuvant trial, 3 patients died from sepsis/neutropenic sepsis. Grade 3 and 4 events were reported in 35% and 18% of the patients previously untreated for advanced colorectal cancer, respectively. Grade 3 and 4 events were reported in 27% and 17% of previously treated patients, respectively. In adjuvant patients the incidence of either febrile neutropenia (0.7%) or documented infection with concomitant grade 3/4 neutropenia (1.1%) was 1.8% in the Oxaliplatin and 5-fluorouracil/Leucovorin arm. The incidence of febrile neutropenia in the patients previously untreated for advanced colorectal cancer was 15% (3% of cycles) in the irinotecan plus 5-fluorouracil/Leucovorin arm and 4% (less than 1% of cycles) in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm. Additionally, in this same population, infection with grade 3 or 4 neutropenia was 12% in the irinotecan plus 5-fluorouracil/Leucovorin, and 8% in the Oxaliplatin and 5-fluorouracil/Leucovorin combination. The incidence of febrile neutropenia in the previously treated patients was 1% in the 5-fluorouracil/Leucovorin arm and 6% (less than 1% of cycles) in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm.
- In patients receiving the combination of Oxaliplatin plus infusional 5-fluorouracil/Leucovorin for adjuvant treatment for colon cancer the incidence of Grade 3/4 nausea and vomiting was greater than those receiving infusional 5-fluorouracil/Leucovorin alone (see table). In patients previously untreated for advanced colorectal cancer receiving the combination of Oxaliplatin and 5-fluorouracil/Leucovorin, the incidence of Grade 3 and 4 vomiting and diarrhea was less compared to irinotecan plus 5-fluorouracil/Leucovorin controls (see table). In previously treated patients receiving the combination of Oxaliplatin and 5-fluorouracil/Leucovorin, the incidence of Grade 3 and 4 nausea, vomiting, diarrhea, and mucositis/stomatitis increased compared to 5-fluorouracil/Leucovorin controls (see table).
- The incidence of gastrointestinal adverse reactions in the previously untreated and previously treated patients appears to be similar across cycles. Premedication with antiemetics, including 5-HT3 blockers, is recommended. Diarrhea and mucositis may be exacerbated by the addition of Oxaliplatin to 5-fluorouracil/Leucovorin, and should be managed with appropriate supportive care. Since cold temperature can exacerbate acute neurological symptoms, ice (mucositis prophylaxis) should be avoided during the infusion of Oxaliplatin.
- Oxaliplatin did not increase the incidence of alopecia compared to 5-fluorouracil/Leucovorin alone. No complete alopecia was reported. The incidence of Grade 3/4 skin disorders was 2% in both the Oxaliplatin plus infusional 5-fluorouracil/Leucovorin and the infusional 5-fluorouracil/Leucovorin alone arms in the adjuvant colon cancer patients. The incidence of hand-foot syndrome in patients previously untreated for advanced colorectal cancer was 2% in the irinotecan plus 5-fluorouracil/Leucovorin arm and 7% in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm. The incidence of hand-foot syndrome in previously treated patients was 13% in the 5-fluorouracil/Leucovorin arm and 11% in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm.
- Extravasation, in some cases including necrosis, has been reported.
Injection site reaction, including redness, swelling, and pain, has been reported.
- There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin plus 5-fluorouracil/Leucovorin while on anticoagulants. Patients receiving Oxaliplatin plus 5-fluorouracil/Leucovorin and requiring oral anticoagulants may require closer monitoring.
- About 5–10% of patients in all groups had some degree of elevation of serum creatinine. The incidence of Grade 3/4 elevations in serum creatinine in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm was 1% in the previously treated patients. Serum creatinine measurements were not reported in the adjuvant trial.
- Hepatotoxicity (defined as elevation of liver enzymes) appears to be related to Oxaliplatin combination therapy. The following tables list the clinical chemistry changes associated with hepatic toxicity occurring in ≥5% of patients, based on adverse reactions reported and NCI CTC grade for adjuvant patients and patients previously untreated for advanced colorectal cancer, laboratory values and NCI CTC grade for previously treated patients.
- The incidence of thromboembolic events in adjuvant patients with colon cancer was 6% (1.8% grade 3/4) in the infusional 5-fluorouracil/Leucovorin arm and 6% (1.2% grade 3/4) in the Oxaliplatin and infusional 5-fluorouracil/Leucovorin combined arm, respectively. The incidence was 6 and 9% of the patients previously untreated for advanced colorectal cancer and previously treated patients in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm, respectively
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of Oxaliplatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- angioedema, anaphylactic shock
- loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsion, Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES).
- deafness
- laryngospasm
- severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis; ileus; intestinal obstruction, pancreatitis; veno-occlusive disease of liver also known as sinusoidal obstruction syndrome, and perisinusoidal fibrosis which rarely may progress.
- immuno-allergic thrombocytopenia
prolongation of prothrombin time and of INR in patients receiving anticoagulants
- hemolytic uremic syndrome, immuno-allergic hemolytic anemia
- Acute tubular necrosis, acute interstitial nephritis and acute renal failure.
- pulmonary fibrosis, and other interstitial lung diseases (sometimes fatal)
- decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following therapy discontinuation)
# Drug Interactions
- No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 Oxaliplatin and 5-fluorouracil/Leucovorin has been observed in patients treated every 2 weeks. Increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 Oxaliplatin dosed every 3 weeks. Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds; although, this has not been specifically studied
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on direct interaction with DNA, Oxaliplatin may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Oxaliplatin in pregnant women. Reproductive toxicity studies in rats demonstrated adverse effects on fertility and embryo-fetal development at maternal doses that were below the recommended human dose based on body surface area. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant and use effective contraception while receiving treatment with Oxaliplatin.
- Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days 1–5 (pre-implantation), 6–10, or 11–16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6–10 and 11–16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6–10. Administration of oxaliplatin to male and female rats prior to mating resulted in 97% post-implantation loss in animals that received approximately one-seventh the recommended human dose based on the body surface area.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxaliplatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Oxaliplatin during labor and delivery.
### Nursing Mothers
- It is not known whether Oxaliplatin or its derivatives are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Oxaliplatin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The effectiveness of oxaliplatin in children has not been established. Oxaliplatin has been tested in 2 Phase 1 and 2 Phase 2 trials in 235 patients ages 7 months to 22 years with solid tumors (see below) and no significant activity observed.
- In a Phase 1/2 study, oxaliplatin was administered as a 2-hour intravenous infusion on Days 1, 8 and 15 every 4 weeks (1 cycle), for a maximum of 6 cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty eight pediatric patients in the Phase 1 study received oxaliplatin at 6 dose levels starting at 40 mg/m2 with escalation to 110 mg/m2. The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m2 dose. Fifteen patients received oxaliplatin at a dose of 90 mg/m2 intravenous in the Phase 2 portion of the study. At this dose, paresthesia (60%, G3/4: 7%), fever (40%, G3/4: 7%) and thrombocytopenia (40%, G3/4: 27%) were the main adverse reactions. No responses were observed.
- In a second Phase 1 study, oxaliplatin was administered to 26 pediatric patients as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) at 5 dose levels starting at 100 mg/m2 with escalation to 160 mg/m2, for a maximum of 6 cycles. In a separate cohort, oxaliplatin 85 mg/m2 was administered on day 1 every 2 weeks, for a maximum of 9 doses. Patients had metastatic or unresectable solid tumors mainly neuroblastoma and ganglioneuroblastoma. No responses were observed. The DLT was sensory neuropathy at the 160 mg/m2 dose. Based on these studies, oxaliplatin 130 mg/m2 as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) was used in subsequent Phase II studies. A dose of 85 mg/m2 on day 1 every 2 weeks was also found to be tolerable.
- In one Phase 2 study, 43 pediatric patients with recurrent or refractory embryonal CNS tumors received oxaliplatin 130 mg/m2 every 3 weeks for a maximum of 12 months in absence of progressive disease or unacceptable toxicity. In patients < 10 kg the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were leukopenia (67%, G3/4: 12%), anemia (65%, G3/4: 5%), thrombocytopenia (65%, G3/4: 26%), vomiting (65%, G3/4: 7%), neutropenia (58%, G3/4: 16%) and sensory neuropathy (40%, G3/4: 5%). One partial response was observed.
- In a second Phase 2 study, 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, Ewing sarcoma or peripheral PNET, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, Brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors of interest received oxaliplatin 130 mg/m2 every 3 weeks for a maximum of 12 months or 17 cycles. In patients ≤ 12 months old the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were sensory neuropathy (52%, G3/4: 12%), thrombocytopenia (37%, G3/4: 17%), anemia (37%, G3/4: 9%), vomiting (26%, G3/4:4%), ALT increased (24%, G3/4: 6%), AST increased (24%, G3/4: 2%), and nausea (23%, G3/:4 3%). Two partial responses were observed.
- The pharmacokinetic parameters of ultrafiltrable platinum have been evaluated in 105 pediatric patients during the first cycle. The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h. The inter-patient variability of platinum clearance in pediatric cancer patients was 41%. Mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 ± 0.24 mcg/mL, AUC0–48 of 7.52 ± 5.07 mcg∙h/mL and AUCinf of 8.83 ± 1.57 mcg∙h/mL at 85 mg/m2 of oxaliplatin and Cmax of 1.10 ± 0.43 mcg/mL, AUC0–48 of 9.74 ± 2.52 mcg∙h/mL and AUCinf of 17.3 ± 5.34 mcg∙h/mL at 130 mg/m2 of oxaliplatin.
### Geriatic Use
- No significant effect of age on the clearance of ultrafilterable platinum has been observed.
- In the adjuvant therapy colon cancer randomized clinical trial, 723 patients treated with Oxaliplatin and infusional 5-fluorouracil/Leucovorin were <65 years and 400 patients were ≥65 years.
- A descriptive subgroup analysis demonstrated that the improvement in DFS for the Oxaliplatin combination arm compared to the infusional 5-fluorouracil/Leucovorin alone arm appeared to be maintained across genders. The effect of Oxaliplatin in patients ≥65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race.
- Patients ≥ 65 years of age receiving the Oxaliplatin combination therapy experienced more grade 3–4 granulocytopenia than patients < 65 years of age (45% versus 39%).
- In the previously untreated for advanced colorectal cancer randomized clinical trial of Oxaliplatin, 160 patients treated with Oxaliplatin and 5-fluorouracil/Leucovorin were < 65 years and 99 patients were ≥65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the ≥65 year old patients as in the overall study population. In the previously treated for advanced colorectal cancer randomized clinical trial of Oxaliplatin, 95 patients treated with Oxaliplatin and 5-fluorouracil/Leucovorin were <65 years and 55 patients were ≥65 years. The rates of overall adverse reactions, including grade 3 and 4 events, were similar across and within arms in the different age groups in all studies. The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope were higher in patients ≥65 years old. No adjustment to starting dose was required in patients ≥65 years old.
### Gender
There is no FDA guidance on the use of Oxaliplatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Oxaliplatin with respect to specific racial populations.
### Renal Impairment
- The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients. Caution and close monitoring should be exercised when Oxaliplatin is administered to patients with renal impairment. The starting Oxaliplatin dose does not need to be reduced in patients with mild (creatinine clearance=50-80 mL/min) or moderate (creatinine clearance=30-49 mL/min) renal impairment. However, the starting dose of Oxaliplatin should be reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min)
### Hepatic Impairment
There is no FDA guidance on the use of Oxaliplatin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oxaliplatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oxaliplatin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Monitor for development of rash, urticaria, erythema, pruritis, bronchospasm, and hypotension
- Hepatotoxicity: Monitor liver function tests.
- Caution and close monitoring should be exercised when Oxaliplatin is administered to patients with renal impairment.
# IV Compatibility
There is limited information regarding IV Compatibility of Oxaliplatin in the drug label.
# Overdosage
- There is no known antidote for Oxaliplatin overdose. In addition to thrombocytopenia, the anticipated complications of an Oxaliplatin overdose include hypersensitivity reaction, myelosuppression, nausea, vomiting, diarrhea and neurotoxicity.
- Several cases of overdoses have been reported with Oxaliplatin. Adverse reactions observed were Grade 4 thrombocytopenia (<25,000/mm3) without any bleeding, anemia, sensory neuropathy such as paresthesia, dysesthesia, laryngospasm and facial muscle spasms, gastrointestinal disorders such as nausea, vomiting, stomatitis, flatulence, abdomen enlarged and Grade 4 intestinal obstruction, Grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia and death.
- Patients suspected of receiving an overdose should be monitored, and supportive treatment should be administered. The maximum dose of oxaliplatin that has been administered in a single infusion is 825 mg.
# Pharmacology
There is limited information regarding Oxaliplatin Pharmacology in the drug label.
## Mechanism of Action
- Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.
- In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with , oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models .
## Structure
- Oxaliplatin® (oxaliplatin injection) is an antineoplastic agent with the molecular formula C8H14N2O4Pt and the chemical name of cis- platinum. Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane(DACH) and with an oxalate ligand as a leaving group.
- The molecular weight is 397.3. Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone.
- Oxaliplatin is supplied in vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. Water for Injection, USP is present as an inactive ingredient.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Oxaliplatin in the drug label.
## Pharmacokinetics
- The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t1/2α; 0.43 hours and t1/2β; 16.8 hours) and a long terminal elimination phase (t1/2γ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour intravenous infusion of Oxaliplatin at a dose of 85 mg/m2 expressed as ultrafilterable platinum were Cmax of 0.814 mcg/mL and volume of distribution of 440 L.
Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC0–48hr) assessed over 3 cycles was moderate to low (23% and 6%, respectively). A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.
- At the end of a 2-hour infusion of Oxaliplatin, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m2 every two weeks.
- Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro.
- Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species.
- The major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of Oxaliplatin, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at a rate (10 – 17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinum is significantly correlated with GFR.
- A study was conducted in 38 patients with advanced GI cancer and varying degrees of renal impairment. Patients in the normal (creatinine clearance (CrCL) > 80 mL/min, N=11), mild (CrCL=50-80 mL/min, N=13), and moderate (CrCL=30-49 mL/min, N=10) groups were treated with 85 mg/m2 Oxaliplatin and those in the severe (CrCL < 30 mL/min, N=4) group were treated with 65 mg/m2 Oxaliplatin. The mean AUC of unbound platinum was 40%, 95%, and 342% higher in the mild, moderate, and severe groups, respectively, than in the normal group. Mean Cmax of unbound platinum appeared to be similar among the normal, mild and moderate renal function groups, but was 38% higher in the severe group than in the normal group. Caution should be exercised in renally impaired patients. The starting dose of Oxaliplatin should be reduced in patients with severe renal impairment. The starting dose of Oxaliplatin should be reduced in patients with severe renal impairment.
- No pharmacokinetic interaction between 85 mg/m2 of Oxaliplatin and infusional 5-fluorouracil has been observed in patients treated every 2 weeks, but increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 of Oxaliplatin administered every 3 weeks. In vitro, platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitro, oxaliplatin is not metabolized by, nor does it inhibit, human cytochrome P450 isoenzymes. No P450-mediated drug-drug interactions are therefore anticipated in patients.
- Since platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds, although this has not been specifically studied.
## Nonclinical Toxicology
- Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).
- In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but caused developmental mortality (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).
- Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day × 5 days every 28 days for three cycles. A no effect level was not identified. This daily dose is approximately one-sixth of the recommended human dose on a body surface area basis.
# Clinical Studies
- An international, multicenter, randomized study compared the efficacy and evaluated the safety of Oxaliplatin in combination with an infusional schedule of 5-fluorouracil/Leucovorin to infusional 5-fluorouracil/Leucovorin alone, in patients with stage II (Dukes' B2) or III (Dukes' C) colon cancer who had undergone complete resection of the primary tumor. The primary objective of the study was to compare the 3-year disease-free survival (DFS) in patients receiving Oxaliplatin and infusional 5-fluorouracil/Leucovorin to those receiving 5-fluorouracil/Leucovorin alone. Patients were to be treated for a total of 6 months (i.e., 12 cycles). A total of 2246 patients were randomized; 1123 patients per study arm. Patients in the study had to be between 18 and 75 years of age, have histologically proven stage II (T3–T4 N0 M0; Dukes' B2) or III (any T N1–2 M0; Dukes' C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., ≥15 cm from the anal margin) and undergone (within 7 weeks prior to randomization) complete resection of the primary tumor without gross or microscopic evidence of residual disease. Patients had to have had no prior chemotherapy, immunotherapy or radiotherapy, and have an ECOG performance status of 0,1, or 2 (KPS ≥ 60%), absolute neutrophil count (ANC) > 1.5x109/L, platelets ≥100×109/L, serum creatinine ≤ 1.25 × ULN total bilirubin < 2 × ULN, AST/ALT < 2 × ULN and carcino-embyrogenic antigen (CEA) < 10 ng/mL. Patients with preexisting peripheral neuropathy (NCI grade ≥ 1) were ineligible for this trial.
- The following table shows the dosing regimens for the two arms of the study.
- The following tables show the baseline characteristics and dosing of the patient population entered into this study. The baseline characteristics were well balanced between arms.
- The following table and figures summarize the disease-free survival (DFS) results in the overall randomized population and in patients with stage II and III disease based on an ITT analysis. The median duration of follow-up was approximately 77 months.
- In the overall and stage III colon cancer populations DFS was statistically significantly improved in the Oxaliplatin combination arm compared to infusional 5-fluorouracil/Leucovorin alone. However, a statistically significant improvement in DFS was not noted in Stage II patients.
- Figure 2 shows the DFS Kaplan-Meier curves for the comparison of Oxaliplatin and infusional 5-fluorouracil/Leucovorin combination and infusional 5-fluorouracil/Leucovorin alone for the overall population (ITT analysis).
- Figure 3 shows the DFS Kaplan-Meier curves for the comparison of Oxaliplatin and infusional 5-fluorouracil/Leucovorin combination and infusional 5-fluorouracil/Leucovorin alone in Stage III patients.
- The following table summarizes the overall survival (OS) results in the overall randomized population and in patients with stage II and III disease, based on the ITT analysis.
- A North American, multicenter, open-label, randomized controlled study was sponsored by the National Cancer Institute (NCI) as an intergroup study led by the North Central Cancer Treatment Group (NCCTG). The study had 7 arms at different times during its conduct, four of which were closed due to either changes in the standard of care, toxicity, or simplification. During the study, the control arm was changed to irinotecan plus 5-fluorouracil/Leucovorin. The results reported below compared the efficacy and safety of two experimental regimens, Oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin and a combination of Oxaliplatin plus irinotecan, to an approved control regimen of irinotecan plus 5-fluorouracil/Leucovorin in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. After completion of enrollment, the dose of irinotecan plus 5-fluorouracil/Leucovorin was decreased due to toxicity. Patients had to be at least 18 years of age, have known locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy with curative intent, histologically proven colorectal adenocarcinoma, measurable or evaluable disease, with an ECOG performance status 0,1, or 2. Patients had to have granulocyte count ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, hemoglobin ≥9.0 gm/dL, creatinine ≤ 1.5 × ULN, total bilirubin ≤ 1.5 mg/dL, AST ≤ 5 × ULN, and alkaline phosphatase ≤ 5 × ULN. Patients may have received adjuvant therapy for resected Stage II or III disease without recurrence within 12 months. The patients were stratified for ECOG performance status (0, 1 vs. 2), prior adjuvant chemotherapy (yes vs. no), prior immunotherapy (yes vs. no), and age (<65 vs. ≥65 years). Although no post study treatment was specified in the protocol, 65 to 72% of patients received additional post study chemotherapy after study treatment discontinuation on all arms. Fifty-eight percent of patients on the Oxaliplatin plus 5-fluorouracil/Leucovorin arm received an irinotecan-containing regimen and 23% of patients on the irinotecan plus 5-fluorouracil/Leucovorin arm received oxaliplatin-containing regimens. Oxaliplatin was not commercially available during the trial.
- The following table presents the dosing regimens of the three arms of the study.
- The following table presents the demographics of the patient population entered into this study.
- The length of a treatment cycle was 2 weeks for the Oxaliplatin and 5-fluorouracil/Leucovorin regimen; 6 weeks for the irinotecan plus 5-fluorouracil/Leucovorin regimen; and 3 weeks for the Oxaliplatin plus irinotecan regimen. The median number of cycles administered per patient was 10 (23.9 weeks) for the Oxaliplatin and 5-fluorouracil/Leucovorin regimen, 4 (23.6 weeks) for the irinotecan plus 5-fluorouracil/Leucovorin regimen, and 7 (21.0 weeks) for the Oxaliplatin plus irinotecan regimen. Patients treated with the Oxaliplatin and 5-fluorouracil/Leucovorin combination had a significantly longer time to tumor progression based on investigator assessment, longer overall survival, and a significantly higher confirmed response rate based on investigator assessment compared to patients given irinotecan plus 5-fluorouracil/Leucovorin. The following table summarizes the efficacy results.
- A descriptive subgroup analysis demonstrated that the improvement in survival for Oxaliplatin plus 5-fluorouracil/Leucovorin compared to irinotecan plus 5-fluorouracil/Leucovorin appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved. An estimated survival advantage in Oxaliplatin plus 5-fluorouracil/Leucovorin versus irinotecan plus 5-fluorouracil/Leucovorin was seen in both genders; however it was greater among women than men. Insufficient subgroup sizes prevented analysis by race.
- A multicenter, open-label, randomized, three-arm controlled study was conducted in the US and Canada comparing the efficacy and safety of Oxaliplatin in combination with an infusional schedule of 5-fluorouracil/Leucovorin to the same dose and schedule of 5-fluorouracil/Leucovorin alone and to single agent oxaliplatin in patients with advanced colorectal cancer who had relapsed/progressed during or within 6 months of first-line therapy with bolus 5-fluorouracil/Leucovorin and irinotecan. The study was intended to be analyzed for response rate after 450 patients were enrolled. Survival will be subsequently assessed in all patients enrolled in the completed study. Accrual to this study is complete, with 821 patients enrolled. Patients in the study had to be at least 18 years of age, have unresectable, measurable, histologically proven colorectal adenocarcinoma, with a Karnofsky performance status >50%. Patients had to have SGOT(AST) and SGPT(ALT) ≤2× the institution's upper limit of normal (ULN), unless liver metastases were present and documented at baseline by CT or MRI scan, in which case ≤5× ULN was permitted. Patients had to have alkaline phosphatase ≤2× the institution's ULN, unless liver metastases were present and documented at baseline by CT or MRI scan, in which cases ≤5× ULN was permitted. Prior radiotherapy was permitted if it had been completed at least 3 weeks before randomization.
- The dosing regimens of the three arms of the study are presented in the table below.
- Patients entered into the study for evaluation of response must have had at least one unidimensional lesion measuring ≥20mm using conventional CT or MRI scans, or ≥10mm using a spiral CT scan. Tumor response and progression were assessed every 3 cycles (6 weeks) using the Response Evaluation Criteria in Solid Tumors (RECIST) until radiological documentation of progression or for 13 months following the first dose of study drug(s), whichever came first. Confirmed responses were based on two tumor assessments separated by at least 4 weeks.
The demographics of the patient population entered into this study are shown in the table below:
- The median number of cycles administered per patient was 6 for the Oxaliplatin and 5-fluorouracil/Leucovorin combination and 3 each for 5-fluorouracil/Leucovorin alone and Oxaliplatin alone.
- Patients treated with the combination of Oxaliplatin and 5-fluorouracil/Leucovorin had an increased response rate compared to patients given 5-fluorouracil/Leucovorin or oxaliplatin alone. The efficacy results are summarized in the tables below.
- At the time of the interim analysis 49% of the radiographic progression events had occurred. In this interim analysis an estimated 2-month increase in median time to radiographic progression was observed compared to 5-fluorouracil/Leucovorin alone.
- Of the 13 patients who had tumor response to the combination of Oxaliplatin and 5-fluorouracil/Leucovorin, 5 were female and 8 were male, and responders included patients <65 years old and ≥65 years old. The small number of non-Caucasian participants made efficacy analyses in these populations uninterpretable.
# How Supplied
- Oxaliplatin is supplied in clear, glass, single-use vials with gray elastomeric stoppers and aluminum flip-off seals containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. Water for Injection, USP is present as an inactive ingredient.
- NDC 0024-0590-10: 50 mg single-use vial with green flip-off seal individually packaged in a carton.
- NDC 0024-0591-20: 100 mg single-use vial with dark blue flip-off seal individually packaged in a carton.
## Storage
Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Do not freeze and protect from light (keep in original outer carton).
- As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from Oxaliplatin. The use of gloves is recommended. If a solution of Oxaliplatin contacts the skin, wash the skin immediately and thoroughly with soap and water. If Oxaliplatin contacts the mucous membranes, flush thoroughly with water.
- Procedures for the handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL - 50 mg Carton
NDC 0024-0590-10
50 mg
Oxaliplatin®
(OXALIplatin injection) 5 mg/mL
INJECTION
50 mg
FOR INTRAVENOUS USE ONLY
SINGLE USE VIAL ONLY
Sterile Aqueous Solution - Preservative Free
See package insert for further
required dilution.
DO NOT MIX OR ADD TO
SODIUM CHLORIDE/
CHLORIDE-CONTAINING
SOLUTIONS
Rx only
SANOFI
NDC 0024-0591-20
100 mg
Oxaliplatin®
(OXALIplatin injection) 5 mg/mL
INJECTION
100 mg
FOR INTRAVENOUS USE ONLY
SINGLE USE VIAL ONLY
Sterile Aqueous Solution - Preservative Free
See package insert for further
required dilution.
DO NOT MIX OR ADD TO
SODIUM CHLORIDE/
CHLORIDE-CONTAINING
SOLUTIONS
Rx only
SANOFI
### INGREDIENTS AND APPEARANCE
# Patient Counseling Information
- Advise patients
- To expect side effects of Oxaliplatin, particularly its neurologic effects, both the acute, reversible effects and the persistent neurosensory toxicity. Patients should be informed that the acute neurosensory toxicity may be precipitated or exacerbated by exposure to cold or cold objects.
- To avoid cold drinks, use of ice, and should cover exposed skin prior to exposure to cold temperature or cold objects.
Of the risk of low blood cell counts and to contact their physician immediately should fever, particularly if associated with persistent diarrhea, or evidence of infection develop.
- To contact their physician if persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties occur, or signs of allergic reaction appear.
- To exercise caution when driving and using machines. No studies on the effects of the ability to operate cars and machines have been performed; however, oxaliplatin treatment resulting in an increase risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to a minor or moderate influence on the ability to drive and use machines.
Of the potential effects of vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), which may affect patients' ability to drive and use machines.
### PATIENT PACKAGE INSERT
Patient Information
Oxaliplatin® (eh-LOX-ah-tin)
(OXALIplatin)
concentrate, for solution for intravenous use
- Read this Patient Information leaflet carefully before you start receiving Oxaliplatin. There may be new information. It will help you learn more about Oxaliplatin. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment. Ask your doctor about any questions you have.
- What is the most important information I should know about Oxaliplatin?
- Serious side effects can happen in people taking ELOXATION, including:
- Serious allergic reactions. Oxaliplatin can cause serious allergic reactions, including allergic reactions that may cause death. Oxaliplatin is a platinum base medicine. Serious allergic reactions including death can occur in people who take Oxaliplatin and who have had previous allergic reactions to platinum medicines. Serious allergic reactions can happen within a few minutes of your infusion or any time during your treatment with Oxaliplatin.
- Get emergency help right away if you:
- have trouble breathing.
- feel like your throat is closing up.
- Call your doctor right away if you have any of the following signs or symptoms of an allergic reaction:
- rash
- flushed face
- hives
- itching
- swelling of your lips or tongue
- sudden cough
- dizziness or feel faint
- sweating
- chest pain
- See "What are the possible side effects of Oxaliplatin?" for information about other serious side effects.
- What is Oxaliplatin?
- Oxaliplatin is an anti-cancer (chemotherapy) medicine that is used with other anti-cancer medicines called 5-fluorouracil and Leucovorin to treat people with:
- stage III colon cancer after surgery to remove the tumor
- advanced colon or rectal cancer (colo-rectal cancer).
- Oxaliplatin with infusional 5-fluorouracil and Leucovorin was shown to lower the chance of colon cancer returning when given to patients with stage III colon cancer after surgery to remove the tumor. Oxaliplatin also increases survival in patients with stage III colon cancer. Oxaliplatin with infusional 5-fluorouracil and Leucovorin was also shown to increase survival, shrink tumors and delay growth of tumors in some patients with advanced colorectal cancer.
- It is not known if Oxaliplatin works in children.
- Who should not use Oxaliplatin?
- Do not use Oxaliplatin if you are allergic to any of the ingredients in Oxaliplatin or other medicines that contain platinum. Cisplatin and carboplatin are other chemotherapy medicines that also contain platinum. See the end of this leaflet for a complete list of the ingredients Oxaliplatin.
- Ask your doctor if you are not sure if you take a medicine that contains platinum.
- What should I tell my doctor before treatment with Oxaliplatin?
- Before receiving Oxaliplatin, tell your doctor if you:
- have kidney problems
- have any other medical conditions
- have had any allergic reactions to any medicines
- are pregnant or plan to become pregnant. Oxaliplatin may harm your unborn child. You should avoid becoming pregnant while taking Oxaliplatin. Talk with your doctor :- about how to avoid pregnancy.
- are breastfeeding or plan to breastfeed. It is not known if Oxaliplatin passes into your breast milk. You and your doctor should decide whether you will stop breastfeeding or not take Oxaliplatin.
- Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
- Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.
- How is Oxaliplatin given to me?
- Oxaliplatin is given to you through your veins (blood vessels).
- Oxaliplatin and Leucovorin are given through a thin plastic tube put into a vein (intravenous infusion or I.V.) and given for 2 hours. You will be watched by a healthcare provider during this time.
- Right after the Oxaliplatin and Leucovorin are finished, 2 doses of 5-fluorouracil will be given. The first dose is given right away into your I.V. tube. The second dose will be given into your I.V. tube over the next 22 hours, using a pump device.
- You will not get Oxaliplatin on Day 2. Leucovorin and 5-fluorouracil will be given the same way as on Day 1.
- During your treatment with Oxaliplatin:
- It is important for you to keep all appointments. Call your doctor if you must miss an appointment. There may be special instructions for you.
- Your doctor may change how often you get Oxaliplatin, how much you get, or how long the infusion will take.
- You and your doctor will discuss how many times you will get Oxaliplatin.
- The 5-fluorouracil will be given through your I.V. with a pump. If you have any problems with the pump or the tube, call your doctor, your nurse, or the person who is responsible for your pump. Do not let anyone other than a healthcare provider touch your infusion pump or tubing.
- What activities should I avoid while on treatment with Oxaliplatin?
- Avoid cold temperatures and cold objects. Cover your skin if you must go outside in cold temperatures.
- Do not drink cold drinks or use ice cubes in drinks.
- Do not put ice or ice packs on your body.
- See "How can I reduce the side effects caused by cold temperatures?" for more information.
- Talk with your doctor and nurse about your level of activity during treatment with Oxaliplatin.
Follow their instructions.
- What are the possible side effects of Oxaliplatin?
- Oxaliplatin can cause serious side effects, including:
- Serious allergic reactions. See "What is the most important information I should know about Oxaliplatin?"
- Nerve problems. Oxaliplatin can affect how your nerves work and make you feel. Tell your doctor right away if you get any signs of nerve problems listed below:
- very sensitive to cold temperatures and cold objects
- trouble breathing, swallowing, or saying words, jaw tightness, odd feelings in your tongue, or chest pressure
- pain, tingling, burning (pins and needles, numb feeling) in your hands, feet, or around your mouth or throat, which may cause problems walking or performing activities of daily living.
- Reversible Posterior Leukoencephalopathy (RPLS). RPLS is a rare condition that affects the brain. Tell your doctor right away if you have any of the following signs and symptoms of RPLS:
- headache
- confusion or a change in the way you think
- seizures
- vision problems, such as blurriness or vision loss. You should not drive, operate heavy machines, or engage in dangerous activities if you have vision problems while receiving Oxaliplatin.
- Lung problems (interstitial fibrosis). Tell your doctor right away if you get a dry cough and have trouble breathing (shortness of breath) before your next treatment. These may be signs of a serious lung disease.
- Liver problems (hepatotoxicity). Your doctor will do blood tests to check your liver.
- Harm to an unborn baby. Oxaliplatin may cause harm to your unborn baby. See "What should I tell my doctor before treatment with Oxaliplatin?"
- The most common side effects of Oxaliplatin include:
- Decreased blood counts: Oxaliplatin can cause a decrease in neutrophils (a type of white blood cells important in fighting bacterial infections), red blood cells (blood cells that carry oxygen to the tissues), and platelets (important for clotting and to control bleeding).
- High blood pressure (hypertension)
- Infection Call your doctor right away if you get any of the following signs of infection:
- Bleeding or bruising. Tell your doctor about any signs or symptoms of bleeding or bruising.
- Diarrhea
- Nausea
- Vomiting
- Constipation
- Mouth sores
- Stomach pain
- Decreased appetite
- Tiredness
- Injection site reactions. Reactions may include redness, swelling, pain, tissue damage at the site of injection.
- Hair loss (alopecia)
- Dehydration (too much water loss). Call you doctor if you have signs of dehydration including:
- Tell your doctor if you have any side effect that bothers your or that does not go away. These are not all the possible side effects of Oxaliplatin. For more information, ask your doctor or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- How can I reduce the side effects caused by cold temperatures?
- Cover yourself with a blanket while you are getting your Oxaliplatin infusion.
- Do not breathe deeply when exposed to cold air.
- Wear warm clothing in cold weather at all times. Cover your mouth and nose with a scarf or a pull-down cap (ski cap) to warm the air that goes to your lungs.
- Wear gloves when taking things from the freezer or refrigerator.
- Drink fluids warm or at room temperature.
- Always drink through a straw.
- Do not use ice chips if you have nausea or mouth sores. Ask your healthcare provider or doctor about what you can use.
- Be aware that most metals are cold to touch, especially in the winter. These include your car door and mailbox. Wear gloves to touch cold objects.
- Do not run the air-conditioning at high levels in the house or in the car in hot weather.
- If your body gets cold, warm-up the affected part. If your hands get cold, wash them with warm water.
- Always let your healthcare provider or doctor know before your next treatment how well you did since your last visit.
- This list is not complete and your healthcare provider or doctor may have other useful tips for helping you with these side effects.
- General information about the safe and effective use of Oxaliplatin
- Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet.
- This Patient Information leaflet summarizes the most important information about Oxaliplatin. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Oxaliplatin that is written for health professionals.
- What are the ingredients in Oxaliplatin?
- Active ingredient: oxaliplatin
- Concentrate for solution for infusion inactive ingredients: water for injection
# Precautions with Alcohol
- Alcohol-Oxaliplatin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Oxaliplatin®
# Look-Alike Drug Names
There is limited information regarding Oxaliplatin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Oxaliplatin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Black Box Warning
# Overview
Oxaliplatin is an Antineoplastic agent and platinum coordination complex that is FDA approved for the treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor, advanced colorectal cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Oxaliplatin, used in combination with infusional 5-fluorouracil/Leucovorin, is indicated for:
- adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.
- treatment of Colorectal canceradvanced colorectal cancer.
### Dosage
- Administer Oxaliplatin in combination with 5-fluorouracil/Leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):
- Day 1: Oxaliplatin 85 mg/m2 intravenous infusion in 250–500 mL 5% Dextrose injection, USP and Leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.
- Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.
- The administration of Oxaliplatin does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.
- For information on 5-fluorouracil and Leucovorin, see the respective package inserts.
- Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory test. Prolongation of infusion time for Oxaliplatin from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and Leucovorin do not need to be changed.
- Neuropathy and other toxicities were graded using the NCI CTC scale version 1.
- For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/Leucovorin regimen need not be altered.
- A dose reduction of Oxaliplatin to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 × 109/L and platelets ≥75 × 109/L.
- Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer
- Neuropathy was graded using a study-specific neurotoxicity scale. Other toxicities were graded by the NCI CTC, Version 2.0.
- For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/Leucovorin regimen need not be altered.
- A dose reduction of Oxaliplatin to 65 mg/m2 and 5-fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 × 109/L and platelets ≥75 × 109/L.
- Dose Modifications in Therapy for Patients with Renal Impairment
- In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin is 85 mg/m2. In patients with severe renal impairment, the initial recommended Oxaliplatin dose should be reduced to 65 mg/m2.
- Do not freeze and protect from light the concentrated solution.
A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.
- The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.
- After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)].
- After final dilution, protection from light is not required.
- Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.
- Needles or intravenous administration sets containing aluminum parts that may come in contact with Oxaliplatin should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.
### DOSAGE FORMS AND STRENGTHS
- Oxaliplatin is supplied in single-use vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxaliplatin in adult patients.
### Non–Guideline-Supported Use
- Breast Cancer[1]
- Carcinoma of stomach, Advanced/metastatic[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Oxaliplatin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxaliplatin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxaliplatin in pediatric patients.
# Contraindications
- Oxaliplatin should not be administered to patients with a history of known allergy to Oxaliplatin or other platinum compounds
# Warnings
- Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to Oxaliplatin has been observed in 2–3% of colon cancer patients. These allergic reactions which can be fatal, can occur within minutes of administration and at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy. Rechallenge is contraindicated in these patients. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.
- Neuropathy
- Oxaliplatin is associated with two types of neuropathy:
- An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing.The symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed. The acute, reversible pattern of sensory neuropathy was observed in about 56% of study patients who received Oxaliplatin with 5-fluorouracil/Leucovorin. In any individual cycle acute neurotoxicity was observed in approximately 30% of patients. In adjuvant patients the median cycle of onset for grade 3 peripheral sensory neuropathy was 9 in the previously treated patients the median number of cycles administered on the Oxaliplatin with 5-fluorouracil/Leucovorin combination arm was 6.
- An acute syndrome of pharyngolaryngeal dysesthesia seen in 1–2% (grade 3/4) of patients previously untreated for advanced colorectal cancer, and the previously treated patients, is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of Oxaliplatin because cold temperature can exacerbate acute neurological symptoms.
- A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception). These forms of neuropathy occurred in 48% of the study patients receiving Oxaliplatin with 5-fluorouracil/Leucovorin. Persistent neuropathy can occur without any prior acute neuropathy event. The majority of the patients (80%) who developed grade 3 persistent neuropathy progressed from prior Grade 1 or 2 events. These symptoms may improve in some patients upon discontinuation of Oxaliplatin.
- In the adjuvant colon cancer trial, neuropathy was graded using a prelisted module derived from the Neuro-Sensory section of the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale, Version 1, as follows:
- Peripheral sensory neuropathy was reported in adjuvant patients treated with the Oxaliplatin combination with a frequency of 92% (all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral sensory neuropathy decreasing to 39% at 6 months follow-up (Grade 1=31%, Grade 2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 2=3%, Grade 3=1%).
- In the advanced colorectal cancer studies, neuropathy was graded using a study-specific neurotoxicity scale, which was different from the NCI CTC scale, Version 2.0
- Overall, neuropathy was reported in patients previously untreated for advanced colorectal cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (grade 3/4) events. Information regarding reversibility of neuropathy was not available from the trial for patients who had not been previously treated for colorectal cancer.
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging.
- Oxaliplatin has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any grade) and <1% (grade 3) with no grade 4 events in the Oxaliplatin plus infusional 5-fluorouracil/Leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5-fluorouracil/Leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the Oxaliplatin combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the Oxaliplatin plus 5-fluorouracil/Leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-fluorouracil/Leucovorin arm of unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, Oxaliplatin should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
- Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the Oxaliplatin combination arm than in the control arm. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases
- Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT,AST, bilirubin and creatinine) is recommended before each Oxaliplatin cycle.
- There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin plus 5-fluorouracil/Leucovorin while on anticoagulants. Patients receiving Oxaliplatin plus 5-fluorouracil/Leucovorin and requiring oral anticoagulants may require closer monitoring.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- More than 1100 patients with stage II or III colon cancer and more than 4,000 patients with advanced colorectal cancer have been treated in clinical studies with Oxaliplatin. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. The most common adverse reactions in previously untreated and treated patients were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea.
- One thousand one hundred and eight patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, have been treated in a clinical study with Oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin. The incidence of grade 3 or 4 adverse reactions was 70% on the Oxaliplatin combination arm, and 31% on the infusional 5-fluorouracil/Leucovorin arm. The adverse reactions in this trial are shown in the tables below. Discontinuation of treatment due to adverse reactions occurred in 15% of the patients receiving Oxaliplatin and infusional 5-fluorouracil/Leucovorin. Both 5-fluorouracil/Leucovorin and Oxaliplatin are associated with gastrointestinal or hematologic adverse reactions. When Oxaliplatin is administered in combination with infusional 5-fluorouracil/Leucovorin, the incidence of these events is increased.
- The incidence of death within 28 days of last treatment, regardless of causality, was 0.5% (n=6) in both the Oxaliplatin combination and infusional 5-fluorouracil/Leucovorin arms, respectively. Deaths within 60 days from initiation of therapy were 0.3% (n=3) in both the Oxaliplatin combination and infusional 5-fluorouracil/Leucovorin arms, respectively. On the Oxaliplatin combination arm, 3 deaths were due to sepsis/neutropenic sepsis, 2 from intracerebral bleeding and one from eosinophilic pneumonia. On the 5-fluorouracil/Leucovorin arm, one death was due to suicide, 2 from Steven-Johnson Syndrome (1 patient also had sepsis), 1 unknown cause, 1 anoxic cerebral infarction and 1 probable abdominal aorta rupture.
- The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial by body system and decreasing order of frequency in the Oxaliplatin and infusional 5-fluorouracil/Leucovorin arm for events with overall incidences ≥ 5% and for NCI grade 3/4 events with incidences ≥ 1%.
- The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial by body system and decreasing order of frequency in the Oxaliplatin and infusional 5-fluorouracil/Leucovorin arm for events with overall incidences ≥ 5% but with incidences <1% NCI grade 3/4 events.
- Although specific events can vary, the overall frequency of adverse reactions was similar in men and women and in patients <65 and ≥65 years. However, the following grade 3/4 events were more common in females: diarrhea, fatigue, granulocytopenia, nausea and vomiting. In patients ≥65 years old, the incidence of grade 3/4 diarrhea and granulocytopenia was higher than in younger patients. Insufficient subgroup sizes prevented analysis of safety by race. The following additional adverse reactions, were reported in ≥2% and <5% of the patients in the Oxaliplatin and infusional 5-fluorouracil/Leucovorin combination arm (listed in decreasing order of frequency): pain, leukopenia, weight decrease, coughing.
- The number of patients who developed secondary malignancies was similar; 62 in the Oxaliplatin combination arm and 68 in the infusional 5-fluorouracil/Leucovorin arm. An exploratory analysis showed that the number of deaths due to secondary malignancies was 1.96% in the Oxaliplatin combination arm and 0.98% in infusional 5-fluorouracil/Leucovorin arm. In addition, the number of cardiovascular deaths was 1.4% in the Oxaliplatin combination arm as compared to 0.7% in the infusional 5-fluorouracil/Leucovorin arm. Clinical significance of these findings is unknown.
- Two hundred and fifty-nine patients were treated in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm of the randomized trial in patients previously untreated for advanced colorectal cancer. The adverse reaction profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below.
- Both 5-fluorouracil and Oxaliplatin are associated with gastrointestinal and hematologic adverse reactions. When Oxaliplatin is administered in combination with 5-fluorouracil, the incidence of these events is increased.
- The incidence of death within 30 days of treatment in the previously untreated for advanced colorectal cancer study, regardless of causality, was 3% with the Oxaliplatin and 5-fluorouracil/Leucovorin combination, 5% with irinotecan plus 5-fluorouracil/Leucovorin, and 3% with Oxaliplatin plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the Oxaliplatin and 5-fluorouracil/Leucovorin combination, 5.1% with irinotecan plus 5-fluorouracil/Leucovorin, and 3.1% with Oxaliplatin plus irinotecan.
- The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study by body system and decreasing order of frequency in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm for events with overall incidences ≥5% and for grade 3/4 events with incidences ≥1%.
- The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study by body system and decreasing order of frequency in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm for events with overall incidences ≥5% but with incidences <1% NCI Grade 3/4 events.
- Adverse reactions were similar in men and women and in patients <65 and ≥65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope. The following additional adverse reactions, at least possibly related to treatment and potentially important, were reported in ≥2% and <5% of the patients in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm (listed in decreasing order of frequency): metabolic, pneumonitis, catheter infection, vertigo, prothrombin time, pulmonary, rectal bleeding, dysuria, nail changes, chest pain, rectal pain, syncope, hypertension, hypoxia, unknown infection, bone pain, pigmentation changes, and urticaria.
- Four hundred and fifty patients (about 150 receiving the combination of Oxaliplatin and 5-fluorouracil/Leucovorin) were studied in a randomized trial in patients with refractory and relapsed colorectal cancer. The adverse reaction profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below.
- Thirteen percent of patients in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm and 18% in the 5-fluorouracil/Leucovorin arm of the previously treated study had to discontinue treatment because of adverse effects related to gastrointestinal, or hematologic adverse reactions, or neuropathies. Both 5-fluorouracil and Oxaliplatin are associated with gastrointestinal and hematologic adverse reactions. When Oxaliplatin is administered in combination with 5-fluorouracil, the incidence of these events is increased.
- The incidence of death within 30 days of treatment in the previously treated study, regardless of causality, was 5% with the Oxaliplatin and 5-fluorouracil/Leucovorin combination, 8% with Oxaliplatin alone, and 7% with 5-fluorouracil/Leucovorin. Of the 7 deaths that occurred on the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm within 30 days of stopping treatment, 3 may have been treatment related, associated with gastrointestinal bleeding or dehydration.
- The following table provides adverse reactions reported in the previously treated study by body system and in decreasing order of frequency in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm for events with overall incidences ≥5% and for grade 3/4 events with incidences ≥1%. This table does not include hematologic and blood chemistry abnormalities; these are shown separately below.
- The following table provides adverse reactions reported in the previously treated study by body system and in decreasing order of frequency in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm for events with overall incidences ≥5% but with incidences <1% NCI Grade 3/4 events.
- Adverse reactions were similar in men and women and in patients <65 and ≥65 years, but older patients may have been more susceptible to dehydration, diarrhea, hypokalemia and fatigue. The following additional adverse reactions, at least possibly related to treatment and potentially important, were reported in ≥2% and <5% of the patients in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm (listed in decreasing order of frequency): anxiety, myalgia, erythematous rash, increased sweating, conjunctivitis, weight decrease, dry mouth, rectal hemorrhage, depression, ataxia, ascites, hemorrhoids, muscle weakness, nervousness, tachycardia, abnormal micturition frequency, dry skin, pruritus, hemoptysis, purpura, vaginal hemorrhage, melena, somnolence, pneumonia, proctitis, involuntary muscle contractions, intestinal obstruction, gingivitis, tenesmus, hot flashes, enlarged abdomen, urinary incontinence.
- The following tables list the hematologic changes occurring in ≥5% of patients, based on laboratory values and NCI grade, with the exception of those events occurring in adjuvant patients and anemia in the patients previously untreated for advanced colorectal cancer, respectively, which are based on AE reporting and NCI grade alone.
- Thrombocytopenia was frequently reported with the combination of Oxaliplatin and infusional 5-fluorouracil/Leucovorin. The incidence of all hemorrhagic events in the adjuvant and previously treated patients was higher on the Oxaliplatin combination arm compared to the infusional 5-fluorouracil/Leucovorin arm. These events included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant trial, two patients died from intracerebral hemorrhages.
- The incidence of Grade 3/4 thrombocytopenia was 2% in adjuvant patients with colon cancer. In patients treated for advanced colorectal cancer the incidence of Grade 3/4 thrombocytopenia was 3–5%, and the incidence of these events was greater for the combination of Oxaliplatin and 5-fluorouracil/Leucovorin over the irinotecan plus 5-fluorouracil/Leucovorin or 5-fluorouracil/Leucovorin control groups. Grade 3/4 gastrointestinal bleeding was reported in 0.2% of adjuvant patients receiving Oxaliplatin and 5-fluorouracil/Leucovorin. In the previously untreated patients, the incidence of epistaxis was 10% in the Oxaliplatin and 5-fluorouracil/Leucovorin arm, and 2% and 1%, respectively, in the irinotecan plus 5-fluorouracil/Leucovorin or irinotecan plus Oxaliplatin arms.
- Neutropenia was frequently observed with the combination of Oxaliplatin and 5-fluorouracil/Leucovorin, with Grade 3 and 4 events reported in 29% and 12% of adjuvant patients with colon cancer, respectively. In the adjuvant trial, 3 patients died from sepsis/neutropenic sepsis. Grade 3 and 4 events were reported in 35% and 18% of the patients previously untreated for advanced colorectal cancer, respectively. Grade 3 and 4 events were reported in 27% and 17% of previously treated patients, respectively. In adjuvant patients the incidence of either febrile neutropenia (0.7%) or documented infection with concomitant grade 3/4 neutropenia (1.1%) was 1.8% in the Oxaliplatin and 5-fluorouracil/Leucovorin arm. The incidence of febrile neutropenia in the patients previously untreated for advanced colorectal cancer was 15% (3% of cycles) in the irinotecan plus 5-fluorouracil/Leucovorin arm and 4% (less than 1% of cycles) in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm. Additionally, in this same population, infection with grade 3 or 4 neutropenia was 12% in the irinotecan plus 5-fluorouracil/Leucovorin, and 8% in the Oxaliplatin and 5-fluorouracil/Leucovorin combination. The incidence of febrile neutropenia in the previously treated patients was 1% in the 5-fluorouracil/Leucovorin arm and 6% (less than 1% of cycles) in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm.
- In patients receiving the combination of Oxaliplatin plus infusional 5-fluorouracil/Leucovorin for adjuvant treatment for colon cancer the incidence of Grade 3/4 nausea and vomiting was greater than those receiving infusional 5-fluorouracil/Leucovorin alone (see table). In patients previously untreated for advanced colorectal cancer receiving the combination of Oxaliplatin and 5-fluorouracil/Leucovorin, the incidence of Grade 3 and 4 vomiting and diarrhea was less compared to irinotecan plus 5-fluorouracil/Leucovorin controls (see table). In previously treated patients receiving the combination of Oxaliplatin and 5-fluorouracil/Leucovorin, the incidence of Grade 3 and 4 nausea, vomiting, diarrhea, and mucositis/stomatitis increased compared to 5-fluorouracil/Leucovorin controls (see table).
- The incidence of gastrointestinal adverse reactions in the previously untreated and previously treated patients appears to be similar across cycles. Premedication with antiemetics, including 5-HT3 blockers, is recommended. Diarrhea and mucositis may be exacerbated by the addition of Oxaliplatin to 5-fluorouracil/Leucovorin, and should be managed with appropriate supportive care. Since cold temperature can exacerbate acute neurological symptoms, ice (mucositis prophylaxis) should be avoided during the infusion of Oxaliplatin.
- Oxaliplatin did not increase the incidence of alopecia compared to 5-fluorouracil/Leucovorin alone. No complete alopecia was reported. The incidence of Grade 3/4 skin disorders was 2% in both the Oxaliplatin plus infusional 5-fluorouracil/Leucovorin and the infusional 5-fluorouracil/Leucovorin alone arms in the adjuvant colon cancer patients. The incidence of hand-foot syndrome in patients previously untreated for advanced colorectal cancer was 2% in the irinotecan plus 5-fluorouracil/Leucovorin arm and 7% in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm. The incidence of hand-foot syndrome in previously treated patients was 13% in the 5-fluorouracil/Leucovorin arm and 11% in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm.
- Extravasation, in some cases including necrosis, has been reported.
Injection site reaction, including redness, swelling, and pain, has been reported.
- There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin plus 5-fluorouracil/Leucovorin while on anticoagulants. Patients receiving Oxaliplatin plus 5-fluorouracil/Leucovorin and requiring oral anticoagulants may require closer monitoring.
- About 5–10% of patients in all groups had some degree of elevation of serum creatinine. The incidence of Grade 3/4 elevations in serum creatinine in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm was 1% in the previously treated patients. Serum creatinine measurements were not reported in the adjuvant trial.
- Hepatotoxicity (defined as elevation of liver enzymes) appears to be related to Oxaliplatin combination therapy. The following tables list the clinical chemistry changes associated with hepatic toxicity occurring in ≥5% of patients, based on adverse reactions reported and NCI CTC grade for adjuvant patients and patients previously untreated for advanced colorectal cancer, laboratory values and NCI CTC grade for previously treated patients.
- The incidence of thromboembolic events in adjuvant patients with colon cancer was 6% (1.8% grade 3/4) in the infusional 5-fluorouracil/Leucovorin arm and 6% (1.2% grade 3/4) in the Oxaliplatin and infusional 5-fluorouracil/Leucovorin combined arm, respectively. The incidence was 6 and 9% of the patients previously untreated for advanced colorectal cancer and previously treated patients in the Oxaliplatin and 5-fluorouracil/Leucovorin combination arm, respectively
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of Oxaliplatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- angioedema, anaphylactic shock
- loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsion, Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES).
- deafness
- laryngospasm
- severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis; ileus; intestinal obstruction, pancreatitis; veno-occlusive disease of liver also known as sinusoidal obstruction syndrome, and perisinusoidal fibrosis which rarely may progress.
- immuno-allergic thrombocytopenia
prolongation of prothrombin time and of INR in patients receiving anticoagulants
- hemolytic uremic syndrome, immuno-allergic hemolytic anemia
- Acute tubular necrosis, acute interstitial nephritis and acute renal failure.
- pulmonary fibrosis, and other interstitial lung diseases (sometimes fatal)
- decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following therapy discontinuation)
# Drug Interactions
- No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 Oxaliplatin and 5-fluorouracil/Leucovorin has been observed in patients treated every 2 weeks. Increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 Oxaliplatin dosed every 3 weeks. Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds; although, this has not been specifically studied
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on direct interaction with DNA, Oxaliplatin may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Oxaliplatin in pregnant women. Reproductive toxicity studies in rats demonstrated adverse effects on fertility and embryo-fetal development at maternal doses that were below the recommended human dose based on body surface area. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant and use effective contraception while receiving treatment with Oxaliplatin.
- Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days 1–5 (pre-implantation), 6–10, or 11–16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6–10 and 11–16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6–10. Administration of oxaliplatin to male and female rats prior to mating resulted in 97% post-implantation loss in animals that received approximately one-seventh the recommended human dose based on the body surface area.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxaliplatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Oxaliplatin during labor and delivery.
### Nursing Mothers
- It is not known whether Oxaliplatin or its derivatives are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Oxaliplatin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The effectiveness of oxaliplatin in children has not been established. Oxaliplatin has been tested in 2 Phase 1 and 2 Phase 2 trials in 235 patients ages 7 months to 22 years with solid tumors (see below) and no significant activity observed.
- In a Phase 1/2 study, oxaliplatin was administered as a 2-hour intravenous infusion on Days 1, 8 and 15 every 4 weeks (1 cycle), for a maximum of 6 cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty eight pediatric patients in the Phase 1 study received oxaliplatin at 6 dose levels starting at 40 mg/m2 with escalation to 110 mg/m2. The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m2 dose. Fifteen patients received oxaliplatin at a dose of 90 mg/m2 intravenous in the Phase 2 portion of the study. At this dose, paresthesia (60%, G3/4: 7%), fever (40%, G3/4: 7%) and thrombocytopenia (40%, G3/4: 27%) were the main adverse reactions. No responses were observed.
- In a second Phase 1 study, oxaliplatin was administered to 26 pediatric patients as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) at 5 dose levels starting at 100 mg/m2 with escalation to 160 mg/m2, for a maximum of 6 cycles. In a separate cohort, oxaliplatin 85 mg/m2 was administered on day 1 every 2 weeks, for a maximum of 9 doses. Patients had metastatic or unresectable solid tumors mainly neuroblastoma and ganglioneuroblastoma. No responses were observed. The DLT was sensory neuropathy at the 160 mg/m2 dose. Based on these studies, oxaliplatin 130 mg/m2 as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) was used in subsequent Phase II studies. A dose of 85 mg/m2 on day 1 every 2 weeks was also found to be tolerable.
- In one Phase 2 study, 43 pediatric patients with recurrent or refractory embryonal CNS tumors received oxaliplatin 130 mg/m2 every 3 weeks for a maximum of 12 months in absence of progressive disease or unacceptable toxicity. In patients < 10 kg the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were leukopenia (67%, G3/4: 12%), anemia (65%, G3/4: 5%), thrombocytopenia (65%, G3/4: 26%), vomiting (65%, G3/4: 7%), neutropenia (58%, G3/4: 16%) and sensory neuropathy (40%, G3/4: 5%). One partial response was observed.
- In a second Phase 2 study, 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, Ewing sarcoma or peripheral PNET, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, Brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors of interest received oxaliplatin 130 mg/m2 every 3 weeks for a maximum of 12 months or 17 cycles. In patients ≤ 12 months old the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were sensory neuropathy (52%, G3/4: 12%), thrombocytopenia (37%, G3/4: 17%), anemia (37%, G3/4: 9%), vomiting (26%, G3/4:4%), ALT increased (24%, G3/4: 6%), AST increased (24%, G3/4: 2%), and nausea (23%, G3/:4 3%). Two partial responses were observed.
- The pharmacokinetic parameters of ultrafiltrable platinum have been evaluated in 105 pediatric patients during the first cycle. The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h. The inter-patient variability of platinum clearance in pediatric cancer patients was 41%. Mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 ± 0.24 mcg/mL, AUC0–48 of 7.52 ± 5.07 mcg∙h/mL and AUCinf of 8.83 ± 1.57 mcg∙h/mL at 85 mg/m2 of oxaliplatin and Cmax of 1.10 ± 0.43 mcg/mL, AUC0–48 of 9.74 ± 2.52 mcg∙h/mL and AUCinf of 17.3 ± 5.34 mcg∙h/mL at 130 mg/m2 of oxaliplatin.
### Geriatic Use
- No significant effect of age on the clearance of ultrafilterable platinum has been observed.
- In the adjuvant therapy colon cancer randomized clinical trial, 723 patients treated with Oxaliplatin and infusional 5-fluorouracil/Leucovorin were <65 years and 400 patients were ≥65 years.
- A descriptive subgroup analysis demonstrated that the improvement in DFS for the Oxaliplatin combination arm compared to the infusional 5-fluorouracil/Leucovorin alone arm appeared to be maintained across genders. The effect of Oxaliplatin in patients ≥65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race.
- Patients ≥ 65 years of age receiving the Oxaliplatin combination therapy experienced more grade 3–4 granulocytopenia than patients < 65 years of age (45% versus 39%).
- In the previously untreated for advanced colorectal cancer randomized clinical trial of Oxaliplatin, 160 patients treated with Oxaliplatin and 5-fluorouracil/Leucovorin were < 65 years and 99 patients were ≥65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the ≥65 year old patients as in the overall study population. In the previously treated for advanced colorectal cancer randomized clinical trial of Oxaliplatin, 95 patients treated with Oxaliplatin and 5-fluorouracil/Leucovorin were <65 years and 55 patients were ≥65 years. The rates of overall adverse reactions, including grade 3 and 4 events, were similar across and within arms in the different age groups in all studies. The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope were higher in patients ≥65 years old. No adjustment to starting dose was required in patients ≥65 years old.
### Gender
There is no FDA guidance on the use of Oxaliplatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Oxaliplatin with respect to specific racial populations.
### Renal Impairment
- The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients. Caution and close monitoring should be exercised when Oxaliplatin is administered to patients with renal impairment. The starting Oxaliplatin dose does not need to be reduced in patients with mild (creatinine clearance=50-80 mL/min) or moderate (creatinine clearance=30-49 mL/min) renal impairment. However, the starting dose of Oxaliplatin should be reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min)
### Hepatic Impairment
There is no FDA guidance on the use of Oxaliplatin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oxaliplatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oxaliplatin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Monitor for development of rash, urticaria, erythema, pruritis, bronchospasm, and hypotension
- Hepatotoxicity: Monitor liver function tests.
- Caution and close monitoring should be exercised when Oxaliplatin is administered to patients with renal impairment.
# IV Compatibility
There is limited information regarding IV Compatibility of Oxaliplatin in the drug label.
# Overdosage
- There is no known antidote for Oxaliplatin overdose. In addition to thrombocytopenia, the anticipated complications of an Oxaliplatin overdose include hypersensitivity reaction, myelosuppression, nausea, vomiting, diarrhea and neurotoxicity.
- Several cases of overdoses have been reported with Oxaliplatin. Adverse reactions observed were Grade 4 thrombocytopenia (<25,000/mm3) without any bleeding, anemia, sensory neuropathy such as paresthesia, dysesthesia, laryngospasm and facial muscle spasms, gastrointestinal disorders such as nausea, vomiting, stomatitis, flatulence, abdomen enlarged and Grade 4 intestinal obstruction, Grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia and death.
- Patients suspected of receiving an overdose should be monitored, and supportive treatment should be administered. The maximum dose of oxaliplatin that has been administered in a single infusion is 825 mg.
# Pharmacology
There is limited information regarding Oxaliplatin Pharmacology in the drug label.
## Mechanism of Action
- Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.
- In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with , oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models [HT29 (colon), GR (mammary), and L1210 (leukemia)].
## Structure
- Oxaliplatin® (oxaliplatin injection) is an antineoplastic agent with the molecular formula C8H14N2O4Pt and the chemical name of cis-[(1 R,2 R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)- O,O'] platinum. Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane(DACH) and with an oxalate ligand as a leaving group.
- The molecular weight is 397.3. Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone.
- Oxaliplatin is supplied in vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. Water for Injection, USP is present as an inactive ingredient.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Oxaliplatin in the drug label.
## Pharmacokinetics
- The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t1/2α; 0.43 hours and t1/2β; 16.8 hours) and a long terminal elimination phase (t1/2γ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour intravenous infusion of Oxaliplatin at a dose of 85 mg/m2 expressed as ultrafilterable platinum were Cmax of 0.814 mcg/mL and volume of distribution of 440 L.
Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC0–48hr) assessed over 3 cycles was moderate to low (23% and 6%, respectively). A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.
- At the end of a 2-hour infusion of Oxaliplatin, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m2 every two weeks.
- Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro.
- Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species.
- The major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of Oxaliplatin, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at a rate (10 – 17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinum is significantly correlated with GFR.
- A study was conducted in 38 patients with advanced GI cancer and varying degrees of renal impairment. Patients in the normal (creatinine clearance (CrCL) > 80 mL/min, N=11), mild (CrCL=50-80 mL/min, N=13), and moderate (CrCL=30-49 mL/min, N=10) groups were treated with 85 mg/m2 Oxaliplatin and those in the severe (CrCL < 30 mL/min, N=4) group were treated with 65 mg/m2 Oxaliplatin. The mean AUC of unbound platinum was 40%, 95%, and 342% higher in the mild, moderate, and severe groups, respectively, than in the normal group. Mean Cmax of unbound platinum appeared to be similar among the normal, mild and moderate renal function groups, but was 38% higher in the severe group than in the normal group. Caution should be exercised in renally impaired patients. The starting dose of Oxaliplatin should be reduced in patients with severe renal impairment. The starting dose of Oxaliplatin should be reduced in patients with severe renal impairment.
- No pharmacokinetic interaction between 85 mg/m2 of Oxaliplatin and infusional 5-fluorouracil has been observed in patients treated every 2 weeks, but increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 of Oxaliplatin administered every 3 weeks. In vitro, platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitro, oxaliplatin is not metabolized by, nor does it inhibit, human cytochrome P450 isoenzymes. No P450-mediated drug-drug interactions are therefore anticipated in patients.
- Since platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds, although this has not been specifically studied.
## Nonclinical Toxicology
- Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).
- In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but caused developmental mortality (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).
- Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day × 5 days every 28 days for three cycles. A no effect level was not identified. This daily dose is approximately one-sixth of the recommended human dose on a body surface area basis.
# Clinical Studies
- An international, multicenter, randomized study compared the efficacy and evaluated the safety of Oxaliplatin in combination with an infusional schedule of 5-fluorouracil/Leucovorin to infusional 5-fluorouracil/Leucovorin alone, in patients with stage II (Dukes' B2) or III (Dukes' C) colon cancer who had undergone complete resection of the primary tumor. The primary objective of the study was to compare the 3-year disease-free survival (DFS) in patients receiving Oxaliplatin and infusional 5-fluorouracil/Leucovorin to those receiving 5-fluorouracil/Leucovorin alone. Patients were to be treated for a total of 6 months (i.e., 12 cycles). A total of 2246 patients were randomized; 1123 patients per study arm. Patients in the study had to be between 18 and 75 years of age, have histologically proven stage II (T3–T4 N0 M0; Dukes' B2) or III (any T N1–2 M0; Dukes' C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., ≥15 cm from the anal margin) and undergone (within 7 weeks prior to randomization) complete resection of the primary tumor without gross or microscopic evidence of residual disease. Patients had to have had no prior chemotherapy, immunotherapy or radiotherapy, and have an ECOG performance status of 0,1, or 2 (KPS ≥ 60%), absolute neutrophil count (ANC) > 1.5x109/L, platelets ≥100×109/L, serum creatinine ≤ 1.25 × ULN total bilirubin < 2 × ULN, AST/ALT < 2 × ULN and carcino-embyrogenic antigen (CEA) < 10 ng/mL. Patients with preexisting peripheral neuropathy (NCI grade ≥ 1) were ineligible for this trial.
- The following table shows the dosing regimens for the two arms of the study.
- The following tables show the baseline characteristics and dosing of the patient population entered into this study. The baseline characteristics were well balanced between arms.
- The following table and figures summarize the disease-free survival (DFS) results in the overall randomized population and in patients with stage II and III disease based on an ITT analysis. The median duration of follow-up was approximately 77 months.
- In the overall and stage III colon cancer populations DFS was statistically significantly improved in the Oxaliplatin combination arm compared to infusional 5-fluorouracil/Leucovorin alone. However, a statistically significant improvement in DFS was not noted in Stage II patients.
- Figure 2 shows the DFS Kaplan-Meier curves for the comparison of Oxaliplatin and infusional 5-fluorouracil/Leucovorin combination and infusional 5-fluorouracil/Leucovorin alone for the overall population (ITT analysis).
- Figure 3 shows the DFS Kaplan-Meier curves for the comparison of Oxaliplatin and infusional 5-fluorouracil/Leucovorin combination and infusional 5-fluorouracil/Leucovorin alone in Stage III patients.
- The following table summarizes the overall survival (OS) results in the overall randomized population and in patients with stage II and III disease, based on the ITT analysis.
- A North American, multicenter, open-label, randomized controlled study was sponsored by the National Cancer Institute (NCI) as an intergroup study led by the North Central Cancer Treatment Group (NCCTG). The study had 7 arms at different times during its conduct, four of which were closed due to either changes in the standard of care, toxicity, or simplification. During the study, the control arm was changed to irinotecan plus 5-fluorouracil/Leucovorin. The results reported below compared the efficacy and safety of two experimental regimens, Oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin and a combination of Oxaliplatin plus irinotecan, to an approved control regimen of irinotecan plus 5-fluorouracil/Leucovorin in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. After completion of enrollment, the dose of irinotecan plus 5-fluorouracil/Leucovorin was decreased due to toxicity. Patients had to be at least 18 years of age, have known locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy with curative intent, histologically proven colorectal adenocarcinoma, measurable or evaluable disease, with an ECOG performance status 0,1, or 2. Patients had to have granulocyte count ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, hemoglobin ≥9.0 gm/dL, creatinine ≤ 1.5 × ULN, total bilirubin ≤ 1.5 mg/dL, AST ≤ 5 × ULN, and alkaline phosphatase ≤ 5 × ULN. Patients may have received adjuvant therapy for resected Stage II or III disease without recurrence within 12 months. The patients were stratified for ECOG performance status (0, 1 vs. 2), prior adjuvant chemotherapy (yes vs. no), prior immunotherapy (yes vs. no), and age (<65 vs. ≥65 years). Although no post study treatment was specified in the protocol, 65 to 72% of patients received additional post study chemotherapy after study treatment discontinuation on all arms. Fifty-eight percent of patients on the Oxaliplatin plus 5-fluorouracil/Leucovorin arm received an irinotecan-containing regimen and 23% of patients on the irinotecan plus 5-fluorouracil/Leucovorin arm received oxaliplatin-containing regimens. Oxaliplatin was not commercially available during the trial.
- The following table presents the dosing regimens of the three arms of the study.
- The following table presents the demographics of the patient population entered into this study.
- The length of a treatment cycle was 2 weeks for the Oxaliplatin and 5-fluorouracil/Leucovorin regimen; 6 weeks for the irinotecan plus 5-fluorouracil/Leucovorin regimen; and 3 weeks for the Oxaliplatin plus irinotecan regimen. The median number of cycles administered per patient was 10 (23.9 weeks) for the Oxaliplatin and 5-fluorouracil/Leucovorin regimen, 4 (23.6 weeks) for the irinotecan plus 5-fluorouracil/Leucovorin regimen, and 7 (21.0 weeks) for the Oxaliplatin plus irinotecan regimen. Patients treated with the Oxaliplatin and 5-fluorouracil/Leucovorin combination had a significantly longer time to tumor progression based on investigator assessment, longer overall survival, and a significantly higher confirmed response rate based on investigator assessment compared to patients given irinotecan plus 5-fluorouracil/Leucovorin. The following table summarizes the efficacy results.
- A descriptive subgroup analysis demonstrated that the improvement in survival for Oxaliplatin plus 5-fluorouracil/Leucovorin compared to irinotecan plus 5-fluorouracil/Leucovorin appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved. An estimated survival advantage in Oxaliplatin plus 5-fluorouracil/Leucovorin versus irinotecan plus 5-fluorouracil/Leucovorin was seen in both genders; however it was greater among women than men. Insufficient subgroup sizes prevented analysis by race.
- A multicenter, open-label, randomized, three-arm controlled study was conducted in the US and Canada comparing the efficacy and safety of Oxaliplatin in combination with an infusional schedule of 5-fluorouracil/Leucovorin to the same dose and schedule of 5-fluorouracil/Leucovorin alone and to single agent oxaliplatin in patients with advanced colorectal cancer who had relapsed/progressed during or within 6 months of first-line therapy with bolus 5-fluorouracil/Leucovorin and irinotecan. The study was intended to be analyzed for response rate after 450 patients were enrolled. Survival will be subsequently assessed in all patients enrolled in the completed study. Accrual to this study is complete, with 821 patients enrolled. Patients in the study had to be at least 18 years of age, have unresectable, measurable, histologically proven colorectal adenocarcinoma, with a Karnofsky performance status >50%. Patients had to have SGOT(AST) and SGPT(ALT) ≤2× the institution's upper limit of normal (ULN), unless liver metastases were present and documented at baseline by CT or MRI scan, in which case ≤5× ULN was permitted. Patients had to have alkaline phosphatase ≤2× the institution's ULN, unless liver metastases were present and documented at baseline by CT or MRI scan, in which cases ≤5× ULN was permitted. Prior radiotherapy was permitted if it had been completed at least 3 weeks before randomization.
- The dosing regimens of the three arms of the study are presented in the table below.
- Patients entered into the study for evaluation of response must have had at least one unidimensional lesion measuring ≥20mm using conventional CT or MRI scans, or ≥10mm using a spiral CT scan. Tumor response and progression were assessed every 3 cycles (6 weeks) using the Response Evaluation Criteria in Solid Tumors (RECIST) until radiological documentation of progression or for 13 months following the first dose of study drug(s), whichever came first. Confirmed responses were based on two tumor assessments separated by at least 4 weeks.
The demographics of the patient population entered into this study are shown in the table below:
- The median number of cycles administered per patient was 6 for the Oxaliplatin and 5-fluorouracil/Leucovorin combination and 3 each for 5-fluorouracil/Leucovorin alone and Oxaliplatin alone.
- Patients treated with the combination of Oxaliplatin and 5-fluorouracil/Leucovorin had an increased response rate compared to patients given 5-fluorouracil/Leucovorin or oxaliplatin alone. The efficacy results are summarized in the tables below.
- At the time of the interim analysis 49% of the radiographic progression events had occurred. In this interim analysis an estimated 2-month increase in median time to radiographic progression was observed compared to 5-fluorouracil/Leucovorin alone.
- Of the 13 patients who had tumor response to the combination of Oxaliplatin and 5-fluorouracil/Leucovorin, 5 were female and 8 were male, and responders included patients <65 years old and ≥65 years old. The small number of non-Caucasian participants made efficacy analyses in these populations uninterpretable.
# How Supplied
- Oxaliplatin is supplied in clear, glass, single-use vials with gray elastomeric stoppers and aluminum flip-off seals containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. Water for Injection, USP is present as an inactive ingredient.
- NDC 0024-0590-10: 50 mg single-use vial with green flip-off seal individually packaged in a carton.
- NDC 0024-0591-20: 100 mg single-use vial with dark blue flip-off seal individually packaged in a carton.
## Storage
Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Do not freeze and protect from light (keep in original outer carton).
- As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from Oxaliplatin. The use of gloves is recommended. If a solution of Oxaliplatin contacts the skin, wash the skin immediately and thoroughly with soap and water. If Oxaliplatin contacts the mucous membranes, flush thoroughly with water.
- Procedures for the handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL - 50 mg Carton
NDC 0024-0590-10
50 mg
Oxaliplatin®
(OXALIplatin injection) 5 mg/mL
INJECTION
50 mg
FOR INTRAVENOUS USE ONLY
SINGLE USE VIAL ONLY
Sterile Aqueous Solution - Preservative Free
See package insert for further
required dilution.
DO NOT MIX OR ADD TO
SODIUM CHLORIDE/
CHLORIDE-CONTAINING
SOLUTIONS
Rx only
SANOFI
NDC 0024-0591-20
100 mg
Oxaliplatin®
(OXALIplatin injection) 5 mg/mL
INJECTION
100 mg
FOR INTRAVENOUS USE ONLY
SINGLE USE VIAL ONLY
Sterile Aqueous Solution - Preservative Free
See package insert for further
required dilution.
DO NOT MIX OR ADD TO
SODIUM CHLORIDE/
CHLORIDE-CONTAINING
SOLUTIONS
Rx only
SANOFI
### INGREDIENTS AND APPEARANCE
# Patient Counseling Information
- Advise patients
- To expect side effects of Oxaliplatin, particularly its neurologic effects, both the acute, reversible effects and the persistent neurosensory toxicity. Patients should be informed that the acute neurosensory toxicity may be precipitated or exacerbated by exposure to cold or cold objects.
- To avoid cold drinks, use of ice, and should cover exposed skin prior to exposure to cold temperature or cold objects.
Of the risk of low blood cell counts and to contact their physician immediately should fever, particularly if associated with persistent diarrhea, or evidence of infection develop.
- To contact their physician if persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties occur, or signs of allergic reaction appear.
- To exercise caution when driving and using machines. No studies on the effects of the ability to operate cars and machines have been performed; however, oxaliplatin treatment resulting in an increase risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to a minor or moderate influence on the ability to drive and use machines.
Of the potential effects of vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), which may affect patients' ability to drive and use machines.
### PATIENT PACKAGE INSERT
Patient Information
Oxaliplatin® (eh-LOX-ah-tin)
(OXALIplatin)
concentrate, for solution for intravenous use
- Read this Patient Information leaflet carefully before you start receiving Oxaliplatin. There may be new information. It will help you learn more about Oxaliplatin. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment. Ask your doctor about any questions you have.
- What is the most important information I should know about Oxaliplatin?
- Serious side effects can happen in people taking ELOXATION, including:
- Serious allergic reactions. Oxaliplatin can cause serious allergic reactions, including allergic reactions that may cause death. Oxaliplatin is a platinum base medicine. Serious allergic reactions including death can occur in people who take Oxaliplatin and who have had previous allergic reactions to platinum medicines. Serious allergic reactions can happen within a few minutes of your infusion or any time during your treatment with Oxaliplatin.
- Get emergency help right away if you:
- have trouble breathing.
- feel like your throat is closing up.
- Call your doctor right away if you have any of the following signs or symptoms of an allergic reaction:
- rash
- flushed face
- hives
- itching
- swelling of your lips or tongue
- sudden cough
- dizziness or feel faint
- sweating
- chest pain
- See "What are the possible side effects of Oxaliplatin?" for information about other serious side effects.
- What is Oxaliplatin?
- Oxaliplatin is an anti-cancer (chemotherapy) medicine that is used with other anti-cancer medicines called 5-fluorouracil and Leucovorin to treat people with:
- stage III colon cancer after surgery to remove the tumor
- advanced colon or rectal cancer (colo-rectal cancer).
- Oxaliplatin with infusional 5-fluorouracil and Leucovorin was shown to lower the chance of colon cancer returning when given to patients with stage III colon cancer after surgery to remove the tumor. Oxaliplatin also increases survival in patients with stage III colon cancer. Oxaliplatin with infusional 5-fluorouracil and Leucovorin was also shown to increase survival, shrink tumors and delay growth of tumors in some patients with advanced colorectal cancer.
- It is not known if Oxaliplatin works in children.
- Who should not use Oxaliplatin?
- Do not use Oxaliplatin if you are allergic to any of the ingredients in Oxaliplatin or other medicines that contain platinum. Cisplatin and carboplatin are other chemotherapy medicines that also contain platinum. See the end of this leaflet for a complete list of the ingredients Oxaliplatin.
- Ask your doctor if you are not sure if you take a medicine that contains platinum.
- What should I tell my doctor before treatment with Oxaliplatin?
- Before receiving Oxaliplatin, tell your doctor if you:
- have kidney problems
- have any other medical conditions
- have had any allergic reactions to any medicines
- are pregnant or plan to become pregnant. Oxaliplatin may harm your unborn child. You should avoid becoming pregnant while taking Oxaliplatin. Talk with your doctor :* about how to avoid pregnancy.
- are breastfeeding or plan to breastfeed. It is not known if Oxaliplatin passes into your breast milk. You and your doctor should decide whether you will stop breastfeeding or not take Oxaliplatin.
- Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
- Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.
- How is Oxaliplatin given to me?
- Oxaliplatin is given to you through your veins (blood vessels).
- Oxaliplatin and Leucovorin are given through a thin plastic tube put into a vein (intravenous infusion or I.V.) and given for 2 hours. You will be watched by a healthcare provider during this time.
- Right after the Oxaliplatin and Leucovorin are finished, 2 doses of 5-fluorouracil will be given. The first dose is given right away into your I.V. tube. The second dose will be given into your I.V. tube over the next 22 hours, using a pump device.
- You will not get Oxaliplatin on Day 2. Leucovorin and 5-fluorouracil will be given the same way as on Day 1.
- During your treatment with Oxaliplatin:
- It is important for you to keep all appointments. Call your doctor if you must miss an appointment. There may be special instructions for you.
- Your doctor may change how often you get Oxaliplatin, how much you get, or how long the infusion will take.
- You and your doctor will discuss how many times you will get Oxaliplatin.
- The 5-fluorouracil will be given through your I.V. with a pump. If you have any problems with the pump or the tube, call your doctor, your nurse, or the person who is responsible for your pump. Do not let anyone other than a healthcare provider touch your infusion pump or tubing.
- What activities should I avoid while on treatment with Oxaliplatin?
- Avoid cold temperatures and cold objects. Cover your skin if you must go outside in cold temperatures.
- Do not drink cold drinks or use ice cubes in drinks.
- Do not put ice or ice packs on your body.
- See "How can I reduce the side effects caused by cold temperatures?" for more information.
- Talk with your doctor and nurse about your level of activity during treatment with Oxaliplatin.
Follow their instructions.
- What are the possible side effects of Oxaliplatin?
- Oxaliplatin can cause serious side effects, including:
- Serious allergic reactions. See "What is the most important information I should know about Oxaliplatin?"
- Nerve problems. Oxaliplatin can affect how your nerves work and make you feel. Tell your doctor right away if you get any signs of nerve problems listed below:
- very sensitive to cold temperatures and cold objects
- trouble breathing, swallowing, or saying words, jaw tightness, odd feelings in your tongue, or chest pressure
- pain, tingling, burning (pins and needles, numb feeling) in your hands, feet, or around your mouth or throat, which may cause problems walking or performing activities of daily living.
- Reversible Posterior Leukoencephalopathy (RPLS). RPLS is a rare condition that affects the brain. Tell your doctor right away if you have any of the following signs and symptoms of RPLS:
- headache
- confusion or a change in the way you think
- seizures
- vision problems, such as blurriness or vision loss. You should not drive, operate heavy machines, or engage in dangerous activities if you have vision problems while receiving Oxaliplatin.
- Lung problems (interstitial fibrosis). Tell your doctor right away if you get a dry cough and have trouble breathing (shortness of breath) before your next treatment. These may be signs of a serious lung disease.
- Liver problems (hepatotoxicity). Your doctor will do blood tests to check your liver.
- Harm to an unborn baby. Oxaliplatin may cause harm to your unborn baby. See "What should I tell my doctor before treatment with Oxaliplatin?"
- The most common side effects of Oxaliplatin include:
- Decreased blood counts: Oxaliplatin can cause a decrease in neutrophils (a type of white blood cells important in fighting bacterial infections), red blood cells (blood cells that carry oxygen to the tissues), and platelets (important for clotting and to control bleeding).
- High blood pressure (hypertension)
- Infection Call your doctor right away if you get any of the following signs of infection:
- Bleeding or bruising. Tell your doctor about any signs or symptoms of bleeding or bruising.
- Diarrhea
- Nausea
- Vomiting
- Constipation
- Mouth sores
- Stomach pain
- Decreased appetite
- Tiredness
- Injection site reactions. Reactions may include redness, swelling, pain, tissue damage at the site of injection.
- Hair loss (alopecia)
- Dehydration (too much water loss). Call you doctor if you have signs of dehydration including:
- Tell your doctor if you have any side effect that bothers your or that does not go away. These are not all the possible side effects of Oxaliplatin. For more information, ask your doctor or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- How can I reduce the side effects caused by cold temperatures?
- Cover yourself with a blanket while you are getting your Oxaliplatin infusion.
- Do not breathe deeply when exposed to cold air.
- Wear warm clothing in cold weather at all times. Cover your mouth and nose with a scarf or a pull-down cap (ski cap) to warm the air that goes to your lungs.
- Wear gloves when taking things from the freezer or refrigerator.
- Drink fluids warm or at room temperature.
- Always drink through a straw.
- Do not use ice chips if you have nausea or mouth sores. Ask your healthcare provider or doctor about what you can use.
- Be aware that most metals are cold to touch, especially in the winter. These include your car door and mailbox. Wear gloves to touch cold objects.
- Do not run the air-conditioning at high levels in the house or in the car in hot weather.
- If your body gets cold, warm-up the affected part. If your hands get cold, wash them with warm water.
- Always let your healthcare provider or doctor know before your next treatment how well you did since your last visit.
- This list is not complete and your healthcare provider or doctor may have other useful tips for helping you with these side effects.
- General information about the safe and effective use of Oxaliplatin
- Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet.
- This Patient Information leaflet summarizes the most important information about Oxaliplatin. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Oxaliplatin that is written for health professionals.
- What are the ingredients in Oxaliplatin?
- Active ingredient: oxaliplatin
- Concentrate for solution for infusion inactive ingredients: water for injection
# Precautions with Alcohol
- Alcohol-Oxaliplatin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Oxaliplatin®[3]
# Look-Alike Drug Names
There is limited information regarding Oxaliplatin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Eloxatin | |
d96b49587317e1f212438ad067a4c381abd7ece1 | wikidoc | Eltrombopag | Eltrombopag
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# Black Box Warning
# Overview
Eltrombopag is a thrombopoietin receptor agonist that is FDA approved for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include thrombocytopenia, aplastic anemia, hyperbilirubinemia, fatigue, cough, epistaxis, fever, diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Eltrombopag olamine is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
- Eltrombopag olamine is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy.
- Eltrombopag olamine is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.
- Eltrombopag olamine should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.
- Eltrombopag olamine should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy.
- Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection.
- Use the lowest dose of Eltrombopag olamine to achieve and maintain a platelet count greater than or equal to 50 x 109/L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use Eltrombopag olamine to normalize platelet counts . In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting Eltrombopag olamine and decreased within 1 to 2 weeks after discontinuing Eltrombopag olamine .
- Initial Dose Regimen: Initiate Eltrombopag olamine at a dose of 50 mg once daily, except in patients who are of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean) or who have mild to severe hepatic impairment (Child-Pugh Class A, B, C).
- For ITP patients of East Asian ancestry, initiate Eltrombopag olamine at a reduced dose of 25 mg once daily .
- For ITP patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate Eltrombopag olamine at a reduced dose of 25 mg once daily
- For ITP patients of East Asian ancestry with hepatic impairment (Child-Pugh Class A, B, C), consider initiating Eltrombopag olamine at a reduced dose of 12.5 mg once daily
- Monitoring and Dose Adjustment: After initiating Eltrombopag olamine, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 109/L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with Eltrombopag olamine and modify the dosage regimen of Eltrombopag olamine based on platelet counts as outlined in Table 1. During therapy with Eltrombopag olamine, assess CBCs with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter.
- In ITP patients with hepatic impairment (Child-Pugh Class A, B, C), after initiating Eltrombopag olamine or after any subsequent dosing increase, wait 3 weeks before increasing the dose.
- Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with Eltrombopag olamine. Do not administer more than one dose of Eltrombopag olamine within any 24-hour period.
- Discontinuation: Discontinue Eltrombopag olamine if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with Eltrombopag olamine at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities also necessitate discontinuation of Eltrombopag olamine . Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of Eltrombopag olamine.
- Use the lowest dose of Eltrombopag olamine to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use Eltrombopag olamine to normalize platelet counts . In clinical trials, platelet counts generally began to rise within the first week of treatment with Eltrombopag olamine .
- Initial Dose Regimen: Initiate Eltrombopag olamine at a dose of 25 mg once daily.
- Monitoring and Dose Adjustment: Adjust the dose of Eltrombopag olamine in 25-mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy.
- During antiviral therapy, adjust the dose of Eltrombopag olamine to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with Eltrombopag olamine.
- For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information.
- Discontinuation: The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility. Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility.
- Eltrombopag olamine should be discontinued when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2, or important liver test abnormalities also necessitate discontinuation of Eltrombopag olamine.
- Use the lowest dose of Eltrombopag olamine to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting Eltrombopag olamine.
- Initial Dose Regimen: Initiate Eltrombopag olamine at a dose of 50 mg once daily.
- For severe aplastic anemia in patients of East Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate Eltrombopag olamine at a reduced dose of 25 mg once daily
- Monitoring and Dose Adjustment: Adjust the dose of Eltrombopag olamine in 50-mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 109/L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with Eltrombopag olamine and modify the dosage regimen of Eltrombopag olamine based on platelet counts as outlined in Table 3.
- For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of Eltrombopag olamine may be reduced by 50% . If counts remain stable after 8 weeks at the reduced dose, then discontinue Eltrombopag olamine and monitor blood counts. If platelet counts drop to less than 30 x 109/L, hemoglobin to less than 9 g/dL, or ANC to less than 0.5 x 109/L, Eltrombopag olamine may be reinitiated at the previous effective dose.
- Discontinuation: If no hematologic response has occurred after 16 weeks of therapy with Eltrombopag olamine, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of Eltrombopag olamine. Excessive platelet count responses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuation of Eltrombopag olamine .
- Take Eltrombopag olamine on an empty stomach (1 hour before or 2 hours after a meal)
- Allow at least a 4-hour interval between Eltrombopag olamine and other medications (e.g., antacids), calcium-rich foods (e.g., dairy products and calcium fortified juices), or supplements containing polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eltrombopag in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eltrombopag in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Eltrombopag in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eltrombopag in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eltrombopag in pediatric patients.
# Contraindications
- None.
# Warnings
- In patients with chronic hepatitis C, Eltrombopag olamine in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with Eltrombopag olamine plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with Eltrombopag olamine plus antivirals. Discontinue Eltrombopag olamine if antiviral therapy is discontinued.
- Eltrombopag olamine can cause liver enzyme elevations . Measure serum ALT, AST, and bilirubin prior to initiation of Eltrombopag olamine, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose. Eltrombopag olamine inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue Eltrombopag olamine if ALT levels increase to greater than or equal to 3X ULN in patients with normal liver function or greater than or equal to 3X baseline in patients with pre-treatment elevations in transaminases and are:
- progressively increasing, or
- persistent for greater than or equal to 4 weeks, or
- accompanied by increased direct bilirubin, or
- accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.
- If the potential benefit for reinitiating treatment with Eltrombopag olamine is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing Eltrombopag olamine and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if Eltrombopag olamine is reinitiated. If liver tests abnormalities persist, worsen or recur, then permanently discontinue Eltrombopag olamine.
- In 2 controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with Eltrombopag olamine experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with Eltrombopag olamine versus less than 1% for placebo).
- Thrombotic/thromboembolic complications may result from increases in platelet counts with Eltrombopag olamine. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts.
- Consider the potential for an increased risk of thromboembolism when administering Eltrombopag olamine to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use Eltrombopag olamine in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts .
- In a controlled trial in non-ITP thrombocytopenic patients with chronic liver disease undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of Eltrombopag olamine once daily. Seven thrombotic complications (six patients) were reported in the group that received Eltrombopag olamine and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received Eltrombopag olamine were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received Eltrombopag olamine experienced a thrombotic complication within 30 days of completing treatment with Eltrombopag olamine and at a platelet count above 200 x 109/L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of Eltrombopag olamine once daily for 2 weeks in preparation for invasive procedures.
- In the 3 controlled clinical trials in chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of Eltrombopag olamine daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 4% of patients who underwent ocular examination prior to therapy with Eltrombopag olamine. In the 2 controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% patients treated with Eltrombopag olamine and 5% patients treated with placebo.
- Cataracts were observed in toxicology studies of eltrombopag in rodents . Perform a baseline ocular examination prior to administration of Eltrombopag olamine and, during therapy with Eltrombopag olamine, regularly monitor patients for signs and symptoms of cataracts.
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions associated with Eltrombopag olamine are described in other sections.
- Hepatic Decompensation in Patients with Chronic Hepatitis C
- Hepatotoxicity
- Thrombotic/Thromboembolic Complications
- Cataracts
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Chronic Immune (Idiopathic) Thrombocytopenia: In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of Eltrombopag olamine. Other serious adverse reactions included thrombotic/thromboembolic complications .
- The data described below reflect exposure of Eltrombopag olamine to 446 patients with chronic ITP aged 18 to 85, of whom 65% were female across the ITP clinical development program including 3 placebo-controlled trials. Eltrombopag olamine was administered to 277 patients for at least 6 months and 202 patients for at least 1 year.
- Table 4 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving Eltrombopag olamine) from the 3 placebo-controlled trials, with a higher incidence in Eltrombopag olamine versus placebo.
- In the 3 controlled clinical chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with Eltrombopag olamine and in no patients who received placebo.
- Among 299 patients with chronic ITP who received Eltrombopag olamine in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 5 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving Eltrombopag olamine) from the extension trial.
- In the 3 controlled chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for Eltrombopag olamine and placebo, respectively. Four patients (1%) treated with Eltrombopag olamine and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seven of the patients treated with Eltrombopag olamine in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to Eltrombopag olamine in the extension trial. Six of these patients again experienced liver test abnormalities (predominantly Grade 1) resulting in discontinuation of Eltrombopag olamine in one patient. In the extension chronic ITP trial, one additional patient had Eltrombopag olamine discontinued due to liver test abnormalities (less than or equal to Grade 3).
- In a placebo-controlled trial of Eltrombopag olamine in non-ITP thrombocytopenic patients with chronic liver disease, six patients treated with Eltrombopag olamine and one patient in the placebo group developed portal vein thromboses.
- Chronic Hepatitis C-associated Thrombocytopenia: In the 2 placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received Eltrombopag olamine. Table 6 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving Eltrombopag olamine compared with placebo).
- Severe Aplastic Anemia: In the single-arm, open-label trial, 43 patients with severe aplastic anemia received Eltrombopag olamine. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Eltrombopag in the drug label.
- The following adverse reactions have been identified during post approval use of Eltrombopag olamine. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.
- Vascular Disorders: Thrombotic microangiopathy with acute renal failure.
# Drug Interactions
- n vitro, CYP1A2, CYP2C8, UDP-glucuronosyltransferase (UGT)1A1 and UGT1A3 are involved in the metabolism of eltrombopag. In vitro, eltrombopag inhibits the following metabolic or transporter systems: CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15, OATP1B1 and breast cancer resistance protein (BCRP) .
- Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. In a clinical trial, administration of Eltrombopag olamine with a polyvalent cation-containing antacid decreased plasma eltrombopag systemic exposure by approximately 70%.
- Eltrombopag olamine must not be taken within 4 hours of any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of Eltrombopag olamine due to chelation
- Coadministration of Eltrombopag olamine with the OATP1B1 and BCRP substrate, rosuvastatin, to healthy adult subjects increased plasma rosuvastatin AUC0-∞ by 55% and Cmax by 103%
- Use caution when concomitantly administering Eltrombopag olamine and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 , valsartan) or BCRP (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with Eltrombopag olamine, a dose reduction of rosuvastatin by 50% was recommended.
- HIV Protease Inhibitors: In a drug interaction trial, coadministration of Eltrombopag olamine with lopinavir/ritonavir (LPV/RTV) decreased plasma eltrombopag exposure by 17% adjustment is recommended when Eltrombopag olamine is coadministered with LPV/RTV. Drug interactions with other HIV protease inhibitors have not been evaluated.
- Hepatitis C Virus (HCV) Protease Inhibitors: Coadministration of Eltrombopag olamine with either boceprevir or telaprevir did not affect eltrombopag or protease inhibitor exposure significantly . No dose adjustments are recommended. Drug interactions with other HCV protease inhibitors have not been evaluated.
- Coadministration of peginterferon alfa 2a (PEGASYS®) or 2b (PEGINTRON®) did not affect eltrombopag exposure in 2 randomized, double-blind, placebo-controlled trials with adult patients with chronic hepatitis C
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of eltrombopag use in pregnancy. In animal reproduction and developmental toxicity studies, there was evidence of embryolethality and reduced fetal weights at maternally toxic doses. Eltrombopag olamine should be used in pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
- In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity.
- Eltrombopag was administered orally to pregnant rats at 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed.
- Pregnant rabbits were treated with oral eltrombopag doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed.
- In a pre- and post-natal developmental toxicity study in pregnant rats (F0), no adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and similar to the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eltrombopag in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eltrombopag during labor and delivery.
### Nursing Mothers
- It is not known whether eltrombopag is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Eltrombopag olamine, a decision should be made whether to discontinue nursing or to discontinue Eltrombopag olamine taking into account the importance of Eltrombopag olamine to the mother.
### Pediatric Use
- The safety and efficacy of Eltrombopag olamine in pediatric patients have not been established.
### Geriatic Use
- Of the 106 patients in 2 randomized clinical trials of Eltrombopag olamine 50 mg in chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. In the 2 randomized clinical trials of Eltrombopag olamine in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while fewer than 1% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients in the placebo-controlled trials, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Eltrombopag with respect to specific gender populations.
### Race
- Patients of East Asian ethnicity (i.e., Japanese, Chinese, Taiwanese, and Korean) exhibit higher eltrombopag exposures. A reduction in the initial dose of Eltrombopag olamine is recommended for ITP or severe aplastic anemia patients of East Asian ancestry and patients of East Asian ancestry with hepatic impairment (Child-Pugh Class A, B, C) . No dose reduction is needed in patients of East Asian ethnicity with chronic hepatitis C
### Renal Impairment
- No adjustment in the initial dose of Eltrombopag olamine is needed for patients with renal impairment . Closely monitor patients with impaired renal function when administering Eltrombopag olamine.
### Hepatic Impairment
- Hepatic impairment influences the exposure of Eltrombopag olamine .Reduce the initial dose of Eltrombopag olamine in patients with chronic ITP or severe aplastic anemia who also have hepatic impairment (Child-Pugh Class A, B, C) . No dosage adjustment is necessary for HCV patients with hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eltrombopag in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eltrombopag in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Eltrombopag in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Eltrombopag in the drug label.
# Overdosage
- In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications.
- In one report, a subject who ingested 5,000 mg of Eltrombopag olamine had a platelet count increase to a maximum of 929 x 109/L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months follow-up, all events had resolved without sequelae.
- In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with Eltrombopag olamine in accordance with dosing and administration recommendations
# Pharmacology
## Mechanism of Action
- Eltrombopag is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor and initiates signaling cascades that induce proliferation and differentiation from bone marrow progenitor cells.
## Structure
- Eltrombopag olamine (eltrombopag) tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag interacts with the transmembrane domain of the TPO receptor (also known as cMpl) leading to increased platelet production. Each tablet contains eltrombopag olamine in the amount equivalent to 12.5 mg, 25 mg, 50 mg, 75 mg, or 100 mg of eltrombopag free acid.
Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3'-{(2Z)-2-hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid - 2-aminoethanol (1:2). It has the molecular formula C25H22N4O4●2(C2H7NO). The molecular weight is 564.65 for eltrombopag olamine and 442.5 for eltrombopag free acid. Eltrombopag olamine has the following structural formula:
- Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water.
- The inactive ingredients of Eltrombopag olamine are: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: hypromellose (12.5-mg, 25-mg, 50-mg, and 75-mg tablets) or polyvinyl alcohol and talc (100-mg tablet), polyethylene glycol 400, titanium dioxide, polysorbate 80 (12.5-mg tablet), FD&C Yellow No. 6 aluminum lake (25-mg tablet), FD&C Blue No. 2 aluminum lake (50-mg tablet), Iron Oxide Red and Iron Oxide Black (75-mg tablet), or Iron Oxide Yellow and Iron Oxide Black (100-mg tablet).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Eltrombopag in the drug label.
## Pharmacokinetics
- Absorption: Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Based on urinary excretion and biotransformation products eliminated in feces, the oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%.
- An open-label, randomized, crossover trial was conducted to assess the effect of food on the bioavailability of eltrombopag. A standard high-fat breakfast significantly decreased plasma eltrombopag AUC0-∞ by approximately 59% and Cmax by 65% and delayed Tmax by 1 hour. The calcium content of this meal may have also contributed to this decrease in exposure.
- Distribution: The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1.
- Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitrostudies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.
- Elimination: The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in ITP patients.
- Drug Interactions: Polyvalent Cation-containing Antacids: In a clinical trial, coadministration of 75 mg of Eltrombopag olamine with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) to 26 healthy adult subjects decreased plasma eltrombopag AUC0-∞ and Cmax by approximately 70%. The contribution of sodium alginate to this interaction is not known.
- Cytochrome P450 Enzymes (CYPs): In a clinical trial, Eltrombopag olamine 75 mg once daily was administered for 7 days to 24 healthy male subjects did not show inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Probe substrates for CYP2C8 were not evaluated in this trial.
- Rosuvastatin: In a clinical trial, coadministration of 75 mg of Eltrombopag olamine once daily for 5 days with a single 10-mg dose of the OATP1B1 and BCRP substrate, rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin AUC0-∞ by 55% and Cmax by 103%.
- Protease Inhibitors: HIV Protease Inhibitors: In a clinical trial, coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg twice daily with a single dose of Eltrombopag olamine 100 mg to 40 healthy adult subjects decreased plasma eltrombopag AUC0-∞ by 17%.
- HCV Protease Inhibitors: In a clinical trial, coadministration of repeat-dose telaprevir 750 mg every 8 hours or boceprevir 800 mg every 8 hours with a single dose of Eltrombopag olamine 200 mg to healthy adult subjects did not alter plasma telaprevir, boceprevir, or eltrombopag AUC0-∞ or Cmax to a significant extent.
- Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin: The pharmacokinetics of eltrombopag in both the presence and absence of pegylated interferon alfa 2a and 2b therapy were evaluated using a population pharmacokinetic analysis in 635 patients with chronic hepatitis C. The population PK model estimates of clearance indicate no significant difference in eltrombopag clearance in the presence of pegylated interferon alfa plus ribavirin therapy.
- In vitro Studies: Eltrombopag is an inhibitor of CYP2C8 and CYP2C9 in vitro. Eltrombopag is an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 in vitro. Eltrombopag is an inhibitor of the organic anion transporting polypeptide OATP1B1 and BCRP in vitro.
- Specific Populations: Ethnicity: Based on two population PK analyses of eltrombopag concentrations in ITP and chronic hepatitis C patients, East Asian (i.e., Japanese, Chinese, Taiwanese, and Korean) subjects exhibited 50% to 55% higher eltrombopag plasma concentrations compared with non-East Asian subjects .
- An approximately 40% higher systemic eltrombopag exposure in healthy African-American subjects was noted in at least one clinical pharmacology trial. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established.
- Hepatic Impairment: In a pharmacokinetic trial, the disposition of a single 50-mg dose of Eltrombopag olamine in patients with mild, moderate, and severe hepatic impairment was compared with subjects with normal hepatic function. The degree of hepatic impairment was based on Child-Pugh score. Plasma eltrombopag AUC0-∞ was 41% higher in patients with mild hepatic impairment (Child-Pugh Class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC0-∞ was approximately 2-fold higher in patients with moderate (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C). The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein binding effects.
- Chronic Liver Disease: A population PK analysis in thrombocytopenic patients with chronic liver disease following repeat doses of eltrombopag demonstrated that mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC(0-τ) and patients with moderate hepatic impairment had approximately 141% to 240% higher plasma eltrombopag AUC(0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein binding effects.
- Chronic Hepatitis C: A population PK in 28 healthy adults and 635 patients with chronic hepatitis C demonstrated that patients with chronic hepatitis C treated with Eltrombopag olamine had higher plasma AUC(0-τ) values as compared with healthy subjects, and AUC(0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC(0-τ) compared with healthy subjects. This clinical trial did not evaluate protein binding effects.
- Renal Impairment: The disposition of a single 50-mg dose of Eltrombopag olamine in patients with mild (creatinine clearance of 50 to 80 mL/min), moderate (CrCl of 30 to 49 mL/min), and severe (CrCl less than 30 mL/min) renal impairment was compared with subjects with normal renal function. Average total plasma eltrombopag AUC0-∞ was 32% to 36% lower in subjects with mild to moderate renal impairment and 60% lower in subjects with severe renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed.
- There is no indication of a QT/QTc prolonging effect of Eltrombopag olamine at doses up to 150 mg daily for 5 days. The effects of Eltrombopag olamine at doses up to 150 mg daily for 5 days (supratherapeutic doses) on the QT/QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg, single oral dose) crossover trial in healthy adult subjects. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.
## Nonclinical Toxicology
- Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans.
- Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day).
- Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in 2 in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on Cmax in ITP patients at 75 mg/day and 7 times the human clinical exposure based on Cmax in chronic hepatitis C patients at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency).
- Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and similar to the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day).
- Eltrombopag is phototoxic in vitro. There was no evidence of in vivo cutaneous or ocular phototoxicity in rodents.
- Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 3 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing .
- Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.6 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent.
# Clinical Studies
- The efficacy and safety of Eltrombopag olamine in adult patients with chronic ITP were evaluated in 3 randomized, double-blind, placebo-controlled trials and in an open-label extension trial.
- Trials 1 and 2: In trials 1 and 2, patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 109/L were randomized to receive either Eltrombopag olamine or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, Eltrombopag olamine or placebo was discontinued if the platelet count exceeded 200 x 109/L. The primary efficacy endpoint was response rate, defined as a shift from a baseline platelet count of less than 30 x 109/L to greater than or equal to 50 x 109/L at any time during the treatment period.
- The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 109/L) were similar among all treatment groups.
- Trial 1 randomized 114 patients (2:1) to Eltrombopag olamine 50 mg or placebo. Trial 2 randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of Eltrombopag olamine, 30 mg, 50 mg, or 75 mg each administered daily.
- Table 8 shows for each trial the primary efficacy outcomes for the placebo groups and the patient groups who received the 50-mg daily regimen of Eltrombopag olamine.
- The platelet count response to Eltrombopag olamine was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of Eltrombopag olamine and the maximum response was observed after 2 weeks of therapy. In the placebo and 50-mg–dose groups of Eltrombopag olamine, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 109/L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50-mg dose of Eltrombopag olamine was 42 days in Trial 1 and 43 days in Trial 2.
- Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with Eltrombopag olamine. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with Eltrombopag olamine.
- Trial 3: In this trial, 197 patients were randomized (2:1) to receive either Eltrombopag olamine 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of Eltrombopag olamine could be adjusted based on individual platelet counts. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with Eltrombopag olamine for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated. The primary endpoint was the odds of achieving a platelet count greater than or equal to 50 x 109/L and less than or equal to 400 x 109/L for patients receiving Eltrombopag olamine relative to placebo and was based on patient response profiles throughout the 6-month treatment period.
- The median age of the patients treated with Eltrombopag olamine and placebo was 47 years and 52.5 years, respectively. Approximately half of the patients treated with Eltrombopag olamine and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to15 x 109/L (50% and 48%, respectively). A similar percentage of patients treated with Eltrombopag olamine and placebo (37% and 34%, respectively) had a prior splenectomy.
- In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 109/L and less than or equal to 400 x 109/L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with Eltrombopag olamine, compared with 10% of patients treated with placebo (splenectomized patients: Eltrombopag olamine 51%, placebo 8%; non-splenectomized patients: Eltrombopag olamine 66%, placebo 11%). The proportion of responders in the group of patients treated with Eltrombopag olamine was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with Eltrombopag olamine were significantly more likely to achieve a platelet count between 50 x 109/L and 400 x 109/L during the entire 6-month treatment period compared with those patients treated with placebo.
- Outcomes of treatment are presented in Table 9 for all patients enrolled in the trial.
- Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with Eltrombopag olamine and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial.
- Extension Trial: Patients who completed any prior clinical trial with Eltrombopag olamine were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. Eltrombopag olamine was administered to 299 patients; 249 completed 6 months, 210 patients completed 12 months, and 138 patients completed 24 months of therapy. The median baseline platelet count was 19 x 109/L prior to administration of Eltrombopag olamine.
- The efficacy and safety of Eltrombopag olamine for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in 2 randomized, double-blind, placebo-controlled trials. Trial 1 utilized peginterferon alfa-2a (PEGASYS®) plus ribavirin for antiviral treatment and Trial 2 utilized peginterferon alfa-2b (PEGINTRON®) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 109/L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6 with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh level A (score 5-6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 109/L) were similar in both treatment groups. The trials consisted of two phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label Eltrombopag olamine to increase the platelet count to a threshold of greater than or equal to 90 x 109/L for Trial 1 and greater than or equal to 100 x 109/L for Trial 2. Eltrombopag olamine was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25-mg increments over 2- to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label Eltrombopag olamine was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of Eltrombopag olamine at the end of the pre-treatment phase or to placebo. Eltrombopag olamine was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks.
- The primary efficacy endpoint for both trials was sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 109/L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy.
- In both trials, a significantly greater proportion of patients treated with Eltrombopag olamine achieved SVR (see Table 10). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 109/L versus greater than or equal to 50 x 109/L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for Eltrombopag olamine versus 8% (20/239) for placebo.
- The majority of patients treated with Eltrombopag olamine (76%) maintained a platelet count greater than or equal to 50 x 109/L compared with 19% for placebo. A greater proportion of patients on Eltrombopag olamine did not require any antiviral dose reduction as compared with placebo (45% versus 27%).
- Eltrombopag olamine was studied in a single-arm, single-center, open-label trial in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 109/L. Eltrombopag olamine was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2 week periods up to a maximum dose of 150 mg once daily. The primary endpoint was hematologic response assessed after 12 weeks of treatment with Eltrombopag olamine. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 109/L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of RBC transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 109/L. Eltrombopag olamine was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial.
- The treated population had median age of 45 years (range 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 109/L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 109/L and absolute reticulocyte count was 24.3 x109/L. Eighty-six percent of patients were RBC transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline.
- Table 11 presents the primary efficacy results.
- In the 17 responders, the platelet transfusion-free period ranged from 8 to 1,096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1,082 days with a median of 208 days.
- In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with Eltrombopag olamine and maintained the response(median follow up: 8.1 months, range: 7.2 to 10.6 months).
# How Supplied
- The 12.5-mg tablets are round, biconvex, white, film-coated tablets debossed with GS MZ1 and 12.5 on one side and are available in bottles of 30: NDC 0007-4643-13.
- The 25-mg tablets are round, biconvex, orange, film-coated tablets debossed with GS NX3 and 25 on one side and are available in bottles of 30: NDC 0007-4640-13.
- The 50-mg tablets are round, biconvex, blue, film-coated tablets debossed with GS UFU and 50 on one side and are available in bottles of 30: NDC 0007-4641-13.
- The 75-mg tablets are round, biconvex, pink, film-coated tablets debossed with GS FFS and 75 on one side and are available in bottles of 30: NDC 0007-4642-13.
- The 100-mg tablets are round, biconvex, green, film-coated tablets debossed with GS 1L5 and are available in bottles of 30: NDC 0007-4646-13. This product contains a desiccant.
- Store at room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) . Do not remove desiccant if present. Dispense in original bottle.
## Storage
There is limited information regarding Eltrombopag Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Prior to treatment, patients should fully understand and be informed of the following risks and considerations for Eltrombopag olamine:
- For patients with chronic ITP, therapy with Eltrombopag olamine is administered to achieve and maintain a platelet count greater than or equal to 50 x 10 9/L as necessary to reduce the risk for bleeding.
- For patients with chronic hepatitis C, therapy with Eltrombopag olamine is administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin.
- Therapy with Eltrombopag olamine may be associated with hepatobiliary laboratory abnormalities.
- Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving alfa interferon therapy.
- Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away.
- yellowing of the skin or the whites of the eyes (jaundice)
- unusual darkening of the urine
- unusual tiredness
- right upper stomach area pain
- confusion
- swelling of the stomach area (abdomen)
- Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing Eltrombopag olamine, particularly if Eltrombopag olamine is discontinued while the patient is on anticoagulants or antiplatelet agents.
- Advise patients that too much Eltrombopag olamine may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.
- Advise patients that during therapy with Eltrombopag olamine, they should continue to avoid situations or medications that may increase the risk for bleeding.
- Advise patients to have a baseline ocular examination prior to administration of Eltrombopag olamine and be monitored for signs and symptoms of cataracts during therapy.
- Advise patients to keep at least a 4-hour interval between Eltrombopag olamine and foods, mineral supplements, and antacids which contain polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc.
# Precautions with Alcohol
- Alcohol-Eltrombopag interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Eltrombopag olamine
# Look-Alike Drug Names
There is limited information regarding Eltrombopag Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Eltrombopag
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Black Box Warning
# Overview
Eltrombopag is a thrombopoietin receptor agonist that is FDA approved for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include thrombocytopenia, aplastic anemia, hyperbilirubinemia, fatigue, cough, epistaxis, fever, diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Eltrombopag olamine is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
- Eltrombopag olamine is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy.
- Eltrombopag olamine is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.
- Eltrombopag olamine should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.
- Eltrombopag olamine should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy.
- Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection.
- Use the lowest dose of Eltrombopag olamine to achieve and maintain a platelet count greater than or equal to 50 x 109/L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use Eltrombopag olamine to normalize platelet counts . In clinical trials, platelet counts generally increased within 1 to 2 weeks after starting Eltrombopag olamine and decreased within 1 to 2 weeks after discontinuing Eltrombopag olamine .
- Initial Dose Regimen: Initiate Eltrombopag olamine at a dose of 50 mg once daily, except in patients who are of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean) or who have mild to severe hepatic impairment (Child-Pugh Class A, B, C).
- For ITP patients of East Asian ancestry, initiate Eltrombopag olamine at a reduced dose of 25 mg once daily .
- For ITP patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate Eltrombopag olamine at a reduced dose of 25 mg once daily
- For ITP patients of East Asian ancestry with hepatic impairment (Child-Pugh Class A, B, C), consider initiating Eltrombopag olamine at a reduced dose of 12.5 mg once daily
- Monitoring and Dose Adjustment: After initiating Eltrombopag olamine, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 109/L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with Eltrombopag olamine and modify the dosage regimen of Eltrombopag olamine based on platelet counts as outlined in Table 1. During therapy with Eltrombopag olamine, assess CBCs with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter.
- In ITP patients with hepatic impairment (Child-Pugh Class A, B, C), after initiating Eltrombopag olamine or after any subsequent dosing increase, wait 3 weeks before increasing the dose.
- Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with Eltrombopag olamine. Do not administer more than one dose of Eltrombopag olamine within any 24-hour period.
- Discontinuation: Discontinue Eltrombopag olamine if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with Eltrombopag olamine at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities also necessitate discontinuation of Eltrombopag olamine . Obtain CBCs with differentials, including platelet counts, weekly for at least 4 weeks following discontinuation of Eltrombopag olamine.
- Use the lowest dose of Eltrombopag olamine to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use Eltrombopag olamine to normalize platelet counts . In clinical trials, platelet counts generally began to rise within the first week of treatment with Eltrombopag olamine .
- Initial Dose Regimen: Initiate Eltrombopag olamine at a dose of 25 mg once daily.
- Monitoring and Dose Adjustment: Adjust the dose of Eltrombopag olamine in 25-mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy.
- During antiviral therapy, adjust the dose of Eltrombopag olamine to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with Eltrombopag olamine.
- For specific dosage instructions for peginterferon or ribavirin, refer to their respective prescribing information.
- Discontinuation: The prescribing information for pegylated interferon and ribavirin include recommendations for antiviral treatment discontinuation for treatment futility. Refer to pegylated interferon and ribavirin prescribing information for discontinuation recommendations for antiviral treatment futility.
- Eltrombopag olamine should be discontinued when antiviral therapy is discontinued. Excessive platelet count responses, as outlined in Table 2, or important liver test abnormalities also necessitate discontinuation of Eltrombopag olamine.
- Use the lowest dose of Eltrombopag olamine to achieve and maintain a hematologic response. Dose adjustments are based upon the platelet count. Hematologic response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting Eltrombopag olamine.
- Initial Dose Regimen: Initiate Eltrombopag olamine at a dose of 50 mg once daily.
- For severe aplastic anemia in patients of East Asian ancestry or those with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate Eltrombopag olamine at a reduced dose of 25 mg once daily
- Monitoring and Dose Adjustment: Adjust the dose of Eltrombopag olamine in 50-mg increments every 2 weeks as necessary to achieve the target platelet count greater than or equal to 50 x 109/L as necessary. Do not exceed a dose of 150 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with Eltrombopag olamine and modify the dosage regimen of Eltrombopag olamine based on platelet counts as outlined in Table 3.
- For patients who achieve tri-lineage response, including transfusion independence, lasting at least 8 weeks: the dose of Eltrombopag olamine may be reduced by 50% . If counts remain stable after 8 weeks at the reduced dose, then discontinue Eltrombopag olamine and monitor blood counts. If platelet counts drop to less than 30 x 109/L, hemoglobin to less than 9 g/dL, or ANC to less than 0.5 x 109/L, Eltrombopag olamine may be reinitiated at the previous effective dose.
- Discontinuation: If no hematologic response has occurred after 16 weeks of therapy with Eltrombopag olamine, discontinue therapy. If new cytogenetic abnormalities are observed, consider discontinuation of Eltrombopag olamine. Excessive platelet count responses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuation of Eltrombopag olamine .
- Take Eltrombopag olamine on an empty stomach (1 hour before or 2 hours after a meal)
- Allow at least a 4-hour interval between Eltrombopag olamine and other medications (e.g., antacids), calcium-rich foods (e.g., dairy products and calcium fortified juices), or supplements containing polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eltrombopag in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eltrombopag in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Eltrombopag in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eltrombopag in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eltrombopag in pediatric patients.
# Contraindications
- None.
# Warnings
- In patients with chronic hepatitis C, Eltrombopag olamine in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with Eltrombopag olamine plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with Eltrombopag olamine plus antivirals. Discontinue Eltrombopag olamine if antiviral therapy is discontinued.
- Eltrombopag olamine can cause liver enzyme elevations . Measure serum ALT, AST, and bilirubin prior to initiation of Eltrombopag olamine, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose. Eltrombopag olamine inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue Eltrombopag olamine if ALT levels increase to greater than or equal to 3X ULN in patients with normal liver function or greater than or equal to 3X baseline in patients with pre-treatment elevations in transaminases and are:
- progressively increasing, or
- persistent for greater than or equal to 4 weeks, or
- accompanied by increased direct bilirubin, or
- accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.
- If the potential benefit for reinitiating treatment with Eltrombopag olamine is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing Eltrombopag olamine and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if Eltrombopag olamine is reinitiated. If liver tests abnormalities persist, worsen or recur, then permanently discontinue Eltrombopag olamine.
- In 2 controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with Eltrombopag olamine experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with Eltrombopag olamine versus less than 1% for placebo).
- Thrombotic/thromboembolic complications may result from increases in platelet counts with Eltrombopag olamine. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts.
- Consider the potential for an increased risk of thromboembolism when administering Eltrombopag olamine to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use Eltrombopag olamine in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts .
- In a controlled trial in non-ITP thrombocytopenic patients with chronic liver disease undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of Eltrombopag olamine once daily. Seven thrombotic complications (six patients) were reported in the group that received Eltrombopag olamine and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received Eltrombopag olamine were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received Eltrombopag olamine experienced a thrombotic complication within 30 days of completing treatment with Eltrombopag olamine and at a platelet count above 200 x 109/L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of Eltrombopag olamine once daily for 2 weeks in preparation for invasive procedures.
- In the 3 controlled clinical trials in chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of Eltrombopag olamine daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 4% of patients who underwent ocular examination prior to therapy with Eltrombopag olamine. In the 2 controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% patients treated with Eltrombopag olamine and 5% patients treated with placebo.
- Cataracts were observed in toxicology studies of eltrombopag in rodents . Perform a baseline ocular examination prior to administration of Eltrombopag olamine and, during therapy with Eltrombopag olamine, regularly monitor patients for signs and symptoms of cataracts.
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions associated with Eltrombopag olamine are described in other sections.
- Hepatic Decompensation in Patients with Chronic Hepatitis C
- Hepatotoxicity
- Thrombotic/Thromboembolic Complications
- Cataracts
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Chronic Immune (Idiopathic) Thrombocytopenia: In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of Eltrombopag olamine. Other serious adverse reactions included thrombotic/thromboembolic complications .
- The data described below reflect exposure of Eltrombopag olamine to 446 patients with chronic ITP aged 18 to 85, of whom 65% were female across the ITP clinical development program including 3 placebo-controlled trials. Eltrombopag olamine was administered to 277 patients for at least 6 months and 202 patients for at least 1 year.
- Table 4 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving Eltrombopag olamine) from the 3 placebo-controlled trials, with a higher incidence in Eltrombopag olamine versus placebo.
- In the 3 controlled clinical chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with Eltrombopag olamine and in no patients who received placebo.
- Among 299 patients with chronic ITP who received Eltrombopag olamine in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 5 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving Eltrombopag olamine) from the extension trial.
- In the 3 controlled chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for Eltrombopag olamine and placebo, respectively. Four patients (1%) treated with Eltrombopag olamine and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seven of the patients treated with Eltrombopag olamine in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to Eltrombopag olamine in the extension trial. Six of these patients again experienced liver test abnormalities (predominantly Grade 1) resulting in discontinuation of Eltrombopag olamine in one patient. In the extension chronic ITP trial, one additional patient had Eltrombopag olamine discontinued due to liver test abnormalities (less than or equal to Grade 3).
- In a placebo-controlled trial of Eltrombopag olamine in non-ITP thrombocytopenic patients with chronic liver disease, six patients treated with Eltrombopag olamine and one patient in the placebo group developed portal vein thromboses.
- Chronic Hepatitis C-associated Thrombocytopenia: In the 2 placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received Eltrombopag olamine. Table 6 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving Eltrombopag olamine compared with placebo).
- Severe Aplastic Anemia: In the single-arm, open-label trial, 43 patients with severe aplastic anemia received Eltrombopag olamine. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Eltrombopag in the drug label.
- The following adverse reactions have been identified during post approval use of Eltrombopag olamine. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.
- Vascular Disorders: Thrombotic microangiopathy with acute renal failure.
# Drug Interactions
- n vitro, CYP1A2, CYP2C8, UDP-glucuronosyltransferase (UGT)1A1 and UGT1A3 are involved in the metabolism of eltrombopag. In vitro, eltrombopag inhibits the following metabolic or transporter systems: CYP2C8, CYP2C9, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15, OATP1B1 and breast cancer resistance protein (BCRP) [see Clinical Pharmacology (12.3)].
- Eltrombopag chelates polyvalent cations (such as iron, calcium, aluminum, magnesium, selenium, and zinc) in foods, mineral supplements, and antacids. In a clinical trial, administration of Eltrombopag olamine with a polyvalent cation-containing antacid decreased plasma eltrombopag systemic exposure by approximately 70%.
- Eltrombopag olamine must not be taken within 4 hours of any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of Eltrombopag olamine due to chelation
- Coadministration of Eltrombopag olamine with the OATP1B1 and BCRP substrate, rosuvastatin, to healthy adult subjects increased plasma rosuvastatin AUC0-∞ by 55% and Cmax by 103%
- Use caution when concomitantly administering Eltrombopag olamine and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or BCRP (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan). Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 or BCRP and consider reduction of the dose of these drugs, if appropriate. In clinical trials with Eltrombopag olamine, a dose reduction of rosuvastatin by 50% was recommended.
- HIV Protease Inhibitors: In a drug interaction trial, coadministration of Eltrombopag olamine with lopinavir/ritonavir (LPV/RTV) decreased plasma eltrombopag exposure by 17% adjustment is recommended when Eltrombopag olamine is coadministered with LPV/RTV. Drug interactions with other HIV protease inhibitors have not been evaluated.
- Hepatitis C Virus (HCV) Protease Inhibitors: Coadministration of Eltrombopag olamine with either boceprevir or telaprevir did not affect eltrombopag or protease inhibitor exposure significantly . No dose adjustments are recommended. Drug interactions with other HCV protease inhibitors have not been evaluated.
- Coadministration of peginterferon alfa 2a (PEGASYS®) or 2b (PEGINTRON®) did not affect eltrombopag exposure in 2 randomized, double-blind, placebo-controlled trials with adult patients with chronic hepatitis C
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of eltrombopag use in pregnancy. In animal reproduction and developmental toxicity studies, there was evidence of embryolethality and reduced fetal weights at maternally toxic doses. Eltrombopag olamine should be used in pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
- In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). Increased pre- and post-implantation loss and reduced fetal weight were observed at the highest dose which also caused maternal toxicity.
- Eltrombopag was administered orally to pregnant rats at 10, 20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. However, no evidence of major structural malformations was observed.
- Pregnant rabbits were treated with oral eltrombopag doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, and 0.5 times, respectively, the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). No evidence of fetotoxicity, embryolethality, or teratogenicity was observed.
- In a pre- and post-natal developmental toxicity study in pregnant rats (F0), no adverse effects on maternal reproductive function or on the development of the offspring (F1) were observed at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and similar to the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma concentrations in pups increased with dose following administration of drug to the F0 dams.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eltrombopag in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eltrombopag during labor and delivery.
### Nursing Mothers
- It is not known whether eltrombopag is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Eltrombopag olamine, a decision should be made whether to discontinue nursing or to discontinue Eltrombopag olamine taking into account the importance of Eltrombopag olamine to the mother.
### Pediatric Use
- The safety and efficacy of Eltrombopag olamine in pediatric patients have not been established.
### Geriatic Use
- Of the 106 patients in 2 randomized clinical trials of Eltrombopag olamine 50 mg in chronic ITP, 22% were 65 years of age and over, while 9% were 75 years of age and over. In the 2 randomized clinical trials of Eltrombopag olamine in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while fewer than 1% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients in the placebo-controlled trials, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Eltrombopag with respect to specific gender populations.
### Race
- Patients of East Asian ethnicity (i.e., Japanese, Chinese, Taiwanese, and Korean) exhibit higher eltrombopag exposures. A reduction in the initial dose of Eltrombopag olamine is recommended for ITP or severe aplastic anemia patients of East Asian ancestry and patients of East Asian ancestry with hepatic impairment (Child-Pugh Class A, B, C) [see Dosage and Administration (2.1, 2.3)]. No dose reduction is needed in patients of East Asian ethnicity with chronic hepatitis C
### Renal Impairment
- No adjustment in the initial dose of Eltrombopag olamine is needed for patients with renal impairment . Closely monitor patients with impaired renal function when administering Eltrombopag olamine.
### Hepatic Impairment
- Hepatic impairment influences the exposure of Eltrombopag olamine .Reduce the initial dose of Eltrombopag olamine in patients with chronic ITP or severe aplastic anemia who also have hepatic impairment (Child-Pugh Class A, B, C) . No dosage adjustment is necessary for HCV patients with hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eltrombopag in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eltrombopag in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Eltrombopag in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Eltrombopag in the drug label.
# Overdosage
- In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications.
- In one report, a subject who ingested 5,000 mg of Eltrombopag olamine had a platelet count increase to a maximum of 929 x 109/L at 13 days following the ingestion. The patient also experienced rash, bradycardia, ALT/AST elevations, and fatigue. The patient was treated with gastric lavage, oral lactulose, intravenous fluids, omeprazole, atropine, furosemide, calcium, dexamethasone, and plasmapheresis; however, the abnormal platelet count and liver test abnormalities persisted for 3 weeks. After 2 months follow-up, all events had resolved without sequelae.
- In case of an overdose, consider oral administration of a metal cation-containing preparation, such as calcium, aluminum, or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with Eltrombopag olamine in accordance with dosing and administration recommendations
# Pharmacology
## Mechanism of Action
- Eltrombopag is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor and initiates signaling cascades that induce proliferation and differentiation from bone marrow progenitor cells.
## Structure
- Eltrombopag olamine (eltrombopag) tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag interacts with the transmembrane domain of the TPO receptor (also known as cMpl) leading to increased platelet production. Each tablet contains eltrombopag olamine in the amount equivalent to 12.5 mg, 25 mg, 50 mg, 75 mg, or 100 mg of eltrombopag free acid.
Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid - 2-aminoethanol (1:2). It has the molecular formula C25H22N4O4●2(C2H7NO). The molecular weight is 564.65 for eltrombopag olamine and 442.5 for eltrombopag free acid. Eltrombopag olamine has the following structural formula:
- Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water.
- The inactive ingredients of Eltrombopag olamine are: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: hypromellose (12.5-mg, 25-mg, 50-mg, and 75-mg tablets) or polyvinyl alcohol and talc (100-mg tablet), polyethylene glycol 400, titanium dioxide, polysorbate 80 (12.5-mg tablet), FD&C Yellow No. 6 aluminum lake (25-mg tablet), FD&C Blue No. 2 aluminum lake (50-mg tablet), Iron Oxide Red and Iron Oxide Black (75-mg tablet), or Iron Oxide Yellow and Iron Oxide Black (100-mg tablet).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Eltrombopag in the drug label.
## Pharmacokinetics
- Absorption: Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Based on urinary excretion and biotransformation products eliminated in feces, the oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%.
- An open-label, randomized, crossover trial was conducted to assess the effect of food on the bioavailability of eltrombopag. A standard high-fat breakfast significantly decreased plasma eltrombopag AUC0-∞ by approximately 59% and Cmax by 65% and delayed Tmax by 1 hour. The calcium content of this meal may have also contributed to this decrease in exposure.
- Distribution: The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1.
- Metabolism: Absorbed eltrombopag is extensively metabolized, predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitrostudies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.
- Elimination: The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in ITP patients.
- Drug Interactions: Polyvalent Cation-containing Antacids: In a clinical trial, coadministration of 75 mg of Eltrombopag olamine with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) to 26 healthy adult subjects decreased plasma eltrombopag AUC0-∞ and Cmax by approximately 70%. The contribution of sodium alginate to this interaction is not known.
- Cytochrome P450 Enzymes (CYPs): In a clinical trial, Eltrombopag olamine 75 mg once daily was administered for 7 days to 24 healthy male subjects did not show inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Probe substrates for CYP2C8 were not evaluated in this trial.
- Rosuvastatin: In a clinical trial, coadministration of 75 mg of Eltrombopag olamine once daily for 5 days with a single 10-mg dose of the OATP1B1 and BCRP substrate, rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin AUC0-∞ by 55% and Cmax by 103%.
- Protease Inhibitors: HIV Protease Inhibitors: In a clinical trial, coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg twice daily with a single dose of Eltrombopag olamine 100 mg to 40 healthy adult subjects decreased plasma eltrombopag AUC0-∞ by 17%.
- HCV Protease Inhibitors: In a clinical trial, coadministration of repeat-dose telaprevir 750 mg every 8 hours or boceprevir 800 mg every 8 hours with a single dose of Eltrombopag olamine 200 mg to healthy adult subjects did not alter plasma telaprevir, boceprevir, or eltrombopag AUC0-∞ or Cmax to a significant extent.
- Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin: The pharmacokinetics of eltrombopag in both the presence and absence of pegylated interferon alfa 2a and 2b therapy were evaluated using a population pharmacokinetic analysis in 635 patients with chronic hepatitis C. The population PK model estimates of clearance indicate no significant difference in eltrombopag clearance in the presence of pegylated interferon alfa plus ribavirin therapy.
- In vitro Studies: Eltrombopag is an inhibitor of CYP2C8 and CYP2C9 in vitro. Eltrombopag is an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 in vitro. Eltrombopag is an inhibitor of the organic anion transporting polypeptide OATP1B1 and BCRP in vitro.
- Specific Populations: Ethnicity: Based on two population PK analyses of eltrombopag concentrations in ITP and chronic hepatitis C patients, East Asian (i.e., Japanese, Chinese, Taiwanese, and Korean) subjects exhibited 50% to 55% higher eltrombopag plasma concentrations compared with non-East Asian subjects .
- An approximately 40% higher systemic eltrombopag exposure in healthy African-American subjects was noted in at least one clinical pharmacology trial. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established.
- Hepatic Impairment: In a pharmacokinetic trial, the disposition of a single 50-mg dose of Eltrombopag olamine in patients with mild, moderate, and severe hepatic impairment was compared with subjects with normal hepatic function. The degree of hepatic impairment was based on Child-Pugh score. Plasma eltrombopag AUC0-∞ was 41% higher in patients with mild hepatic impairment (Child-Pugh Class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC0-∞ was approximately 2-fold higher in patients with moderate (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C). The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein binding effects.
- Chronic Liver Disease: A population PK analysis in thrombocytopenic patients with chronic liver disease following repeat doses of eltrombopag demonstrated that mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC(0-τ) and patients with moderate hepatic impairment had approximately 141% to 240% higher plasma eltrombopag AUC(0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein binding effects.
- Chronic Hepatitis C: A population PK in 28 healthy adults and 635 patients with chronic hepatitis C demonstrated that patients with chronic hepatitis C treated with Eltrombopag olamine had higher plasma AUC(0-τ) values as compared with healthy subjects, and AUC(0-τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC(0-τ) compared with healthy subjects. This clinical trial did not evaluate protein binding effects.
- Renal Impairment: The disposition of a single 50-mg dose of Eltrombopag olamine in patients with mild (creatinine clearance [CrCl] of 50 to 80 mL/min), moderate (CrCl of 30 to 49 mL/min), and severe (CrCl less than 30 mL/min) renal impairment was compared with subjects with normal renal function. Average total plasma eltrombopag AUC0-∞ was 32% to 36% lower in subjects with mild to moderate renal impairment and 60% lower in subjects with severe renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed.
- There is no indication of a QT/QTc prolonging effect of Eltrombopag olamine at doses up to 150 mg daily for 5 days. The effects of Eltrombopag olamine at doses up to 150 mg daily for 5 days (supratherapeutic doses) on the QT/QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg, single oral dose) crossover trial in healthy adult subjects. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.
## Nonclinical Toxicology
- Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans.
- Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day).
- Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in 2 in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on Cmax in ITP patients at 75 mg/day and 7 times the human clinical exposure based on Cmax in chronic hepatitis C patients at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (less than 3-fold increase in mutation frequency).
- Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and similar to the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day).
- Eltrombopag is phototoxic in vitro. There was no evidence of in vivo cutaneous or ocular phototoxicity in rodents.
- Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 3 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing .
- Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.6 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent.
# Clinical Studies
- The efficacy and safety of Eltrombopag olamine in adult patients with chronic ITP were evaluated in 3 randomized, double-blind, placebo-controlled trials and in an open-label extension trial.
- Trials 1 and 2: In trials 1 and 2, patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 109/L were randomized to receive either Eltrombopag olamine or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, Eltrombopag olamine or placebo was discontinued if the platelet count exceeded 200 x 109/L. The primary efficacy endpoint was response rate, defined as a shift from a baseline platelet count of less than 30 x 109/L to greater than or equal to 50 x 109/L at any time during the treatment period.
- The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 109/L) were similar among all treatment groups.
- Trial 1 randomized 114 patients (2:1) to Eltrombopag olamine 50 mg or placebo. Trial 2 randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of Eltrombopag olamine, 30 mg, 50 mg, or 75 mg each administered daily.
- Table 8 shows for each trial the primary efficacy outcomes for the placebo groups and the patient groups who received the 50-mg daily regimen of Eltrombopag olamine.
- The platelet count response to Eltrombopag olamine was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of Eltrombopag olamine and the maximum response was observed after 2 weeks of therapy. In the placebo and 50-mg–dose groups of Eltrombopag olamine, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 109/L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50-mg dose of Eltrombopag olamine was 42 days in Trial 1 and 43 days in Trial 2.
- Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with Eltrombopag olamine. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with Eltrombopag olamine.
- Trial 3: In this trial, 197 patients were randomized (2:1) to receive either Eltrombopag olamine 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of Eltrombopag olamine could be adjusted based on individual platelet counts. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with Eltrombopag olamine for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated. The primary endpoint was the odds of achieving a platelet count greater than or equal to 50 x 109/L and less than or equal to 400 x 109/L for patients receiving Eltrombopag olamine relative to placebo and was based on patient response profiles throughout the 6-month treatment period.
- The median age of the patients treated with Eltrombopag olamine and placebo was 47 years and 52.5 years, respectively. Approximately half of the patients treated with Eltrombopag olamine and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to15 x 109/L (50% and 48%, respectively). A similar percentage of patients treated with Eltrombopag olamine and placebo (37% and 34%, respectively) had a prior splenectomy.
- In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 109/L and less than or equal to 400 x 109/L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with Eltrombopag olamine, compared with 10% of patients treated with placebo (splenectomized patients: Eltrombopag olamine 51%, placebo 8%; non-splenectomized patients: Eltrombopag olamine 66%, placebo 11%). The proportion of responders in the group of patients treated with Eltrombopag olamine was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with Eltrombopag olamine were significantly more likely to achieve a platelet count between 50 x 109/L and 400 x 109/L during the entire 6-month treatment period compared with those patients treated with placebo.
- Outcomes of treatment are presented in Table 9 for all patients enrolled in the trial.
- Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with Eltrombopag olamine and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial.
- Extension Trial: Patients who completed any prior clinical trial with Eltrombopag olamine were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. Eltrombopag olamine was administered to 299 patients; 249 completed 6 months, 210 patients completed 12 months, and 138 patients completed 24 months of therapy. The median baseline platelet count was 19 x 109/L prior to administration of Eltrombopag olamine.
- The efficacy and safety of Eltrombopag olamine for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in 2 randomized, double-blind, placebo-controlled trials. Trial 1 utilized peginterferon alfa-2a (PEGASYS®) plus ribavirin for antiviral treatment and Trial 2 utilized peginterferon alfa-2b (PEGINTRON®) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 109/L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6 with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh level A (score 5-6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 109/L) were similar in both treatment groups. The trials consisted of two phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label Eltrombopag olamine to increase the platelet count to a threshold of greater than or equal to 90 x 109/L for Trial 1 and greater than or equal to 100 x 109/L for Trial 2. Eltrombopag olamine was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25-mg increments over 2- to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label Eltrombopag olamine was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of Eltrombopag olamine at the end of the pre-treatment phase or to placebo. Eltrombopag olamine was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks.
- The primary efficacy endpoint for both trials was sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 109/L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy.
- In both trials, a significantly greater proportion of patients treated with Eltrombopag olamine achieved SVR (see Table 10). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 109/L versus greater than or equal to 50 x 109/L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for Eltrombopag olamine versus 8% (20/239) for placebo.
- The majority of patients treated with Eltrombopag olamine (76%) maintained a platelet count greater than or equal to 50 x 109/L compared with 19% for placebo. A greater proportion of patients on Eltrombopag olamine did not require any antiviral dose reduction as compared with placebo (45% versus 27%).
- Eltrombopag olamine was studied in a single-arm, single-center, open-label trial in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 109/L. Eltrombopag olamine was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2 week periods up to a maximum dose of 150 mg once daily. The primary endpoint was hematologic response assessed after 12 weeks of treatment with Eltrombopag olamine. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 109/L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of RBC transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 109/L. Eltrombopag olamine was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial.
- The treated population had median age of 45 years (range 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 109/L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 109/L and absolute reticulocyte count was 24.3 x109/L. Eighty-six percent of patients were RBC transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline.
- Table 11 presents the primary efficacy results.
- In the 17 responders, the platelet transfusion-free period ranged from 8 to 1,096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1,082 days with a median of 208 days.
- In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with Eltrombopag olamine and maintained the response(median follow up: 8.1 months, range: 7.2 to 10.6 months).
# How Supplied
- The 12.5-mg tablets are round, biconvex, white, film-coated tablets debossed with GS MZ1 and 12.5 on one side and are available in bottles of 30: NDC 0007-4643-13.
- The 25-mg tablets are round, biconvex, orange, film-coated tablets debossed with GS NX3 and 25 on one side and are available in bottles of 30: NDC 0007-4640-13.
- The 50-mg tablets are round, biconvex, blue, film-coated tablets debossed with GS UFU and 50 on one side and are available in bottles of 30: NDC 0007-4641-13.
- The 75-mg tablets are round, biconvex, pink, film-coated tablets debossed with GS FFS and 75 on one side and are available in bottles of 30: NDC 0007-4642-13.
- The 100-mg tablets are round, biconvex, green, film-coated tablets debossed with GS 1L5 and are available in bottles of 30: NDC 0007-4646-13. This product contains a desiccant.
- Store at room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not remove desiccant if present. Dispense in original bottle.
## Storage
There is limited information regarding Eltrombopag Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Prior to treatment, patients should fully understand and be informed of the following risks and considerations for Eltrombopag olamine:
- For patients with chronic ITP, therapy with Eltrombopag olamine is administered to achieve and maintain a platelet count greater than or equal to 50 x 10 9/L as necessary to reduce the risk for bleeding.
- For patients with chronic hepatitis C, therapy with Eltrombopag olamine is administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin.
- Therapy with Eltrombopag olamine may be associated with hepatobiliary laboratory abnormalities.
- Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving alfa interferon therapy.
- Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away.
- yellowing of the skin or the whites of the eyes (jaundice)
- unusual darkening of the urine
- unusual tiredness
- right upper stomach area pain
- confusion
- swelling of the stomach area (abdomen)
- Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing Eltrombopag olamine, particularly if Eltrombopag olamine is discontinued while the patient is on anticoagulants or antiplatelet agents.
- Advise patients that too much Eltrombopag olamine may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.
- Advise patients that during therapy with Eltrombopag olamine, they should continue to avoid situations or medications that may increase the risk for bleeding.
- Advise patients to have a baseline ocular examination prior to administration of Eltrombopag olamine and be monitored for signs and symptoms of cataracts during therapy.
- Advise patients to keep at least a 4-hour interval between Eltrombopag olamine and foods, mineral supplements, and antacids which contain polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc.
# Precautions with Alcohol
- Alcohol-Eltrombopag interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Eltrombopag olamine
# Look-Alike Drug Names
There is limited information regarding Eltrombopag Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Eltrombopag | |
04a67e622e8de76c655fca38ed5d33968773edf3 | wikidoc | Eluxadoline | Eluxadoline
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# Overview
Eluxadoline is a mu-opioid receptor agonist that is FDA approved for the treatment of adults with irritable bowel syndrome with diarrhea (IBS-D). Common adverse reactions include constipation, nausea and abdominal pain (>5%)..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Eluxadoline is indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).
The recommended dosage of Eluxadoline is 100 mg taken orally twice daily with food.
The recommended dosage of Eluxadoline is 75 mg taken orally twice daily with food in patients who:
- do not have a gallbladder.
- are unable to tolerate the 100 mg dose of Eluxadoline.
- are receiving concomitant OATP1B1 inhibitors.
- have mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
Discontinue Eluxadoline in patients who develop severe constipation for more than 4 days.
Instruct patients if they miss a dose, take the next dose at the regular time and not to take 2 doses at the same time to make up for a missed dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eluxadoline in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eluxadoline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eluxadoline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eluxadoline in pediatric patients.
# Contraindications
Eluxadoline is contraindicated in patients with:
- Known or suspected biliary duct obstruction; or sphincter of Oddi disease or dysfunction. These patients are at increased risk for sphincter of Oddi spasm.
- Alcoholism, alcohol abuse or alcohol addiction, or in patients who drink more than 3 alcoholic beverages per day. These patients are at increased risk for acute pancreatitis.
- A history of pancreatitis; or structural diseases of the pancreas, including known or suspected pancreatic duct obstruction. These patients are at increased risk for acute pancreatitis.
- Severe hepatic impairment (Child-Pugh Class C). These patients are at risk for significantly increased plasma concentrations of Eluxadoline.
- A history of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction. These patients may be at risk for severe complications of bowel obstruction.
# Warnings
- Sphincter of Oddi Spasm
Given the mu-opioid receptor agonism of Eluxadoline, there is a potential for increased risk of sphincter of Oddi spasm, resulting in pancreatitis or hepatic enzyme elevation associated with acute abdominal pain (e.g., biliary-type pain) with Eluxadoline.
In clinical trials, sphincter of Oddi spasm occurred in less than 1% of patients receiving Eluxadoline. The majority of these patients presented within the first week of treatment and the event resolved on discontinuation of Eluxadoline. Patients without a gallbladder are at increased risk.
Consider alternative therapies before using Eluxadoline in patients without a gallbladder and evaluate the benefits and risks of Eluxadoline in these patients in the context of their symptom severity. The recommended dosage of Eluxadoline is 75 mg twice daily in patients without a gallbladder. If Eluxadoline is used in such a patient, inform them that they may be at increased risk for adverse reactions and monitor them for symptoms of sphincter of Oddi spasm, such as elevated liver transaminases associated with abdominal pain or pancreatitis, especially during the first few weeks of treatment.
Instruct patients to stop Eluxadoline and seek medical attention if they experience symptoms suggestive of sphincter of Oddi spasm such as acute worsening of abdominal pain, (e.g. acute epigastric or biliary pain), that may radiate to the back or shoulder with or without nausea and vomiting, associated with elevations of pancreatic enzymes or liver transaminases. Do not restart Eluxadoline in patients who developed biliary duct obstruction or sphincter of Oddi spasm while taking Eluxadoline.
- Pancreatitis
There is a potential for increased risk of pancreatitis, not associated with sphincter of Oddi spasm, when taking Eluxadoline. Additional cases of pancreatitis, not associated with sphincter of Oddi spasm, were reported in less than 1% of patients receiving Eluxadoline in clinical trials. The majority were associated with excessive alcohol intake. All pancreatic events, whether or not associated with sphincter of Oddi spasm, resolved upon discontinuation of Eluxadoline; patients did not have organ failure or local or systemic complications.
Instruct patients to avoid chronic or acute excessive alcohol use while taking Eluxadoline. Monitor for new or worsening abdominal pain that may radiate to the back or shoulder, with or without nausea and vomiting. Instruct patients to stop Eluxadoline and seek medical attention if they experience symptoms suggestive of pancreatitis such as acute abdominal or epigastric pain radiating to the back associated with elevations of pancreatic enzymes.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Over 1700 patients with IBS-D have been treated with 75 or 100 mg of Eluxadoline twice daily in controlled trials. Exposures from placebo-controlled clinical trials in adult patients with IBS-D included 1391 exposed for 3 months, 1001 exposed for 6 months and 488 exposed for one year.
Demographic characteristics were comparable between the treatment groups. Data described below represent pooled data compared to placebo across the randomized trials.
Sphincter of Oddi Spasm
In clinical trials, sphincter of Oddi spasm occurred in 0.2% (2/807) of patients receiving 75 mg and 0.8% (8/1032) of patients receiving 100 mg Eluxadoline twice daily.
- Among patients receiving 75 mg, 1/807 (0.1%) patient experienced a sphincter of Oddi spasm presenting with abdominal pain but with lipase elevation less than 3 times the upper limit of normal (ULN) and 1/ 807 (0.1%) patient experienced a sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain.
- Among patients receiving 100 mg, 1/1032 (0.1%) patient experienced a sphincter of Oddi spasm manifested as pancreatitis and 7/1032 (0.7%) patients experienced sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain.
In patients without a gallbladder, 2/165 (1.2%) and 8/184 (4.3%) of patients receiving 75 mg and 100 mg, respectively, experienced a sphincter of Oddi spasm vs 0/1317 (0%) in patients with a gallbladder who had received either 75 mg or 100 mg treatment.
Of those patients who experienced a sphincter of Oddi spasm, 80% (8/10) reported their first onset of symptoms within the first week of treatment. The case of sphincter of Oddi spasm-induced pancreatitis occurred within minutes of taking the first dose of Eluxadoline. No cases of sphincter of Oddi spasm occurred greater than 1 month after treatment onset. All events resolved upon discontinuation of Eluxadoline, with symptoms typically improved by the following day.
Pancreatitis
Additional cases of pancreatitis, not associated with sphincter of Oddi spasm, were reported in 2/807 (0.2%) of patients receiving 75 mg and 3/1032 (0.3%) of patients receiving 100 mg Eluxadoline twice daily in clinical trials. Of these 5 cases, 3 were associated with excessive alcohol intake, one was associated with biliary sludge, and in one case the patient discontinued Eluxadoline 2 weeks prior to the onset of symptoms. All pancreatic events resolved with lipase normalization upon discontinuation of Eluxadoline, with 80% (4/5) resolving within 1 week of treatment discontinuation. The case of sphincter of Oddi spasm-induced pancreatitis resolved within 24 hours of discontinuation.
Common Adverse Reactions
TABLE 1 provides the incidence of common adverse reactions reported in > 2% of IBS-D patients in either Eluxadoline treatment group and at an incidence greater than in the placebo group.
- Table 1: Common- Adverse Reactions in the Placebo-Controlled Studies in IBS-D Patients
VIBERZI: Eluxadoline's Brand name
Constipation was the most commonly reported adverse reaction in Eluxadoline-treated patients in these trials. Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving 75 mg and 100 mg Eluxadoline. Similar rates of constipation occurred between the active and placebo arms beyond 3 months of treatment.
Adverse Reactions Leading to Discontinuation
Eight percent of patients treated with 75 mg, 8% of patients treated with 100 mg Eluxadoline and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the Eluxadoline treatment groups, the most common reasons for discontinuation due to adverse reactions were constipation (1% for 75 mg and 2% for 100 mg) and abdominal pain (1% for both 75 mg and 100 mg). In comparison, less than 1% of patients in the placebo group withdrew due to constipation or abdominal pain.
Less Common Adverse Reactions
Adverse reactions that were reported in ≤ 2% of Eluxadoline-treated patients are listed below by body system.
- Gastrointestinal: gastroesophageal reflux disease
- General Disorders and administration site conditions: feeling drunk
- Investigations: increased AST
- Nervous system: sedation, somnolence
- Psychiatric disorders: euphoric mood
- Respiratory: asthma, bronchospasm, respiratory failure, wheezing
## Postmarketing Experience
There is limited information regarding Eluxadoline Postmarketing Experience in the drug label.
# Drug Interactions
The metabolism of Eluxadoline by CYP pathways has not been clearly established. In addition, the potential of Eluxadoline to inhibit CYP3A4 in the gut has not been established.
TABLES 2 and 3 include drugs which demonstrated a clinically important drug interaction with Eluxadoline or which potentially may result in clinically relevant interactions.
- Table 2: Established and Other Potentially Clinically Relevant Interactions Affecting Eluxadoline
VIBERZI: Eluxadoline's Brand name
- Table 3: Established and Other Potentially Clinically Relevant Interactions Affecting Drugs Co-Administered with Eluxadoline
VIBERZI: Eluxadoline's Brand name
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
- Risk Summary
There are no studies with Eluxadoline in pregnant women that inform any drug-associated risks. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. In animal reproduction studies, oral and subcutaneous administration of Eluxadoline to rats and rabbits during organogenesis at doses approximately 51 and 115 times the human exposure after a single oral dose of 100 mg, respectively, demonstrated no teratogenic effects. In a pre- and postnatal development study in rats, no adverse effects were observed in offspring with oral administration of Eluxadoline at doses approximately 10 times the human exposure.
- Data
- Animal Data
Eluxadoline administered as combined oral (1000 mg/kg/day) and subcutaneous (5 mg/kg/day) doses during the period of organogenesis to rats and rabbits (exposures about 51 and 115 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) did not cause any adverse effects on embryofetal development. A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at oral doses of Eluxadoline up to 1000 mg/kg/day (with exposures about 10 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). In the same study, Eluxadoline was detected in the milk of lactating rats administered oral doses of 100, 300 and 1000 mg/kg/day (with exposures about 1.8, 3 and 10 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). Milk samples were collected from six lactating females per group on lactation day 12. Mean concentrations of Eluxadoline in the milk of lactating rats on lactation day 12 were 2.78, 5.49 and 44.02 ng/mL at 100, 300 and 1000 mg/kg/day, respectively.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eluxadoline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eluxadoline during labor and delivery.
### Nursing Mothers
No data are available regarding the presence of Eluxadoline in human milk, the effects of Eluxadoline on the breastfed infant, or the effects of Eluxadoline on milk production. However, Eluxadoline is present in rat milk.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Eluxadoline and any potential adverse effects on the breastfed infant from Eluxadoline or from the underlying maternal condition.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
- Juvenile Toxicology Data
Eluxadoline was orally administered to juvenile rats at 500, 750, and 1500 mg/kg/day (about 16, 54 and 30 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) for 4 weeks. There were no adverse physiologic effects related to Eluxadoline. Based on these results, the NOAEL for male and female juvenile rats was 1500 mg/kg/day (about 30 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg).
### Geriatic Use
Of 1795 IBS-D patients in clinical trials of Eluxadoline who received 75 mg or 100 mg twice daily, 139 (7.7%) were at least 65 years of age, while 15 (0.8%) were at least 75 years old. No overall differences in effectiveness were observed between these patients and younger patients. There were no overall differences in the types of adverse reactions observed between elderly and younger patients; however, a higher proportion of elderly patients than younger patients experienced adverse reactions (66% vs 59%), serious adverse reactions (9% vs 4%), and gastrointestinal adverse reactions (39% vs 28%).
### Gender
There is no FDA guidance on the use of Eluxadoline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eluxadoline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Eluxadoline in patients with renal impairment.
### Hepatic Impairment
Plasma concentrations of Eluxadoline increase in patients with hepatic impairment.
Eluxadoline is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) as plasma concentrations of Eluxadoline increase significantly (16-fold) and there is no information to support the safety of Eluxadoline in these patients.
In patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, plasma concentrations of Eluxadoline increase to a lesser extent (6- and 4-fold, respectively). Administer Eluxadoline at a reduced dose of 75 mg twice daily to these patients. Monitor patients with any degree of hepatic impairment for impaired mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery and for other Eluxadoline-related adverse reactions.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eluxadoline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eluxadoline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
The recommended dosage of Eluxadoline is 100 mg taken orally twice daily with food.
The recommended dosage of Eluxadoline is 75 mg taken orally twice daily with food in patients who:
- do not have a gallbladder.
- are unable to tolerate the 100 mg dose of Eluxadoline.
- are receiving concomitant OATP1B1 inhibitors.
- have mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
Discontinue Eluxadoline in patients who develop severe constipation for more than 4 days.
Instruct patients if they miss a dose, take the next dose at the regular time and not to take 2 doses at the same time to make up for a missed dose.
### Monitoring
There is limited information regarding Eluxadoline Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Eluxadoline and IV administrations.
# Overdosage
No reports of overdosage with Eluxadoline have been reported.
In the event of acute overdose, the stomach should be emptied and adequate hydration maintained. The patient should be carefully observed and given standard supportive treatment as required. Given Eluxadoline's action at opioid receptors, administration of a narcotic mu-opioid antagonist, such as naloxone, should be considered. Considering the short half-life of naloxone, repeated administration may be necessary. In the event of naloxone administration, subjects should be monitored closely for the return of overdose symptoms, which may indicate need for repeated naloxone injection.
- Controlled Substance
Eluxadoline is listed in Schedule IV of the Controlled Substances Act.
- Abuse
In a drug discrimination study in monkeys, intravenous administration of Eluxadoline hydrochloride produced full generalization to the morphine cue. In a self-administration study in monkeys, Eluxadoline hydrochloride was self-administered to a degree that was less than that of heroin but greater than that of saline.
Adverse reactions of euphoria and feeling drunk were reported in clinical trials of IBS-D evaluating 75 mg and 100 mg doses of Eluxadoline. The rate of euphoria was 0% for 75 mg and 0.2% (2/1032) for 100 mg and the rate of feeling drunk was 0.1% (1/807) for 75 mg and 0.1% (1/1032) for 100 mg.
In contrast, in two human abuse potential studies conducted in recreational opioid-experienced individuals, supratherapeutic oral doses of Eluxadoline (300 mg and/or 1000 mg) and intranasal doses of Eluxadoline (100 mg and/or 200 mg) produced the adverse reaction of euphoria (at a rate ranging from 14% to 28%) that was greater than that of placebo (0% to 5%) but less than that of oxycodone (44% to 76%). In the two human abuse potential studies, supratherapeutic oral and intranasal doses of Eluxadoline produced small but significant increases on positive subjective measures such as Drug Liking and High compared to placebo. Supratherapeutic oral and intranasal doses of Eluxadoline also produced small but significant increases on negative subjective measures such as Drug Disliking and Dysphoria compared to placebo. In the same studies, oxycodone (30 mg and 60 mg oral, and 15 and 30 mg intranasal) produced significantly greater responses on positive and negative subjective measures than those produced by Eluxadoline and placebo.
- Dependence
In studies with monkeys and rats in which Eluxadoline and Eluxadoline hydrochloride were chronically administered, discontinuation of the drug did not lead to behavioral signs of withdrawal, a measure of physical dependence. However, the ability of Eluxadoline hydrochloride in monkeys to induce self-administration suggests that the drug is sufficiently rewarding to produce reinforcement. In two human abuse potential studies with Eluxadoline conducted in recreational opioid-experienced individuals, euphoria was reported at a rate of 14% to 28%. These data suggest that Eluxadoline may produce psychological dependence.
# Pharmacology
## Mechanism of Action
Eluxadoline is a mu-opioid receptor agonist; Eluxadoline is also a delta opioid receptor antagonist and a kappa opioid receptor agonist. The binding affinities (Ki) of Eluxadoline for the human mu and delta opioid receptors are 1.8 nM and 430 nM, respectively. The binding affinity (Ki) of Eluxadoline for the human kappa opioid receptor has not been determined; however, the Ki for guinea pig cerebellum kappa opioid receptor is 55 nM. In animals, Eluxadoline interacts with opioid receptors in the gut.
Eluxadoline is available as 75 mg and 100 mg tablets for oral administration. In addition to the active ingredient, Eluxadoline, each tablet contains the following inactive ingredients: silicified microcrystalline cellulose, colloidal silica, crospovidone, mannitol, magnesium stearate, and Opadry II (partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red).
## Structure
Eluxadoline is available as 75 mg and 100 mg tablets for oral administration. In addition to the active ingredient, Eluxadoline , each tablet contains the following inactive ingredients: silicified microcrystalline cellulose, colloidal silica, crospovidone, mannitol, magnesium stearate, and Opadry II (partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red).
## Pharmacodynamics
- Cardiac Electrophysiology
At a dose 10 times the maximum recommended dose (100 mg), Eluxadoline does not prolong the QT interval to any clinically relevant extent.
## Pharmacokinetics
Following oral administration of 100 mg Eluxadoline in healthy subjects, the Cmax of Eluxadoline was approximately 2 to 4 ng/mL and AUC was 12 to 22 ng.h/mL. Eluxadoline has approximately linear pharmacokinetics with no accumulation upon repeated twice daily dosing. The variability of Eluxadoline pharmacokinetic parameters ranges from 51% to 98%.
Absorption
Absolute bioavailability of Eluxadoline has not been determined. The median Tmax value was 1.5 hours (range: 1 to 8 hours) under fed conditions and 2 hours (range: 0.5 to 6 hours) under fasting conditions.
The administration of Eluxadoline with a high fat meal that contained approximately 800 to 1000 total calories, with 50% of calories being derived from fat content decreased the Cmax of Eluxadoline by 50% and AUC by 60%.
Distribution
Plasma protein binding of Eluxadoline was 81%.
Elimination
The mean plasma elimination half-life of Eluxadoline ranged from 3.7 hours to 6 hours.
- Metabolism
Metabolism of Eluxadoline is not clearly established. There is evidence that glucuronidation can occur to form an acyl glucuronide metabolite.
- Excretion
Following a single oral dose of 300 mg Eluxadoline in healthy male subjects, 82.2% of the total radioactivity was recovered in feces within 336 hours and less than 1% was recovered in urine within 192 hours.
Specific Populations
Hepatic Impairment
Following a single oral 100–mg dose in subjects with varying degrees of liver impairment and healthy subjects, mean Eluxadoline plasma exposure was 6-fold, 4-fold, and 16-fold higher in mild, moderate, and severe hepatically impaired subjects (Child Pugh Class A, B, C), respectively, compared to the subjects with normal liver function.
Drug Interactions
- In Vitro Assessment of Drug Interactions
In vitro studies indicate that Eluxadoline is neither an inducer of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant systemic concentrations. Although CYP2E1 was slightly inhibited by Eluxadoline (IC50 of approximately 20 micromolar ), clinically meaningful interactions are unlikely. The in vitro studies were not adequate to establish the potential for Eluxadoline to inhibit CYP3A4 in the gut.
In vitro studies suggest that Eluxadoline is a substrate for OAT3, OATP1B1, BSEP and MRP2, but not for OCT1, OCT2, OAT1, OATP1B3, P-gp and BCRP. Based on the in vitro studies, clinically meaningful interaction via inhibition of OCT1, OCT2, OAT1, OAT3, OATP1B3, BSEP and MRP2 by Eluxadoline is unlikely. However, the in vitro studies were not adequate to establish the potential for eluxadoline to inhibit P-gp in the gut.
- In Vivo Assessment of Drug Interactions
The following drug interactions were studied in healthy subjects:
- Oral Contraceptives
Coadministration of multiple doses of 100 mg Eluxadoline with multiple dose administration of an oral contraceptive (norethindrone 0.5 mg/ethinyl estradiol 0.035 mg) does not change the exposure of either drug.
- Cyclosporine
Coadministration of a single dose of 100 mg Eluxadoline with a single dose of 600 mg cyclosporine resulted in 4.4-fold and 6.2-fold increase in AUC and Cmax of Eluxadoline, respectively, compared to administration of Eluxadoline alone.
- Probenecid
Coadministration of a single dose of 100 mg Eluxadoline with a single dose of 500 mg probenecid resulted in a 35% and 31% increase in Eluxadoline AUC and Cmax, respectively, compared to administration of Eluxadoline alone. This change in Eluxadoline exposures is not expected to be clinically meaningful.
- Rosuvastatin
Coadministration of multiple doses of 100 mg Eluxadoline twice daily with a single dose 20 mg rosuvastatin resulted in an increase in the AUC (40%) and Cmax (18%) of rosuvastatin compared to administration of rosuvastatin alone. Similar results were observed with the active, major metabolite, n-desmethyl rosuvastatin.
## Nonclinical Toxicology
- Carcinogenesis
Two-year oral carcinogenicity studies have been conducted with Eluxadoline in CD-1 mice at doses up to 1500 mg/kg/day (about 14 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) and in Sprague Dawley rats at oral doses up to 1500 mg/kg/day (about 36 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). Oral administration of Eluxadoline for 104 weeks did not produce tumors in mice and rats.
- Mutagenesis
Eluxadoline was negative in the Ames test, chromosome aberration test in human lymphocytes, in the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test and in the in vivo rat bone marrow micronucleus test.
- Impairment of Fertility
Eluxadoline at oral doses up to 1000 mg/kg/day (about 10 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) was found to have no adverse effect on fertility and reproductive performance of male and female rats.
# Clinical Studies
The efficacy and safety of Eluxadoline in IBS-D patients was established in two randomized, multi-center, multi-national, double-blind, placebo-controlled trials (Studies 1 and 2). A total of 1281 patients in Study 1 and 1145 patients in Study 2 received treatment with Eluxadoline 75 mg, Eluxadoline 100 mg or placebo twice daily .
All patients met Rome III criteria for IBS-D (loose or watery stools ≥25% and hard or lumpy stools <25% of bowel movements) and were required to meet both of the following criteria:
- an average of worst abdominal pain scores in the past 24 hours of >3.0 on a 0 to 10 scale over the week prior to randomization.
- an average daily stool consistency score (Bristol Stool Scale or BSS) of ≥5.5 and at least 5 days with a BSS score ≥5 on a 1 to 7 scale over the week prior to randomization.
Pertinent exclusion criteria included: prior pancreatitis, alcohol abuse, cholecystitis prior 6 months, sphincter of Oddi dysfunction, inflammatory bowel disease, intestinal obstruction, gastrointestinal infection or diverticulitis within prior 3 months, lipase greater than 2 xULN, ALT or AST greater than 3 xULN.
Study 1 and Study 2 included identical 26-week double-blind, placebo-controlled treatment periods. Study 1 continued double-blinded for an additional 26 weeks for long-term safety (total of 52 weeks of treatment), followed by a 2-week follow-up. Study 2 included a 4-week single-blinded, placebo-withdrawal period upon completion of the 26-week treatment period. During the double-blind treatment phase and the single-blinded placebo withdrawal phase, patients were allowed to take loperamide rescue medication for the acute treatment of uncontrolled diarrhea, but were not allowed to take any other antidiarrheal, antispasmodic agent or rifaximin for their diarrhea. Additionally, patients were allowed to take aspirin-containing medications or nonsteroidal anti-inflammatory drugs, but no narcotic or opioid containing agents.
Efficacy of Eluxadoline was assessed in both trials using an overall composite responder primary endpoint. The primary endpoint was defined by the simultaneous improvement in the daily worst abdominal pain score by ≥30% as compared to the baseline weekly average AND a reduction in the BSS to <5 on at least 50% of the days within a 12-week time interval. Improvement in daily worst abdominal pain in the absence of a concurrent bowel movement was also considered a response day. Results for endpoints were based on electronic daily diary entries by patients.
The proportion of composite responders over 12 weeks is shown in TABLE 4. In both trials, the proportion of patients who were composite responders to Eluxadoline was statistically significantly higher than placebo for both doses. The proportion of patients who were composite responders to Eluxadoline was similar for male and female patients in both trials.
- Table 4: Efficacy Results in Randomized Clinical Trials
VIBERZI: Eluxadoline's Brand name
Additionally, the proportion of patients who were composite responders to Eluxadoline at each 4-week interval was numerically higher than placebo for both doses as early as month 1 through month 6 demonstrating that efficacy is maintained throughout the course of treatment.
During the 4 week single-blind withdrawal period in Study 2, no evidence of worsening of diarrhea or abdominal pain compared to baseline was demonstrated at either dose.
# How Supplied
Eluxadoline is available as:
- 75 mg tablets: capsule-shaped tablets, coated in pale-yellow to light tan color, debossed with “FX75” on one side.
Bottle of 60: NDC 61874-075-60
- 100 mg tablets: capsule-shaped tablets, coated in pink-orange to peach color, debossed with “FX100” on one side.
Bottle of 60: NDC 61874-100-60
## Storage
Store Eluxadoline tablets at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling.
Instruct patients to:
- stop Eluxadoline and seek medical attention if unusual or severe abdominal pain develops, especially if they do not have a gallbladder.
- avoid chronic or acute excessive alcohol use while taking Eluxadoline.
- take one tablet twice daily with food.
- if they miss a dose, take the next dose at the regular time. Do not take 2 doses at the same time to make up for a missed dose.
- call their healthcare provider if they are unable to tolerate Eluxadoline.
- discontinue Eluxadoline and call their health care provider if they experience constipation lasting more than 4 days
- not take alosetron with Eluxadoline or not take loperamide on a chronic basis with Eluxadoline due to the potential for constipation. Loperamide may occasionally be used with Eluxadoline for acute management of severe diarrhea, but must be discontinued if constipation develops. Also, instruct patients to avoid taking Eluxadoline with other medications that may cause constipation (for example opioids, anticholinergics, etc.).
# Precautions with Alcohol
- Eluxadoline is contraindicated in patients with alcoholism, alcohol abuse, alcohol addiction, or drink more than 3 alcoholic beverages/day.
- Avoid chronic or acute excessive alcohol use while taking Eluxadoline.
# Brand Names
VIBERZI™
# Look-Alike Drug Names
There is limited information regarding Eluxadoline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Eluxadoline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]
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# Overview
Eluxadoline is a mu-opioid receptor agonist that is FDA approved for the treatment of adults with irritable bowel syndrome with diarrhea (IBS-D). Common adverse reactions include constipation, nausea and abdominal pain (>5%)..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Eluxadoline is indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).
The recommended dosage of Eluxadoline is 100 mg taken orally twice daily with food.
The recommended dosage of Eluxadoline is 75 mg taken orally twice daily with food in patients who:
- do not have a gallbladder.
- are unable to tolerate the 100 mg dose of Eluxadoline.
- are receiving concomitant OATP1B1 inhibitors.
- have mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
Discontinue Eluxadoline in patients who develop severe constipation for more than 4 days.
Instruct patients if they miss a dose, take the next dose at the regular time and not to take 2 doses at the same time to make up for a missed dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eluxadoline in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eluxadoline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eluxadoline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eluxadoline in pediatric patients.
# Contraindications
Eluxadoline is contraindicated in patients with:
- Known or suspected biliary duct obstruction; or sphincter of Oddi disease or dysfunction. These patients are at increased risk for sphincter of Oddi spasm.
- Alcoholism, alcohol abuse or alcohol addiction, or in patients who drink more than 3 alcoholic beverages per day. These patients are at increased risk for acute pancreatitis.
- A history of pancreatitis; or structural diseases of the pancreas, including known or suspected pancreatic duct obstruction. These patients are at increased risk for acute pancreatitis.
- Severe hepatic impairment (Child-Pugh Class C). These patients are at risk for significantly increased plasma concentrations of Eluxadoline.
- A history of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction. These patients may be at risk for severe complications of bowel obstruction.
# Warnings
- Sphincter of Oddi Spasm
Given the mu-opioid receptor agonism of Eluxadoline, there is a potential for increased risk of sphincter of Oddi spasm, resulting in pancreatitis or hepatic enzyme elevation associated with acute abdominal pain (e.g., biliary-type pain) with Eluxadoline.
In clinical trials, sphincter of Oddi spasm occurred in less than 1% of patients receiving Eluxadoline. The majority of these patients presented within the first week of treatment and the event resolved on discontinuation of Eluxadoline. Patients without a gallbladder are at increased risk.
Consider alternative therapies before using Eluxadoline in patients without a gallbladder and evaluate the benefits and risks of Eluxadoline in these patients in the context of their symptom severity. The recommended dosage of Eluxadoline is 75 mg twice daily in patients without a gallbladder. If Eluxadoline is used in such a patient, inform them that they may be at increased risk for adverse reactions and monitor them for symptoms of sphincter of Oddi spasm, such as elevated liver transaminases associated with abdominal pain or pancreatitis, especially during the first few weeks of treatment.
Instruct patients to stop Eluxadoline and seek medical attention if they experience symptoms suggestive of sphincter of Oddi spasm such as acute worsening of abdominal pain, (e.g. acute epigastric or biliary [i.e., right upper quadrant] pain), that may radiate to the back or shoulder with or without nausea and vomiting, associated with elevations of pancreatic enzymes or liver transaminases. Do not restart Eluxadoline in patients who developed biliary duct obstruction or sphincter of Oddi spasm while taking Eluxadoline.
- Pancreatitis
There is a potential for increased risk of pancreatitis, not associated with sphincter of Oddi spasm, when taking Eluxadoline. Additional cases of pancreatitis, not associated with sphincter of Oddi spasm, were reported in less than 1% of patients receiving Eluxadoline in clinical trials. The majority were associated with excessive alcohol intake. All pancreatic events, whether or not associated with sphincter of Oddi spasm, resolved upon discontinuation of Eluxadoline; patients did not have organ failure or local or systemic complications.
Instruct patients to avoid chronic or acute excessive alcohol use while taking Eluxadoline. Monitor for new or worsening abdominal pain that may radiate to the back or shoulder, with or without nausea and vomiting. Instruct patients to stop Eluxadoline and seek medical attention if they experience symptoms suggestive of pancreatitis such as acute abdominal or epigastric pain radiating to the back associated with elevations of pancreatic enzymes.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Over 1700 patients with IBS-D have been treated with 75 or 100 mg of Eluxadoline twice daily in controlled trials. Exposures from placebo-controlled clinical trials in adult patients with IBS-D included 1391 exposed for 3 months, 1001 exposed for 6 months and 488 exposed for one year.
Demographic characteristics were comparable between the treatment groups. Data described below represent pooled data compared to placebo across the randomized trials.
Sphincter of Oddi Spasm
In clinical trials, sphincter of Oddi spasm occurred in 0.2% (2/807) of patients receiving 75 mg and 0.8% (8/1032) of patients receiving 100 mg Eluxadoline twice daily.
- Among patients receiving 75 mg, 1/807 (0.1%) patient experienced a sphincter of Oddi spasm presenting with abdominal pain but with lipase elevation less than 3 times the upper limit of normal (ULN) and 1/ 807 (0.1%) patient experienced a sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain.
- Among patients receiving 100 mg, 1/1032 (0.1%) patient experienced a sphincter of Oddi spasm manifested as pancreatitis and 7/1032 (0.7%) patients experienced sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain.
In patients without a gallbladder, 2/165 (1.2%) and 8/184 (4.3%) of patients receiving 75 mg and 100 mg, respectively, experienced a sphincter of Oddi spasm vs 0/1317 (0%) in patients with a gallbladder who had received either 75 mg or 100 mg treatment.
Of those patients who experienced a sphincter of Oddi spasm, 80% (8/10) reported their first onset of symptoms within the first week of treatment. The case of sphincter of Oddi spasm-induced pancreatitis occurred within minutes of taking the first dose of Eluxadoline. No cases of sphincter of Oddi spasm occurred greater than 1 month after treatment onset. All events resolved upon discontinuation of Eluxadoline, with symptoms typically improved by the following day.
Pancreatitis
Additional cases of pancreatitis, not associated with sphincter of Oddi spasm, were reported in 2/807 (0.2%) of patients receiving 75 mg and 3/1032 (0.3%) of patients receiving 100 mg Eluxadoline twice daily in clinical trials. Of these 5 cases, 3 were associated with excessive alcohol intake, one was associated with biliary sludge, and in one case the patient discontinued Eluxadoline 2 weeks prior to the onset of symptoms. All pancreatic events resolved with lipase normalization upon discontinuation of Eluxadoline, with 80% (4/5) resolving within 1 week of treatment discontinuation. The case of sphincter of Oddi spasm-induced pancreatitis resolved within 24 hours of discontinuation.
Common Adverse Reactions
TABLE 1 provides the incidence of common adverse reactions reported in > 2% of IBS-D patients in either Eluxadoline treatment group and at an incidence greater than in the placebo group.
- Table 1: Common* Adverse Reactions in the Placebo-Controlled Studies in IBS-D Patients
VIBERZI: Eluxadoline's Brand name
Constipation was the most commonly reported adverse reaction in Eluxadoline-treated patients in these trials. Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving 75 mg and 100 mg Eluxadoline. Similar rates of constipation occurred between the active and placebo arms beyond 3 months of treatment.
Adverse Reactions Leading to Discontinuation
Eight percent of patients treated with 75 mg, 8% of patients treated with 100 mg Eluxadoline and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the Eluxadoline treatment groups, the most common reasons for discontinuation due to adverse reactions were constipation (1% for 75 mg and 2% for 100 mg) and abdominal pain (1% for both 75 mg and 100 mg). In comparison, less than 1% of patients in the placebo group withdrew due to constipation or abdominal pain.
Less Common Adverse Reactions
Adverse reactions that were reported in ≤ 2% of Eluxadoline-treated patients are listed below by body system.
- Gastrointestinal: gastroesophageal reflux disease
- General Disorders and administration site conditions: feeling drunk
- Investigations: increased AST
- Nervous system: sedation, somnolence
- Psychiatric disorders: euphoric mood
- Respiratory: asthma, bronchospasm, respiratory failure, wheezing
## Postmarketing Experience
There is limited information regarding Eluxadoline Postmarketing Experience in the drug label.
# Drug Interactions
The metabolism of Eluxadoline by CYP pathways has not been clearly established. In addition, the potential of Eluxadoline to inhibit CYP3A4 in the gut has not been established.
TABLES 2 and 3 include drugs which demonstrated a clinically important drug interaction with Eluxadoline or which potentially may result in clinically relevant interactions.
- Table 2: Established and Other Potentially Clinically Relevant Interactions Affecting Eluxadoline
VIBERZI: Eluxadoline's Brand name
- Table 3: Established and Other Potentially Clinically Relevant Interactions Affecting Drugs Co-Administered with Eluxadoline
VIBERZI: Eluxadoline's Brand name
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
- Risk Summary
There are no studies with Eluxadoline in pregnant women that inform any drug-associated risks. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. In animal reproduction studies, oral and subcutaneous administration of Eluxadoline to rats and rabbits during organogenesis at doses approximately 51 and 115 times the human exposure after a single oral dose of 100 mg, respectively, demonstrated no teratogenic effects. In a pre- and postnatal development study in rats, no adverse effects were observed in offspring with oral administration of Eluxadoline at doses approximately 10 times the human exposure.
- Data
- Animal Data
Eluxadoline administered as combined oral (1000 mg/kg/day) and subcutaneous (5 mg/kg/day) doses during the period of organogenesis to rats and rabbits (exposures about 51 and 115 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) did not cause any adverse effects on embryofetal development. A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at oral doses of Eluxadoline up to 1000 mg/kg/day (with exposures about 10 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). In the same study, Eluxadoline was detected in the milk of lactating rats administered oral doses of 100, 300 and 1000 mg/kg/day (with exposures about 1.8, 3 and 10 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). Milk samples were collected from six lactating females per group on lactation day 12. Mean concentrations of Eluxadoline in the milk of lactating rats on lactation day 12 were 2.78, 5.49 and 44.02 ng/mL at 100, 300 and 1000 mg/kg/day, respectively.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eluxadoline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eluxadoline during labor and delivery.
### Nursing Mothers
No data are available regarding the presence of Eluxadoline in human milk, the effects of Eluxadoline on the breastfed infant, or the effects of Eluxadoline on milk production. However, Eluxadoline is present in rat milk.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Eluxadoline and any potential adverse effects on the breastfed infant from Eluxadoline or from the underlying maternal condition.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
- Juvenile Toxicology Data
Eluxadoline was orally administered to juvenile rats at 500, 750, and 1500 mg/kg/day (about 16, 54 and 30 times, respectively, the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) for 4 weeks. There were no adverse physiologic effects related to Eluxadoline. Based on these results, the NOAEL for male and female juvenile rats was 1500 mg/kg/day (about 30 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg).
### Geriatic Use
Of 1795 IBS-D patients in clinical trials of Eluxadoline who received 75 mg or 100 mg twice daily, 139 (7.7%) were at least 65 years of age, while 15 (0.8%) were at least 75 years old. No overall differences in effectiveness were observed between these patients and younger patients. There were no overall differences in the types of adverse reactions observed between elderly and younger patients; however, a higher proportion of elderly patients than younger patients experienced adverse reactions (66% vs 59%), serious adverse reactions (9% vs 4%), and gastrointestinal adverse reactions (39% vs 28%).
### Gender
There is no FDA guidance on the use of Eluxadoline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eluxadoline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Eluxadoline in patients with renal impairment.
### Hepatic Impairment
Plasma concentrations of Eluxadoline increase in patients with hepatic impairment.
Eluxadoline is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) as plasma concentrations of Eluxadoline increase significantly (16-fold) and there is no information to support the safety of Eluxadoline in these patients.
In patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, plasma concentrations of Eluxadoline increase to a lesser extent (6- and 4-fold, respectively). Administer Eluxadoline at a reduced dose of 75 mg twice daily to these patients. Monitor patients with any degree of hepatic impairment for impaired mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery and for other Eluxadoline-related adverse reactions.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eluxadoline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eluxadoline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
The recommended dosage of Eluxadoline is 100 mg taken orally twice daily with food.
The recommended dosage of Eluxadoline is 75 mg taken orally twice daily with food in patients who:
- do not have a gallbladder.
- are unable to tolerate the 100 mg dose of Eluxadoline.
- are receiving concomitant OATP1B1 inhibitors.
- have mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
Discontinue Eluxadoline in patients who develop severe constipation for more than 4 days.
Instruct patients if they miss a dose, take the next dose at the regular time and not to take 2 doses at the same time to make up for a missed dose.
### Monitoring
There is limited information regarding Eluxadoline Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Eluxadoline and IV administrations.
# Overdosage
No reports of overdosage with Eluxadoline have been reported.
In the event of acute overdose, the stomach should be emptied and adequate hydration maintained. The patient should be carefully observed and given standard supportive treatment as required. Given Eluxadoline's action at opioid receptors, administration of a narcotic mu-opioid antagonist, such as naloxone, should be considered. Considering the short half-life of naloxone, repeated administration may be necessary. In the event of naloxone administration, subjects should be monitored closely for the return of overdose symptoms, which may indicate need for repeated naloxone injection.
- Controlled Substance
Eluxadoline is listed in Schedule IV of the Controlled Substances Act.
- Abuse
In a drug discrimination study in monkeys, intravenous administration of Eluxadoline hydrochloride produced full generalization to the morphine cue. In a self-administration study in monkeys, Eluxadoline hydrochloride was self-administered to a degree that was less than that of heroin but greater than that of saline.
Adverse reactions of euphoria and feeling drunk were reported in clinical trials of IBS-D evaluating 75 mg and 100 mg doses of Eluxadoline. The rate of euphoria was 0% for 75 mg and 0.2% (2/1032) for 100 mg and the rate of feeling drunk was 0.1% (1/807) for 75 mg and 0.1% (1/1032) for 100 mg.
In contrast, in two human abuse potential studies conducted in recreational opioid-experienced individuals, supratherapeutic oral doses of Eluxadoline (300 mg and/or 1000 mg) and intranasal doses of Eluxadoline (100 mg and/or 200 mg) produced the adverse reaction of euphoria (at a rate ranging from 14% to 28%) that was greater than that of placebo (0% to 5%) but less than that of oxycodone (44% to 76%). In the two human abuse potential studies, supratherapeutic oral and intranasal doses of Eluxadoline produced small but significant increases on positive subjective measures such as Drug Liking and High compared to placebo. Supratherapeutic oral and intranasal doses of Eluxadoline also produced small but significant increases on negative subjective measures such as Drug Disliking and Dysphoria compared to placebo. In the same studies, oxycodone (30 mg and 60 mg oral, and 15 and 30 mg intranasal) produced significantly greater responses on positive and negative subjective measures than those produced by Eluxadoline and placebo.
- Dependence
In studies with monkeys and rats in which Eluxadoline and Eluxadoline hydrochloride were chronically administered, discontinuation of the drug did not lead to behavioral signs of withdrawal, a measure of physical dependence. However, the ability of Eluxadoline hydrochloride in monkeys to induce self-administration suggests that the drug is sufficiently rewarding to produce reinforcement. In two human abuse potential studies with Eluxadoline conducted in recreational opioid-experienced individuals, euphoria was reported at a rate of 14% to 28%. These data suggest that Eluxadoline may produce psychological dependence.
# Pharmacology
## Mechanism of Action
Eluxadoline is a mu-opioid receptor agonist; Eluxadoline is also a delta opioid receptor antagonist and a kappa opioid receptor agonist. The binding affinities (Ki) of Eluxadoline for the human mu and delta opioid receptors are 1.8 nM and 430 nM, respectively. The binding affinity (Ki) of Eluxadoline for the human kappa opioid receptor has not been determined; however, the Ki for guinea pig cerebellum kappa opioid receptor is 55 nM. In animals, Eluxadoline interacts with opioid receptors in the gut.
Eluxadoline is available as 75 mg and 100 mg tablets for oral administration. In addition to the active ingredient, Eluxadoline, each tablet contains the following inactive ingredients: silicified microcrystalline cellulose, colloidal silica, crospovidone, mannitol, magnesium stearate, and Opadry II (partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red).
## Structure
Eluxadoline is available as 75 mg and 100 mg tablets for oral administration. In addition to the active ingredient, Eluxadoline , each tablet contains the following inactive ingredients: silicified microcrystalline cellulose, colloidal silica, crospovidone, mannitol, magnesium stearate, and Opadry II (partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red).
## Pharmacodynamics
- Cardiac Electrophysiology
At a dose 10 times the maximum recommended dose (100 mg), Eluxadoline does not prolong the QT interval to any clinically relevant extent.
## Pharmacokinetics
Following oral administration of 100 mg Eluxadoline in healthy subjects, the Cmax of Eluxadoline was approximately 2 to 4 ng/mL and AUC was 12 to 22 ng.h/mL. Eluxadoline has approximately linear pharmacokinetics with no accumulation upon repeated twice daily dosing. The variability of Eluxadoline pharmacokinetic parameters ranges from 51% to 98%.
Absorption
Absolute bioavailability of Eluxadoline has not been determined. The median Tmax value was 1.5 hours (range: 1 to 8 hours) under fed conditions and 2 hours (range: 0.5 to 6 hours) under fasting conditions.
The administration of Eluxadoline with a high fat meal that contained approximately 800 to 1000 total calories, with 50% of calories being derived from fat content decreased the Cmax of Eluxadoline by 50% and AUC by 60%.
Distribution
Plasma protein binding of Eluxadoline was 81%.
Elimination
The mean plasma elimination half-life of Eluxadoline ranged from 3.7 hours to 6 hours.
- Metabolism
Metabolism of Eluxadoline is not clearly established. There is evidence that glucuronidation can occur to form an acyl glucuronide metabolite.
- Excretion
Following a single oral dose of 300 mg [14C] Eluxadoline in healthy male subjects, 82.2% of the total radioactivity was recovered in feces within 336 hours and less than 1% was recovered in urine within 192 hours.
Specific Populations
Hepatic Impairment
Following a single oral 100–mg dose in subjects with varying degrees of liver impairment and healthy subjects, mean Eluxadoline plasma exposure was 6-fold, 4-fold, and 16-fold higher in mild, moderate, and severe hepatically impaired subjects (Child Pugh Class A, B, C), respectively, compared to the subjects with normal liver function.
Drug Interactions
- In Vitro Assessment of Drug Interactions
In vitro studies indicate that Eluxadoline is neither an inducer of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant systemic concentrations. Although CYP2E1 was slightly inhibited by Eluxadoline (IC50 of approximately 20 micromolar [11 mcg/mL]), clinically meaningful interactions are unlikely. The in vitro studies were not adequate to establish the potential for Eluxadoline to inhibit CYP3A4 in the gut.
In vitro studies suggest that Eluxadoline is a substrate for OAT3, OATP1B1, BSEP and MRP2, but not for OCT1, OCT2, OAT1, OATP1B3, P-gp and BCRP. Based on the in vitro studies, clinically meaningful interaction via inhibition of OCT1, OCT2, OAT1, OAT3, OATP1B3, BSEP and MRP2 by Eluxadoline is unlikely. However, the in vitro studies were not adequate to establish the potential for eluxadoline to inhibit P-gp in the gut.
- In Vivo Assessment of Drug Interactions
The following drug interactions were studied in healthy subjects:
- Oral Contraceptives
Coadministration of multiple doses of 100 mg Eluxadoline with multiple dose administration of an oral contraceptive (norethindrone 0.5 mg/ethinyl estradiol 0.035 mg) does not change the exposure of either drug.
- Cyclosporine
Coadministration of a single dose of 100 mg Eluxadoline with a single dose of 600 mg cyclosporine resulted in 4.4-fold and 6.2-fold increase in AUC and Cmax of Eluxadoline, respectively, compared to administration of Eluxadoline alone.
- Probenecid
Coadministration of a single dose of 100 mg Eluxadoline with a single dose of 500 mg probenecid resulted in a 35% and 31% increase in Eluxadoline AUC and Cmax, respectively, compared to administration of Eluxadoline alone. This change in Eluxadoline exposures is not expected to be clinically meaningful.
- Rosuvastatin
Coadministration of multiple doses of 100 mg Eluxadoline twice daily with a single dose 20 mg rosuvastatin resulted in an increase in the AUC (40%) and Cmax (18%) of rosuvastatin compared to administration of rosuvastatin alone. Similar results were observed with the active, major metabolite, n-desmethyl rosuvastatin.
## Nonclinical Toxicology
- Carcinogenesis
Two-year oral carcinogenicity studies have been conducted with Eluxadoline in CD-1 mice at doses up to 1500 mg/kg/day (about 14 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) and in Sprague Dawley rats at oral doses up to 1500 mg/kg/day (about 36 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). Oral administration of Eluxadoline for 104 weeks did not produce tumors in mice and rats.
- Mutagenesis
Eluxadoline was negative in the Ames test, chromosome aberration test in human lymphocytes, in the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test and in the in vivo rat bone marrow micronucleus test.
- Impairment of Fertility
Eluxadoline at oral doses up to 1000 mg/kg/day (about 10 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) was found to have no adverse effect on fertility and reproductive performance of male and female rats.
# Clinical Studies
The efficacy and safety of Eluxadoline in IBS-D patients was established in two randomized, multi-center, multi-national, double-blind, placebo-controlled trials (Studies 1 and 2). A total of 1281 patients in Study 1 and 1145 patients in Study 2 received treatment with Eluxadoline 75 mg, Eluxadoline 100 mg or placebo twice daily [overall, patients had a mean age of 45 years (range 18 to 80 years with 10% at least 65 years of age or older), 66% female, 86% white, 11% black, and 27% Hispanic].
All patients met Rome III criteria for IBS-D (loose [mushy] or watery stools ≥25% and hard or lumpy stools <25% of bowel movements) and were required to meet both of the following criteria:
- an average of worst abdominal pain scores in the past 24 hours of >3.0 on a 0 to 10 scale over the week prior to randomization.
- an average daily stool consistency score (Bristol Stool Scale or BSS) of ≥5.5 and at least 5 days with a BSS score ≥5 on a 1 to 7 scale over the week prior to randomization.
Pertinent exclusion criteria included: prior pancreatitis, alcohol abuse, cholecystitis prior 6 months, sphincter of Oddi dysfunction, inflammatory bowel disease, intestinal obstruction, gastrointestinal infection or diverticulitis within prior 3 months, lipase greater than 2 xULN, ALT or AST greater than 3 xULN.
Study 1 and Study 2 included identical 26-week double-blind, placebo-controlled treatment periods. Study 1 continued double-blinded for an additional 26 weeks for long-term safety (total of 52 weeks of treatment), followed by a 2-week follow-up. Study 2 included a 4-week single-blinded, placebo-withdrawal period upon completion of the 26-week treatment period. During the double-blind treatment phase and the single-blinded placebo withdrawal phase, patients were allowed to take loperamide rescue medication for the acute treatment of uncontrolled diarrhea, but were not allowed to take any other antidiarrheal, antispasmodic agent or rifaximin for their diarrhea. Additionally, patients were allowed to take aspirin-containing medications or nonsteroidal anti-inflammatory drugs, but no narcotic or opioid containing agents.
Efficacy of Eluxadoline was assessed in both trials using an overall composite responder primary endpoint. The primary endpoint was defined by the simultaneous improvement in the daily worst abdominal pain score by ≥30% as compared to the baseline weekly average AND a reduction in the BSS to <5 on at least 50% of the days within a 12-week time interval. Improvement in daily worst abdominal pain in the absence of a concurrent bowel movement was also considered a response day. Results for endpoints were based on electronic daily diary entries by patients.
The proportion of composite responders over 12 weeks is shown in TABLE 4. In both trials, the proportion of patients who were composite responders to Eluxadoline was statistically significantly higher than placebo for both doses. The proportion of patients who were composite responders to Eluxadoline was similar for male and female patients in both trials.
- Table 4: Efficacy Results in Randomized Clinical Trials
VIBERZI: Eluxadoline's Brand name
Additionally, the proportion of patients who were composite responders to Eluxadoline at each 4-week interval was numerically higher than placebo for both doses as early as month 1 through month 6 demonstrating that efficacy is maintained throughout the course of treatment.
During the 4 week single-blind withdrawal period in Study 2, no evidence of worsening of diarrhea or abdominal pain compared to baseline was demonstrated at either dose.
# How Supplied
Eluxadoline is available as:
- 75 mg tablets: capsule-shaped tablets, coated in pale-yellow to light tan color, debossed with “FX75” on one side.
Bottle of 60: NDC 61874-075-60
- 100 mg tablets: capsule-shaped tablets, coated in pink-orange to peach color, debossed with “FX100” on one side.
Bottle of 60: NDC 61874-100-60
## Storage
Store Eluxadoline tablets at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling.
Instruct patients to:
- stop Eluxadoline and seek medical attention if unusual or severe abdominal pain develops, especially if they do not have a gallbladder.
- avoid chronic or acute excessive alcohol use while taking Eluxadoline.
- take one tablet twice daily with food.
- if they miss a dose, take the next dose at the regular time. Do not take 2 doses at the same time to make up for a missed dose.
- call their healthcare provider if they are unable to tolerate Eluxadoline.
- discontinue Eluxadoline and call their health care provider if they experience constipation lasting more than 4 days
- not take alosetron with Eluxadoline or not take loperamide on a chronic basis with Eluxadoline due to the potential for constipation. Loperamide may occasionally be used with Eluxadoline for acute management of severe diarrhea, but must be discontinued if constipation develops. Also, instruct patients to avoid taking Eluxadoline with other medications that may cause constipation (for example opioids, anticholinergics, etc.).
# Precautions with Alcohol
- Eluxadoline is contraindicated in patients with alcoholism, alcohol abuse, alcohol addiction, or drink more than 3 alcoholic beverages/day.
- Avoid chronic or acute excessive alcohol use while taking Eluxadoline.
# Brand Names
VIBERZI™
# Look-Alike Drug Names
There is limited information regarding Eluxadoline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Eluxadoline | |
1249d0bd04d69d5ee2222e9cdfb721247d5d1869 | wikidoc | Embolectomy | Embolectomy
# Overview
Embolectomy is the emergency surgical removal of emboli which are blocking blood circulation. It usually involves removal of thrombi (blood clots), and is then referred to as thrombectomy. Embolectomy is an emergency procedure often as the last resort because permanent occlusion of a significant blood flow to an organ leads to necrosis. Other involved therapeutic options are anticoagulation and thrombolysis.
# Background knowledge
Emboli are abnormal masses of material (which can be solid, liquid or gas) that are carried in the blood stream from one part of the circulation to another causing a blockage (occlusion) of a blood vessel that leads to lack of oxygen supply (ischemia) and finally infarction of tissue downstream of the embolus.
The most common type of emboli are a blood clot generated by thrombosis which has then broken off and is then transported in the blood stream (see embolism).
There are two areas where emboli can form and therefore impact:
- Arterial emboli form in the left side of the heart or the main arteries, they impact in body tissues but not the lungs, commonly in the brain and the small vessels in the upper and lower limbs
- Venous emboli arise in veins (for example emboli which form from deep venous thrombosis or DVT) and these impact in the lung (see pulmonary embolism).
# Medical uses
Surgical embolectomy for massive pulmonary embolism (PE) has become a rare procedure and is often viewed as a last resort. Thrombolytic therapy has become the treatment of choice.
Surgical or catheter embolectomy is normally performed in patients with pulmonary embolism (formed from venous embolisms). Embolectomy is used for patients with persisting shock despite supportive care and who have an absolute contraindication for thrombolytic therapy. And although other treatments have improved urgent surgical embolectomy or catheter embolectomy may be a life saving procedure in severe pulmonary embolism.
Embolectomies are performed for arterial embolisms in acute limb ischemia. However, there are also other options, such as catheter-directed thrombolysis and anticoagulation with observation.
It can also be used for other ischemias due to embolism for example mesenteric ischemia and stroke.
# Methods
## Catheter embolectomy
### Balloon embolectomy
Typically this is done by inserting a catheter with an inflatable balloon attached to its tip into an artery, passing the catheter tip beyond the clot, inflating the balloon, and removing the clot by withdrawing the catheter. The catheter is called Fogarty, named after its inventor Thomas J. Fogarty.
Possible complications of balloon embolectomy include intimal lesions, which can lead to another thrombosis. The vessel may also be affected by a dissection or rupture or causing cholesterol embolism from atherosclerotic plaques.
### Aspiration embolectomy
Catheter embolectomy is also used for aspiration embolectomy, where the thrombus is removed by suction rather than pushing with a balloon. It is a rapid and effective way of removing thrombi in thromboembolic occlusions of the limb arteries below the inguinal ligament, as in leg infarction.
## Surgical embolectomy
Surgical embolectomy is the simple surgical removal of a clot following incision into a vessel by open surgery on the artery.
# Outcome
Outcome of embolectomy varies with size and location of the embolus.
In pulmonary embolism recent data shows mortality as being approximately 20%. Although this is a high mortality, it may have life-saving potential in some instances. | Embolectomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Embolectomy is the emergency surgical removal of emboli which are blocking blood circulation. It usually involves removal of thrombi (blood clots), and is then referred to as thrombectomy. Embolectomy is an emergency procedure often as the last resort because permanent occlusion of a significant blood flow to an organ leads to necrosis. Other involved therapeutic options are anticoagulation and thrombolysis.
# Background knowledge
Emboli are abnormal masses of material (which can be solid, liquid or gas) that are carried in the blood stream from one part of the circulation to another causing a blockage (occlusion) of a blood vessel that leads to lack of oxygen supply (ischemia) and finally infarction of tissue downstream of the embolus.
The most common type of emboli are a blood clot generated by thrombosis which has then broken off and is then transported in the blood stream (see embolism).
There are two areas where emboli can form and therefore impact:
- Arterial emboli form in the left side of the heart or the main arteries, they impact in body tissues but not the lungs, commonly in the brain and the small vessels in the upper and lower limbs
- Venous emboli arise in veins (for example emboli which form from deep venous thrombosis or DVT) and these impact in the lung (see pulmonary embolism).
# Medical uses
Surgical embolectomy for massive pulmonary embolism (PE) has become a rare procedure and is often viewed as a last resort. Thrombolytic therapy has become the treatment of choice.[1]
Surgical or catheter embolectomy is normally performed in patients with pulmonary embolism (formed from venous embolisms). Embolectomy is used for patients with persisting shock despite supportive care and who have an absolute contraindication for thrombolytic therapy.[2] And although other treatments have improved urgent surgical embolectomy or catheter embolectomy may be a life saving procedure in severe pulmonary embolism.[3]
Embolectomies are performed for arterial embolisms in acute limb ischemia. However, there are also other options, such as catheter-directed thrombolysis and anticoagulation with observation.[4]
It can also be used for other ischemias due to embolism for example mesenteric ischemia and stroke.[5]
# Methods
## Catheter embolectomy
### Balloon embolectomy
Typically this is done by inserting a catheter with an inflatable balloon attached to its tip into an artery, passing the catheter tip beyond the clot, inflating the balloon, and removing the clot by withdrawing the catheter. The catheter is called Fogarty, named after its inventor Thomas J. Fogarty.
Possible complications of balloon embolectomy include intimal lesions, which can lead to another thrombosis.[6] The vessel may also be affected by a dissection or rupture or causing cholesterol embolism from atherosclerotic plaques.[6]
### Aspiration embolectomy
Catheter embolectomy is also used for aspiration embolectomy, where the thrombus is removed by suction rather than pushing with a balloon.[7] It is a rapid and effective way of removing thrombi in thromboembolic occlusions of the limb arteries below the inguinal ligament,[7] as in leg infarction.
## Surgical embolectomy
Surgical embolectomy is the simple surgical removal of a clot following incision into a vessel by open surgery on the artery.[8]
# Outcome
Outcome of embolectomy varies with size and location of the embolus.[citation needed]
In pulmonary embolism recent data shows mortality as being approximately 20%. Although this is a high mortality, it may have life-saving potential in some instances.[9] | https://www.wikidoc.org/index.php/Embolectomy | |
99e9b04234fd3de42dbc26656e1f18dece34d3a9 | wikidoc | Embryophyte | Embryophyte
The embryophytes are the most familiar group of plants. They include trees, flowers, ferns, mosses, and various other green land plants. All are complex multicellular eukaryotes with specialized reproductive organs. With very few exceptions, embryophytes obtain their energy through photosynthesis (that is, by absorbing light); and they synthesize their food from carbon dioxide. Embryophyta may be distinguished from chlorophyll-using multicellular algae by having sterile tissue within the reproductive organs. Furthermore, embryophytes are primarily adapted for life on land, although some are secondarily aquatic. Accordingly, they are often called land plants or terrestrial plants.
Embryophytes developed from complex green algae (Chlorophyta) during the Paleozoic era. The Charales or stoneworts appear to be the best living illustration of that developmental step. These alga-like plants undergo an alternation between haploid and diploid generations (respectively called gametophytes and sporophytes). In the first embryophytes, however, the sporophytes became very different in structure and function, remaining small and dependent on the parent for their entire brief life. Such plants are informally called 'bryophytes'. They include three surviving groups:
- Bryophyta (mosses)
- Anthocerotophyta (hornworts)
- Marchantiophyta (liverworts)
All of the above 'bryophytes' are relatively small and are usually confined to moist environments, relying on water to disperse their spores. Other plants, better adapted to terrestrial conditions, appeared during the Silurian period. During the Devonian period, they diversified and spread to many different land environments, becoming the vascular plants or tracheophytes. Tracheophyta have vascular tissues or tracheids, which transport water throughout the body, and an outer layer or cuticle that resists drying out. In most vascular plants, the sporophyte is the dominant individual, and develops true leaves, stems, and roots, while the gametophyte remains very small.
Many vascular plants, however, still disperse using spores. They include two extant groups:
- Lycopodiophyta (clubmosses)
- Pteridophyta (ferns, whisk ferns, and horsetails)
Other groups, which first appeared towards the end of the Paleozoic era, reproduce using desiccation-resistant capsules called seeds. These groups are accordingly called spermatophytes or seed plants. In these forms, the gametophyte is completely reduced, taking the form of single-celled pollen and ova, while the sporophyte begins its life enclosed within the seed. Some seed plants may even survive in extremely arid conditions, unlike their more water-bound precursors. The seed plants include the following extant groups:
- Cycadophyta (cycads)
- Ginkgophyta (ginkgo)
- Pinophyta (conifers)
- Gnetophyta (gnetae)
- Magnoliophyta (flowering plants)
The first four groups are referred to as gymnosperms, since the embryonic sporophyte is not enclosed until after pollination. In contrast, among the flowering plants or angiosperms, the pollen has to grow a tube to penetrate the seed coat. Angiosperms were the last major group of plants to appear, developing from gymnosperms during the Jurassic period, and then spreading rapidly during the Cretaceous. They are the predominant group of plants in most terrestrial biomes today.
Note that the higher-level classification of plants varies considerably. Some authors have restricted the kingdom Plantae to include only embryophytes, others have given them various names and ranks. The groups listed here are often considered divisions or phyla, but have also been treated as classes, and they are occasionally compressed into as few as two divisions. Some classifications, indeed, consider the term Embryophyta at the superphylum (superdivision) level, and include Land Plants and some Charophyceae in a subkingdom named Streptophyta.
On a microscopic level, embryophyte cells remain very similar to those of green algae. They are eukaryotic, with a cell wall composed of cellulose and plastids surrounded by two membranes. These usually take the form of chloroplasts, which conduct photosynthesis and store food in the form of starch, and characteristically are pigmented with chlorophylls a and b, generally giving them a bright green color. Embryophytes also generally have an enlarged central vacuole or tonoplast, which maintains cell turgor and keeps the plant rigid. They lack flagella and centrioles except in certain gametes. | Embryophyte
The embryophytes are the most familiar group of plants. They include trees, flowers, ferns, mosses, and various other green land plants. All are complex multicellular eukaryotes with specialized reproductive organs. With very few exceptions, embryophytes obtain their energy through photosynthesis (that is, by absorbing light); and they synthesize their food from carbon dioxide. Embryophyta may be distinguished from chlorophyll-using multicellular algae by having sterile tissue within the reproductive organs. Furthermore, embryophytes are primarily adapted for life on land, although some are secondarily aquatic. Accordingly, they are often called land plants or terrestrial plants.
Embryophytes developed from complex green algae (Chlorophyta) during the Paleozoic era. The Charales or stoneworts appear to be the best living illustration of that developmental step. These alga-like plants undergo an alternation between haploid and diploid generations (respectively called gametophytes and sporophytes). In the first embryophytes, however, the sporophytes became very different in structure and function, remaining small and dependent on the parent for their entire brief life. Such plants are informally called 'bryophytes'. They include three surviving groups:
- Bryophyta (mosses)
- Anthocerotophyta (hornworts)
- Marchantiophyta (liverworts)
All of the above 'bryophytes' are relatively small and are usually confined to moist environments, relying on water to disperse their spores. Other plants, better adapted to terrestrial conditions, appeared during the Silurian period. During the Devonian period, they diversified and spread to many different land environments, becoming the vascular plants or tracheophytes. Tracheophyta have vascular tissues or tracheids, which transport water throughout the body, and an outer layer or cuticle that resists drying out. In most vascular plants, the sporophyte is the dominant individual, and develops true leaves, stems, and roots, while the gametophyte remains very small.
Many vascular plants, however, still disperse using spores. They include two extant groups:
- Lycopodiophyta (clubmosses)
- Pteridophyta (ferns, whisk ferns, and horsetails)
Other groups, which first appeared towards the end of the Paleozoic era, reproduce using desiccation-resistant capsules called seeds. These groups are accordingly called spermatophytes or seed plants. In these forms, the gametophyte is completely reduced, taking the form of single-celled pollen and ova, while the sporophyte begins its life enclosed within the seed. Some seed plants may even survive in extremely arid conditions, unlike their more water-bound precursors. The seed plants include the following extant groups:
- Cycadophyta (cycads)
- Ginkgophyta (ginkgo)
- Pinophyta (conifers)
- Gnetophyta (gnetae)
- Magnoliophyta (flowering plants)
The first four groups are referred to as gymnosperms, since the embryonic sporophyte is not enclosed until after pollination. In contrast, among the flowering plants or angiosperms, the pollen has to grow a tube to penetrate the seed coat. Angiosperms were the last major group of plants to appear, developing from gymnosperms during the Jurassic period, and then spreading rapidly during the Cretaceous. They are the predominant group of plants in most terrestrial biomes today.
Note that the higher-level classification of plants varies considerably. Some authors have restricted the kingdom Plantae to include only embryophytes, others have given them various names and ranks. The groups listed here are often considered divisions or phyla, but have also been treated as classes, and they are occasionally compressed into as few as two divisions. Some classifications, indeed, consider the term Embryophyta at the superphylum (superdivision) level, and include Land Plants and some Charophyceae in a subkingdom named Streptophyta.
On a microscopic level, embryophyte cells remain very similar to those of green algae. They are eukaryotic, with a cell wall composed of cellulose and plastids surrounded by two membranes. These usually take the form of chloroplasts, which conduct photosynthesis and store food in the form of starch, and characteristically are pigmented with chlorophylls a and b, generally giving them a bright green color. Embryophytes also generally have an enlarged central vacuole or tonoplast, which maintains cell turgor and keeps the plant rigid. They lack flagella and centrioles except in certain gametes. | https://www.wikidoc.org/index.php/Embryophyte | |
946305039bef55f09393f81ae094f60eac603101 | wikidoc | Emetophilia | Emetophilia
# Overview
Emetophilia is a sexual fetish in which an individual is aroused by vomiting or observing others vomit. When emetophiles put emetophilia into practice by actually vomiting, especially on a partner, it is called a Roman shower, after the supposed frequent induction of vomiting at Roman feasts.
Some emetophiles find the act of vomiting arousing; for them, the sequence of "spasm, ejaculation, relief" in vomiting is erotically charged. Other emetophiles are aroused by seeing and/or hearing others vomit. Some desire a partner who will vomit on them, while others wish to induce vomiting in a partner, or even force them to vomit. (Wanting to be vomited on may be related to a desire to be dominated, while wanting to make someone else vomit may stem from a desire to dominate the partner - see erotic humiliation.) Of course, most emetophiles have more than one of these desires, in various combinations.
An online site theorizes, "vomiting was probably something either arousing or frightening to emetophiles at some point ... it aroused powerful emotions, and the emetophile called upon these emotions for the purpose of sexual gratification." (Frequently Asked Questions about Vomiting) Often emetophobia can, paradoxically, lead to emetophilia, or even a mixture of the two in which a person is afraid to vomit, but aroused by witnessing someone else vomiting.
In some cases, emetophilia is directly related to vorarephilia. The emetophile fantasizes that he or she is consumed by the person who is vomiting, and imagines him/herself as covered by the contents of the person's stomach while within the stomach of the person who is the target of their fantasy. | Emetophilia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Search infobox
Emetophilia is a sexual fetish in which an individual is aroused by vomiting or observing others vomit. When emetophiles put emetophilia into practice by actually vomiting, especially on a partner, it is called a Roman shower, after the supposed frequent induction of vomiting at Roman feasts.
Some emetophiles find the act of vomiting arousing; for them, the sequence of "spasm, ejaculation, relief" in vomiting is erotically charged. Other emetophiles are aroused by seeing and/or hearing others vomit. Some desire a partner who will vomit on them, while others wish to induce vomiting in a partner, or even force them to vomit. (Wanting to be vomited on may be related to a desire to be dominated, while wanting to make someone else vomit may stem from a desire to dominate the partner - see erotic humiliation.) Of course, most emetophiles have more than one of these desires, in various combinations.
An online site theorizes, "vomiting was probably something either arousing or frightening to emetophiles at some point ... it aroused powerful emotions, and the emetophile called upon these emotions for the purpose of sexual gratification." (Frequently Asked Questions about Vomiting) Often emetophobia can, paradoxically, lead to emetophilia, or even a mixture of the two in which a person is afraid to vomit, but aroused by witnessing someone else vomiting.
In some cases, emetophilia is directly related to vorarephilia. The emetophile fantasizes that he or she is consumed by the person who is vomiting, and imagines him/herself as covered by the contents of the person's stomach while within the stomach of the person who is the target of their fantasy. | https://www.wikidoc.org/index.php/Emetophilia | |
7f192f1edeac739c0125dd2efe2cd18381d73b7a | wikidoc | Emetophobia | Emetophobia
# Overview
Emetophobia is the irrational fear of vomiting, being around others who are vomiting, and/or the vomit itself.
In worst case scenarios, people with the phobia tend to avoid eating out, socializing and going to parties. They may hardly eat at all and that's why many are often diagnosed as anorexic, but not bulimic as this illness involves the induction of vomiting. Emetophobes will go to extraordinary lengths to avoid becoming violently sick, or seeing someone else becoming sick.
The phobia is extremely life encompassing for many; the phobia is not only felt when the person is ill, but an ongoing, constant fear that they will vomit. It can affect them day in and day out, with many sufferers reporting feelings of sickness between 5 times a month up to 30, which will induce a panic attack for many as they will believe they will actually vomit. Many emetophobes fear others vomiting too. They will constantly worry that someone near them feels sick and that they will be sick.
Emetophobics will often go into panic attacks. Symptoms of a panic attack include:
- sweating
- shivering
- clammy hands
- whimpering / even shouting
- a feeling of unreality
- a feeling of losing control
Most emetophobics will hate and/or avoid public restrooms. Also, they may feel mutual to the aspect of public transportation. This sometimes leads to social withdrawal, for fear of anyone getting sick or themselves catching a virus.
Not much research has been done on emetophobia and can be hard to treat for the patient that fears themselves vomiting. However, possible treatment options include Exposure Therapy and cognitive behavioral therapy.
This phobia can easily take over the sufferers life and some women have been known to terminate a pregnancy, even though they desperately want a child, as the fear of morning sickness or the child being ill is too much. People have also been known to refuse cancer treatment in case the drugs induce sickness. | Emetophobia
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Emetophobia is the irrational fear of vomiting, being around others who are vomiting, and/or the vomit itself.
In worst case scenarios, people with the phobia tend to avoid eating out, socializing and going to parties. They may hardly eat at all and that's why many are often diagnosed as anorexic, but not bulimic as this illness involves the induction of vomiting. Emetophobes will go to extraordinary lengths to avoid becoming violently sick, or seeing someone else becoming sick.
The phobia is extremely life encompassing for many; the phobia is not only felt when the person is ill, but an ongoing, constant fear that they will vomit. It can affect them day in and day out, with many sufferers reporting feelings of sickness between 5 times a month up to 30, which will induce a panic attack for many as they will believe they will actually vomit. Many emetophobes fear others vomiting too. They will constantly worry that someone near them feels sick and that they will be sick.
Emetophobics will often go into panic attacks. Symptoms of a panic attack include:
- sweating
- shivering
- clammy hands
- whimpering / even shouting
- a feeling of unreality
- a feeling of losing control
Most emetophobics will hate and/or avoid public restrooms. Also, they may feel mutual to the aspect of public transportation. This sometimes leads to social withdrawal, for fear of anyone getting sick or themselves catching a virus.
Not much research has been done on emetophobia and can be hard to treat for the patient that fears themselves vomiting. However, possible treatment options include Exposure Therapy and cognitive behavioral therapy.
This phobia can easily take over the sufferers life and some women have been known to terminate a pregnancy, even though they desperately want a child, as the fear of morning sickness or the child being ill is too much. People have also been known to refuse cancer treatment in case the drugs induce sickness. | https://www.wikidoc.org/index.php/Emetophobia | |
b3dab07b06216d5ecaee10759830c584b8a875dd | wikidoc | Enalaprilat | Enalaprilat
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# Black Box Warning
# Overview
Enalaprilat is an Angiontensin converting enzyme inhibitor that is FDA approved for the {{{indicationType}}} of hypertension, malignant hypertension and adjunct in Kidney imaging when there is underlying renovascular hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hyperkalemia, nausea, headache..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Hypertension
- Dosing Information
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limit information about the guideline-supported off-label use
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
FDA Package Insert for Enalaprilat contains no information regarding safety and efficacy in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
FDA Package Insert for Enalaprilat contains no information regarding guidelines in pediatric patients.
### Non–Guideline-Supported Use
Condition 1
- Dosing Information
- There is limited information about Off-Label Non–Guideline-Supported Use of Enalaprilat injection in pediatric patients.
# Contraindications
- History of hypersensitivity or angioedema related to previous treatment with an angiotensin converting enzyme inhibitor.
- Patients with hereditary or idiopathic angioedema.
# Warnings
### Anaphylactoid and Possibly Related Reactions
- Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including enalaprilat) may be subject to a variety of adverse reactions, some of them serious.
### Head and Neck Angioedema
- Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalaprilat. This may occur at any time during treatment. In such cases enalaprilat should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS).
### Intestinal Angioedema
- Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
### Anaphylactoid reactions during desensitization
- Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
### Anaphylactoid reactions during membrane exposure
- Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
### Hypotension
- Excessive hypotension is rare in uncomplicated hypertensive patients treated with enalaprilat alone. Patients with heart failure given enalaprilat commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy. Patients at risk for excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with enalaprilat in patients at risk for excessive hypotension who are able to tolerate such adjustments. In patients at risk for excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
- If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of enalaprilat, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of enalaprilat or concomitant diuretic may be necessary.
### Neutropenia/Agranulocytosis
- Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.
### Hepatic Failure
- Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
### Fetal/Neonatal Morbidity and Mortality
- ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
- In a published restrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been repeated.
- The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.
- These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of enalaprilat as soon as possible.
- Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.
- If oligohydramnios is observed, enalaprilat should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
- Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.
- No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD).
# Adverse Reactions
## Clinical Trials Experience
- Enalaprilat has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. enalaprilat has been found to be generally well tolerated in controlled clinical trials involving 2987 patients.
- For the most part, adverse experiences were mild and transient in nature. In clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 3.3 percent of patients with hypertension and in 5.7 percent of patients with heart failure. The frequency of adverse experiences was not related to total daily dosage within the usual dosage ranges. In patients with hypertension the overall percentage of patients treated with enalaprilat reporting adverse experiences was comparable to placebo.
### Hypertension
- Adverse experiences occurring in greater than one percent of patients with hypertension treated with enalaprilat in controlled clinical trials are shown below. In patients treated with enalaprilat, the maximum duration of therapy was three years; in placebo treated patients the maximum duration of therapy was 12 weeks.
### Heart Failure
- Adverse experiences occurring in greater than one percent of patients with heart failure treated with enalaprilat are shown below. The incidences represent the experiences from both controlled and uncontrolled clinical trials (maximum duration of therapy was approximately one year). In the placebo treated patients, the incidences reported are from the controlled trials (maximum duration of therapy is 12 weeks). The percentage of patients with severe heart failure (NYHA Class IV) was 29 percent and 43 percent for patients treated with enalaprilat and placebo, respectively.
- Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in order of decreasing severity.
- Body As A Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related Reactions).
### Cardiovascular
- Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension); pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; palpitation, Raynaud's phenomenon.
### Digestive
- Ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS, Hepatic Failure), melena, anorexia, dyspepsia, constipation, glossitis, stomatitis, dry mouth.
### Hematologic
- Rare cases of neutropenia, thrombocytopenia and bone marrow depression.
### Musculoskeletal
- Muscle cramps
### Nervous/Psychiatric
- Depression, confusion, ataxia, somnolence, insomnia, nervousness, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality.
### Respiratory
- Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection, pulmonary infiltrates, eosinophilic pneumonitis.
### Skin
- Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity.
### Special Senses
- Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing.
### Urogenital
- Renal failure, oliguria, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), flank pain, gynecomastia, impotence.
### Miscellaneous
- A symptom complex has been reported which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations.
### Angioedema
- Angioedema has been reported in patients receiving enalaprilat, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalaprilat should be discontinued and appropriate therapy instituted immediately (see WARNINGS).
### Hypotension
- In the hypertensive patients, hypotension occurred in 0.9 percent and syncope occurred in 0.5 percent of patients following the initial dose or during extended therapy. Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients. In heart failure patients, hypotension occurred in 6.7 percent and syncope occurred in 2.2 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 1.9 percent of patients with heart failure (see WARNINGS).
### Fetal/Neonatal Morbidity and Mortality
- See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
### Cough
### Pediatric Patients
- The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.
### Clinical Laboratory Test Findings
### Serum Electrolytes
- Hyperkalemia (see PRECAUTIONS), hyponatremia.
### Creatinine, Blood Urea Nitrogen
- In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with enalaprilat alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (see PRECAUTIONS). In patients with heart failure who were also receiving diuretics with or without digitalis, increases in blood urea nitrogen or serum creatinine, usually reversible upon discontinuation of enalaprilat and/or other concomitant diuretic therapy, were observed in about 11 percent of patients. Increases in blood urea nitrogen or creatinine were a cause for discontinuation in 1.2 percent of patients.
### Hematology
- Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in either hypertension or congestive heart failure patients treated with enalaprilat but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded.
### Liver Function Tests
- Elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure).
## Postmarketing Experience
FDA Package Insert for Enalaprilat contains no information regarding Postmarketing Experience.
# Drug Interactions
### Hypotension
Patients on Diuretic Therapy
- Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and DOSAGE AND ADMINISTRATION).
### Agents Causing Renin Release
- The antihypertensive effect of enalaprilat is augmented by antihypertensive agents that cause renin release (e.g., diuretics).
### Non-steroidal Anti-inflammatory Agents
- In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of enalapril may result in a further deterioration of renal function. These effects are usually reversible.
- In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalaprilat. In this study there was no evidence of a blunting of the antihypertensive action of enalaprilat. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.
### Other Cardiovascular Agents
- Enalaprilat has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine, prazosin and digoxin without evidence of clinically significant adverse interactions.
### Agents Increasing Serum Potassium
- Enalaprilat attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium sparing agents should generally not be used in patients with heart failure receiving enalaprilat.
### Lithium
- Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalaprilat and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.
### Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalaprilat.
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis.
- Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.
- There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Enalaprilat in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enalaprilat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Enalaprilat during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Enalaprilat in women who are nursing.
### Pediatric Use
FDA Package Insert for Enalaprilat contains no information regarding safety and .
### Geriatic Use
FDA Package Insert for Enalaprilat contains no information regarding Postmarketing Experience.
### Gender
FDA Package Insert for Enalaprilat contains no information regarding Postmarketing Experience.
### Race
FDA Package Insert for Enalaprilat contains no information regarding Postmarketing Experience.
### Renal Impairment
There is no FDA guidance on the use of Enalaprilat in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Enalaprilat in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Enalaprilat in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Enalaprilat in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Enalaprilat Injection should be administered as a slow intravenous infusion, as indicated above. It may be administered as provided or diluted with up to 50 mL of a compatible diluent. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit.
### Monitoring
- Angioedema
- Monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred
- Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalaprilat. This may occur at any time during treatment. In such cases, Enalaprilat Injection should be promptly discontinued and appropriate therapy and monitoring. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided.
- Neutropenia/Agranulocytosis
- Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered. As another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis in similar rates. Marketing experience has revealed cases of neutropenia, or agranulocytosis in which a causal relationship to enalapril cannot be excluded.
- Bilateral Renal Artery Stenosis
- Renal function should be monitored during the first few weeks of therapy
- In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients receiving enalapril. These increases were almost always reversible upon discontinuation of enalapril or enalaprilat and/or diuretic therapy.
- Agents Increasing Serum Potassium
- Enalaprilat Injection attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium.
- Lithium
- Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.
# IV Compatibility
- Enalaprilat Injection as supplied and mixed with the following intravenous diluents has been found to maintain full activity for 24 hours at room temperature:
- 5 percent Dextrose Injection
- 0.9 percent Sodium Chloride Injection
- 0.9 percent Sodium Chloride Injection in 5 percent Dextrose
- 5 percent Dextrose in Lactated Ringer's Injection
- B. Braun ISOLYTE*E.
# Overdosage
- In clinical studies, some hypertensive patients received a maximum dose of 80 mg of enalaprilat intravenously over a fifteen minute period. At this high dose, no adverse effects beyond those as associated with the recommended dosages were observed.
- A single intravenous dose of ≤4167 mg/kg of enalaprilat was associated with lethality in female mice. No lethality occurred after an intravenous dose of 3472 mg/kg.
- The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution.
- Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis.
# Pharmacology
There is limited information regarding Enalaprilat Pharmacology in the drug label.
## Mechanism of Action
- Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of enalapril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with enalaprilat alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalaprilat plus a thiazide diuretic, there was essentially no change in serum potassium (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
- ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of enalaprilat remains to be elucidated.
- While the mechanism through which enalaprilat lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalaprilat is antihypertensive even in patients with low-renin hypertension. Although enalaprilat was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril monotherapy than non-black patients.
## Structure
There is limited information regarding Enalaprilat Structure in the drug label.
## Pharmacodynamics
- Administration of enalaprilat to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure usually with no orthostatic component. Symptomatic postural hypotension is therefore infrequent, although it might be anticipated in volume-depleted patients (see WARNINGS).
- In most patients studied, after oral administration of a single dose of enalapril, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours.
- At recommended doses, antihypertensive effects have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval (see DOSAGE AND ADMINISTRATION).
- In some patients achievement of optimal blood pressure reduction may require several weeks of therapy.
- The antihypertensive effects of enalaprilat have continued during long term therapy. Abrupt withdrawal of enalaprilat has not been associated with a rapid increase in blood pressure.
- In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalaprilat, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension.
- When given together with thiazide-type diuretics, the blood pressure lowering effects of enalaprilat are approximately additive.
## Pharmacokinetics
- Following oral administration of VASOTEC, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately 60 percent. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Excretion of VASOTEC is primarily renal. Approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat.
- The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours.
- The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With glomerular filtration rate ≤30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency (see DOSAGE AND ADMINISTRATION). Enalaprilat is dialyzable at the rate of 62 mL/min.
- Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C-enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters.
## Nonclinical Toxicology
There is limited information regarding Enalaprilat Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Enalaprilat Clinical Studies in the drug label.
# How Supplied
Enalaprilat Injection, USP 1.25 mg per mL, is a clear, colorless solution and is supplied as follows:
## Storage
Store at 20 to 25°C (68 to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Enalaprilat Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Enalaprilat injection interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Enalaprilat Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Enalaprilat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Enalaprilat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2], Amr Marawan, M.D. [3]
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# Black Box Warning
# Overview
Enalaprilat is an Angiontensin converting enzyme inhibitor that is FDA approved for the {{{indicationType}}} of hypertension, malignant hypertension and adjunct in Kidney imaging when there is underlying renovascular hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hyperkalemia, nausea, headache..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Hypertension
- Dosing Information
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limit information about the guideline-supported off-label use
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
FDA Package Insert for Enalaprilat contains no information regarding safety and efficacy in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
FDA Package Insert for Enalaprilat contains no information regarding guidelines in pediatric patients.
### Non–Guideline-Supported Use
Condition 1
- Dosing Information
- There is limited information about Off-Label Non–Guideline-Supported Use of Enalaprilat injection in pediatric patients.
# Contraindications
- History of hypersensitivity or angioedema related to previous treatment with an angiotensin converting enzyme inhibitor.
- Patients with hereditary or idiopathic angioedema.
# Warnings
### Anaphylactoid and Possibly Related Reactions
- Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including enalaprilat) may be subject to a variety of adverse reactions, some of them serious.
### Head and Neck Angioedema
- Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalaprilat. This may occur at any time during treatment. In such cases enalaprilat should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS).
### Intestinal Angioedema
- Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
### Anaphylactoid reactions during desensitization
- Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
### Anaphylactoid reactions during membrane exposure
- Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
### Hypotension
- Excessive hypotension is rare in uncomplicated hypertensive patients treated with enalaprilat alone. Patients with heart failure given enalaprilat commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy. Patients at risk for excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with enalaprilat in patients at risk for excessive hypotension who are able to tolerate such adjustments. In patients at risk for excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
- If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of enalaprilat, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of enalaprilat or concomitant diuretic may be necessary.
### Neutropenia/Agranulocytosis
- Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.
### Hepatic Failure
- Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
### Fetal/Neonatal Morbidity and Mortality
- ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
- In a published restrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been repeated.
- The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.
- These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of enalaprilat as soon as possible.
- Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.
- If oligohydramnios is observed, enalaprilat should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
- Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.
- No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD).
# Adverse Reactions
## Clinical Trials Experience
- Enalaprilat has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. enalaprilat has been found to be generally well tolerated in controlled clinical trials involving 2987 patients.
- For the most part, adverse experiences were mild and transient in nature. In clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 3.3 percent of patients with hypertension and in 5.7 percent of patients with heart failure. The frequency of adverse experiences was not related to total daily dosage within the usual dosage ranges. In patients with hypertension the overall percentage of patients treated with enalaprilat reporting adverse experiences was comparable to placebo.
### Hypertension
- Adverse experiences occurring in greater than one percent of patients with hypertension treated with enalaprilat in controlled clinical trials are shown below. In patients treated with enalaprilat, the maximum duration of therapy was three years; in placebo treated patients the maximum duration of therapy was 12 weeks.
### Heart Failure
- Adverse experiences occurring in greater than one percent of patients with heart failure treated with enalaprilat are shown below. The incidences represent the experiences from both controlled and uncontrolled clinical trials (maximum duration of therapy was approximately one year). In the placebo treated patients, the incidences reported are from the controlled trials (maximum duration of therapy is 12 weeks). The percentage of patients with severe heart failure (NYHA Class IV) was 29 percent and 43 percent for patients treated with enalaprilat and placebo, respectively.
- Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in order of decreasing severity.
- Body As A Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related Reactions).
### Cardiovascular
- Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension); pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; palpitation, Raynaud's phenomenon.
### Digestive
- Ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice) (see WARNINGS, Hepatic Failure), melena, anorexia, dyspepsia, constipation, glossitis, stomatitis, dry mouth.
### Hematologic
- Rare cases of neutropenia, thrombocytopenia and bone marrow depression.
### Musculoskeletal
- Muscle cramps
### Nervous/Psychiatric
- Depression, confusion, ataxia, somnolence, insomnia, nervousness, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality.
### Respiratory
- Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection, pulmonary infiltrates, eosinophilic pneumonitis.
### Skin
- Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity.
### Special Senses
- Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing.
### Urogenital
- Renal failure, oliguria, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), flank pain, gynecomastia, impotence.
### Miscellaneous
- A symptom complex has been reported which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations.
### Angioedema
- Angioedema has been reported in patients receiving enalaprilat, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalaprilat should be discontinued and appropriate therapy instituted immediately (see WARNINGS).
### Hypotension
- In the hypertensive patients, hypotension occurred in 0.9 percent and syncope occurred in 0.5 percent of patients following the initial dose or during extended therapy. Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients. In heart failure patients, hypotension occurred in 6.7 percent and syncope occurred in 2.2 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 1.9 percent of patients with heart failure (see WARNINGS).
### Fetal/Neonatal Morbidity and Mortality
- See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
### Cough
### Pediatric Patients
- The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.
### Clinical Laboratory Test Findings
### Serum Electrolytes
- Hyperkalemia (see PRECAUTIONS), hyponatremia.
### Creatinine, Blood Urea Nitrogen
- In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with enalaprilat alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (see PRECAUTIONS). In patients with heart failure who were also receiving diuretics with or without digitalis, increases in blood urea nitrogen or serum creatinine, usually reversible upon discontinuation of enalaprilat and/or other concomitant diuretic therapy, were observed in about 11 percent of patients. Increases in blood urea nitrogen or creatinine were a cause for discontinuation in 1.2 percent of patients.
### Hematology
- Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in either hypertension or congestive heart failure patients treated with enalaprilat but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded.
### Liver Function Tests
- Elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure).
## Postmarketing Experience
FDA Package Insert for Enalaprilat contains no information regarding Postmarketing Experience.
# Drug Interactions
### Hypotension
Patients on Diuretic Therapy
- Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and DOSAGE AND ADMINISTRATION).
### Agents Causing Renin Release
- The antihypertensive effect of enalaprilat is augmented by antihypertensive agents that cause renin release (e.g., diuretics).
### Non-steroidal Anti-inflammatory Agents
- In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of enalapril may result in a further deterioration of renal function. These effects are usually reversible.
- In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalaprilat. In this study there was no evidence of a blunting of the antihypertensive action of enalaprilat. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.
### Other Cardiovascular Agents
- Enalaprilat has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine, prazosin and digoxin without evidence of clinically significant adverse interactions.
### Agents Increasing Serum Potassium
- Enalaprilat attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium sparing agents should generally not be used in patients with heart failure receiving enalaprilat.
### Lithium
- Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalaprilat and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.
### Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalaprilat.
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis.
- Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.
- There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Enalaprilat in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enalaprilat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Enalaprilat during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Enalaprilat in women who are nursing.
### Pediatric Use
FDA Package Insert for Enalaprilat contains no information regarding safety and .
### Geriatic Use
FDA Package Insert for Enalaprilat contains no information regarding Postmarketing Experience.
### Gender
FDA Package Insert for Enalaprilat contains no information regarding Postmarketing Experience.
### Race
FDA Package Insert for Enalaprilat contains no information regarding Postmarketing Experience.
### Renal Impairment
There is no FDA guidance on the use of Enalaprilat in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Enalaprilat in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Enalaprilat in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Enalaprilat in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Enalaprilat Injection should be administered as a slow intravenous infusion, as indicated above. It may be administered as provided or diluted with up to 50 mL of a compatible diluent. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit.
### Monitoring
- Angioedema
- Monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred
- Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalaprilat. This may occur at any time during treatment. In such cases, Enalaprilat Injection should be promptly discontinued and appropriate therapy and monitoring. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided.
- Neutropenia/Agranulocytosis
- Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered. As another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis in similar rates. Marketing experience has revealed cases of neutropenia, or agranulocytosis in which a causal relationship to enalapril cannot be excluded.
- Bilateral Renal Artery Stenosis
- Renal function should be monitored during the first few weeks of therapy
- In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients receiving enalapril. These increases were almost always reversible upon discontinuation of enalapril or enalaprilat and/or diuretic therapy.
- Agents Increasing Serum Potassium
- Enalaprilat Injection attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium.
- Lithium
- Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.
# IV Compatibility
- Enalaprilat Injection as supplied and mixed with the following intravenous diluents has been found to maintain full activity for 24 hours at room temperature:
- 5 percent Dextrose Injection
- 0.9 percent Sodium Chloride Injection
- 0.9 percent Sodium Chloride Injection in 5 percent Dextrose
- 5 percent Dextrose in Lactated Ringer's Injection
- B. Braun ISOLYTE***E.
# Overdosage
- In clinical studies, some hypertensive patients received a maximum dose of 80 mg of enalaprilat intravenously over a fifteen minute period. At this high dose, no adverse effects beyond those as associated with the recommended dosages were observed.
- A single intravenous dose of ≤4167 mg/kg of enalaprilat was associated with lethality in female mice. No lethality occurred after an intravenous dose of 3472 mg/kg.
- The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution.
- Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis.
# Pharmacology
There is limited information regarding Enalaprilat Pharmacology in the drug label.
## Mechanism of Action
- Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of enalapril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with enalaprilat alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalaprilat plus a thiazide diuretic, there was essentially no change in serum potassium (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
- ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of enalaprilat remains to be elucidated.
- While the mechanism through which enalaprilat lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalaprilat is antihypertensive even in patients with low-renin hypertension. Although enalaprilat was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril monotherapy than non-black patients.
## Structure
There is limited information regarding Enalaprilat Structure in the drug label.
## Pharmacodynamics
- Administration of enalaprilat to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure usually with no orthostatic component. Symptomatic postural hypotension is therefore infrequent, although it might be anticipated in volume-depleted patients (see WARNINGS).
- In most patients studied, after oral administration of a single dose of enalapril, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours.
- At recommended doses, antihypertensive effects have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval (see DOSAGE AND ADMINISTRATION).
- In some patients achievement of optimal blood pressure reduction may require several weeks of therapy.
- The antihypertensive effects of enalaprilat have continued during long term therapy. Abrupt withdrawal of enalaprilat has not been associated with a rapid increase in blood pressure.
- In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalaprilat, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension.
- When given together with thiazide-type diuretics, the blood pressure lowering effects of enalaprilat are approximately additive.
## Pharmacokinetics
- Following oral administration of VASOTEC, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately 60 percent. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Excretion of VASOTEC is primarily renal. Approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat.
- The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours.
- The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With glomerular filtration rate ≤30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency (see DOSAGE AND ADMINISTRATION). Enalaprilat is dialyzable at the rate of 62 mL/min.
- Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C-enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters.
## Nonclinical Toxicology
There is limited information regarding Enalaprilat Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Enalaprilat Clinical Studies in the drug label.
# How Supplied
Enalaprilat Injection, USP 1.25 mg per mL, is a clear, colorless solution and is supplied as follows:
## Storage
Store at 20 to 25°C (68 to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Enalaprilat Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Enalaprilat injection interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Enalaprilat Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Enalaprilat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Enalaprilat | |
882020dd89cecd2ad28f2cbdd09849edd3b3ff18 | wikidoc | Enamel knot | Enamel knot
In tooth development, the enamel knot is a localization of cells on an enamel organ that appear thickened in the center of the inner enamel epithelium. The enamel knot is frequently associated with an enamel cord.
# The enamel knot as signaling center
The enamel knot is a signalling center of the tooth that provides positional information for tooth morphogenesis and regulates the growth of tooth cusps. The enamel knot produces a range of molecular signals from all the major signaling families, such as Fibroblast Growth Factors (FGF), Bone morphogenetic proteins (BMP), Hedgehog (Hh) and Wnt signals. These molecular signals direct the growth of the surrounding epithelium and mesenchyme.
# Primary and secondary enamel knots
The primary enamel knot forms at the tip of the bud during the bud stage of tooth development. This primary enamel knot is removed by apoptosis. Later secondary enamel knots appear that regulate the formation of the future cusps of the teeth. | Enamel knot
In tooth development, the enamel knot is a localization of cells on an enamel organ that appear thickened in the center of the inner enamel epithelium. The enamel knot is frequently associated with an enamel cord.
# The enamel knot as signaling center
The enamel knot is a signalling center of the tooth that provides positional information for tooth morphogenesis and regulates the growth of tooth cusps. The enamel knot produces a range of molecular signals from all the major signaling families, such as Fibroblast Growth Factors (FGF), Bone morphogenetic proteins (BMP), Hedgehog (Hh) and Wnt signals. These molecular signals direct the growth of the surrounding epithelium and mesenchyme.
# Primary and secondary enamel knots
The primary enamel knot forms at the tip of the bud during the bud stage of tooth development. This primary enamel knot is removed by apoptosis. Later secondary enamel knots appear that regulate the formation of the future cusps of the teeth. | https://www.wikidoc.org/index.php/Enamel_knot | |
4c9c4d427fda5c029950f61cd366aa3a7e6e8584 | wikidoc | Endocardium | Endocardium
# Overview
In the heart, the endocardium is the innermost layer of tissue that lines the chambers of the heart. Its cells, embryologically and biologically, are similar to the endothelial cells that line blood vessels.
The endocardium overlies the much more voluminous myocardium, the muscular tissue responsible for the contraction of the heart. The outer layer of the heart is termed epicardium and the heart is surrounded by a small amount of fluid enclosed by a fibrous sac called the pericardium.
# Function
Recently, it has become evident that the endocardium, which is primarily made up of endothelial cells, controls myocardial function. This modulating role is separate from the homeometric and heterometric regulatory mechanisms that control myocardial contractility. Moreover, the endothelium of the myocardial (heart muscle) capillaries, which is also closely appositioned to the cardiomyocytes (heart muscle cells) are involved in this modulatory role. Thus, the cardiac endothelium (both the endocardial endothelium and the endothelium of the myocardial capillaries) controls the development of the heart in the embryo as well as in the adult, for example during hypertrophy. Additionally, the contractility and electrophysiological environment of the cardiomyocyte are regulated by the cardiac endothelium.
The endocardial endothelium may also act as a kind of blood-heart barrier (analogous to the blood-brain barrier), thus controlling the ionic composition of the extracellular fluid in which the cardiomyocytes bathe.
# Role in disease
In infective endocarditis, the endocardium (especially the endocardium lining the heart valves) may be affected by bacteria. | Endocardium
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In the heart, the endocardium is the innermost layer of tissue that lines the chambers of the heart. Its cells, embryologically and biologically, are similar to the endothelial cells that line blood vessels.
The endocardium overlies the much more voluminous myocardium, the muscular tissue responsible for the contraction of the heart. The outer layer of the heart is termed epicardium and the heart is surrounded by a small amount of fluid enclosed by a fibrous sac called the pericardium.
# Function
Recently, it has become evident that the endocardium, which is primarily made up of endothelial cells, controls myocardial function. This modulating role is separate from the homeometric and heterometric regulatory mechanisms that control myocardial contractility. Moreover, the endothelium of the myocardial (heart muscle) capillaries, which is also closely appositioned to the cardiomyocytes (heart muscle cells) are involved in this modulatory role. Thus, the cardiac endothelium (both the endocardial endothelium and the endothelium of the myocardial capillaries) controls the development of the heart in the embryo as well as in the adult, for example during hypertrophy. Additionally, the contractility and electrophysiological environment of the cardiomyocyte are regulated by the cardiac endothelium.
The endocardial endothelium may also act as a kind of blood-heart barrier (analogous to the blood-brain barrier), thus controlling the ionic composition of the extracellular fluid in which the cardiomyocytes bathe.
# Role in disease
In infective endocarditis, the endocardium (especially the endocardium lining the heart valves) may be affected by bacteria.
# External links
- Template:UIUCHistologySubject
- Template:OklahomaHistology - "Heart and AV valve" (atrial endocardium)
- Template:OklahomaHistology - "Heart and AV valve" (ventricular endocardium)
de:Endokard
it:Endocardio
nl:Endocard
sk:Endokard
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Endocardial | |
9864777c7d63fc0f129babfcf67da73af8d50315 | wikidoc | Endocytosis | Endocytosis
# Overview
Endocytosis is a process where cells absorb material (molecules such as proteins) from the outside by engulfing it with their cell membrane. It is used by all cells of the body because most substances important to them are large polar molecules, and thus cannot pass through the hydrophobic plasma membrane. The function of endocytosis is the opposite of exocytosis.
# Types
The absorption of material from the outside environment of the cell is commonly divided into two processes: phagocytosis and pinocytosis.
- Phagocytosis (literally, cell-eating) is the process by which cells ingest large objects, such as cells which have undergone apoptosis, bacteria, or viruses. The membrane folds around the object, and the object is sealed off into a large vacuole known as a phagosome.
- Pinocytosis (literally, cell-drinking). This process is concerned with the uptake of solutes and single molecules such as proteins.
- Receptor-mediated endocytosis is a more specific active event where the cytoplasm membrane folds inward to form coated pits. These inward budding vesicles bud to form cytoplasmic vesicles.
# Endocytosis pathways
There are three types of endocytosis: namely, macropinocytosis, caveolar endocytosis, and clathrin-mediated endocytosis.
- Macropinocytosis is the invagination of the cell membrane to form a pocket, which then pinches off into the cell to form a vesicle filled with extracellular fluid (and molecules within it). The filling of the pocket occurs in a non-specific manner. The vesicle then travels into the cytosol and fuses with other vesicles such as endosomes and lysosomes.
- Caveolae consists of the protein caveolin-1 with a bilayer enriched in cholesterol and glycolipids. Caveolae are flask-shape pits in the membrane that resemble the shape of a cave (hence the name caveolae). Uptake of extracellular molecules are also believed to be specifically mediated via receptors in caveolae.
- Clathrin-mediated endocytosis is the specific uptake of large extracellular molecules such as proteins, membrane localized receptors and ion-channels. These receptors are associated with the cytosolic protein clathrin, which initiates the formation of a vesicle by forming a crystalline coat on the inner surface of the cell's membrane.
# Clathrin-mediated endocytosis
The major route for endocytosis in most cells, and the best-understood, is that mediated by the molecule clathrin. This large protein assists in the formation of a coated pit on the inner surface of the plasma membrane of the cell. This pit then buds into the cell to form a coated vesicle in the cytoplasm of the cell. In so doing, it brings into the cell not only a small area of the surface of the cell but also a small volume of fluid from outside the cell.
Vesicles selectively concentrate and exclude certain proteins during formation and are not representative of the membrane as a whole. AP2 adaptors are multisubunit complexes that perform this function at the plasma membrane. The best-understood receptors that are found concentrated in coated vesicles of mammalian cells are the LDL receptor (which removes LDL from the blood circulation), the transferrin receptor (which brings ferric ions bound by transferrin into the cell) and certain hormone receptors (such as that for EGF).
At any one moment, about 25% of the plasma membrane of a fibroblast is made up of coated pits. As a coated pit has a life of about a minute before it buds into the cell, a fibroblast takes up its surface by this route about once every 50 minutes. Coated vesicles formed from the plasma membrane have a diameter of about 100nm and a lifetime measured in a few seconds. Once the coat has been shed, the remaining vesicle fuses with endosomes and proceeds down the endocytic pathway. The actual budding-in process, whereby a pit is converted to a vesicle, is carried out by clathrin assisted by a set of cytoplasmic proteins, which includes dynamin and adaptors such as adaptin.
Coated pits and vesicles were first seen in thin sections of tissue in the electron microscope by Thomas Roth and Keith Porter in 1964. The importance of them for the clearance of LDL from blood was discovered by R. G Anderson, Michael S. Brown and Joseph L. Goldstein in 1976. Coated vesicles were first purified by Barbara Pearse, who discovered the clathrin coat molecule, also in 1976.
# Trans-endocytosis
Trans-endocytosis is the biological process where material created in one cell undergoes endocytosis (enters) into another cell. If the material is large enough, this can be observed using an electron microscope. Trans-endocytosis from neurons to glia has been observed using time-lapse microscopy.
Trans-endocytosis also applies to molecules. For example, this process is involved when a part of the protein Notch is cleaved off and undergoes endocytosis into its neighboring cell. Without Notch trans-endocytosis, there would be too many neurons in a developing embryo. Trans-endocytosis is also involved in cell movement when the protein ephrin is bound by its receptor from a neighboring cell. | Endocytosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Endocytosis is a process where cells absorb material (molecules such as proteins) from the outside by engulfing it with their cell membrane. It is used by all cells of the body because most substances important to them are large polar molecules, and thus cannot pass through the hydrophobic plasma membrane. The function of endocytosis is the opposite of exocytosis.
# Types
The absorption of material from the outside environment of the cell is commonly divided into two processes: phagocytosis and pinocytosis.
- Phagocytosis (literally, cell-eating) is the process by which cells ingest large objects, such as cells which have undergone apoptosis, bacteria, or viruses. The membrane folds around the object, and the object is sealed off into a large vacuole known as a phagosome.
- Pinocytosis (literally, cell-drinking). This process is concerned with the uptake of solutes and single molecules such as proteins.
- Receptor-mediated endocytosis is a more specific active event where the cytoplasm membrane folds inward to form coated pits. These inward budding vesicles bud to form cytoplasmic vesicles.
# Endocytosis pathways
There are three types of endocytosis: namely, macropinocytosis, caveolar endocytosis, and clathrin-mediated endocytosis.
- Macropinocytosis is the invagination of the cell membrane to form a pocket, which then pinches off into the cell to form a vesicle filled with extracellular fluid (and molecules within it). The filling of the pocket occurs in a non-specific manner. The vesicle then travels into the cytosol and fuses with other vesicles such as endosomes and lysosomes.
- Caveolae consists of the protein caveolin-1 with a bilayer enriched in cholesterol and glycolipids. Caveolae are flask-shape pits in the membrane that resemble the shape of a cave (hence the name caveolae). Uptake of extracellular molecules are also believed to be specifically mediated via receptors in caveolae.
- Clathrin-mediated endocytosis is the specific uptake of large extracellular molecules such as proteins, membrane localized receptors and ion-channels. These receptors are associated with the cytosolic protein clathrin, which initiates the formation of a vesicle by forming a crystalline coat on the inner surface of the cell's membrane.
# Clathrin-mediated endocytosis
The major route for endocytosis in most cells, and the best-understood, is that mediated by the molecule clathrin. This large protein assists in the formation of a coated pit on the inner surface of the plasma membrane of the cell. This pit then buds into the cell to form a coated vesicle in the cytoplasm of the cell. In so doing, it brings into the cell not only a small area of the surface of the cell but also a small volume of fluid from outside the cell.
Vesicles selectively concentrate and exclude certain proteins during formation and are not representative of the membrane as a whole. AP2 adaptors are multisubunit complexes that perform this function at the plasma membrane. The best-understood receptors that are found concentrated in coated vesicles of mammalian cells are the LDL receptor (which removes LDL from the blood circulation), the transferrin receptor (which brings ferric ions bound by transferrin into the cell) and certain hormone receptors (such as that for EGF).
At any one moment, about 25% of the plasma membrane of a fibroblast is made up of coated pits. As a coated pit has a life of about a minute before it buds into the cell, a fibroblast takes up its surface by this route about once every 50 minutes. Coated vesicles formed from the plasma membrane have a diameter of about 100nm and a lifetime measured in a few seconds. Once the coat has been shed, the remaining vesicle fuses with endosomes and proceeds down the endocytic pathway. The actual budding-in process, whereby a pit is converted to a vesicle, is carried out by clathrin assisted by a set of cytoplasmic proteins, which includes dynamin and adaptors such as adaptin.
Coated pits and vesicles were first seen in thin sections of tissue in the electron microscope by Thomas Roth and Keith Porter in 1964. The importance of them for the clearance of LDL from blood was discovered by R. G Anderson, Michael S. Brown and Joseph L. Goldstein in 1976. Coated vesicles were first purified by Barbara Pearse, who discovered the clathrin coat molecule, also in 1976.
# Trans-endocytosis
Trans-endocytosis is the biological process where material created in one cell undergoes endocytosis (enters) into another cell. If the material is large enough, this can be observed using an electron microscope.[1] Trans-endocytosis from neurons to glia has been observed using time-lapse microscopy.[2]
Trans-endocytosis also applies to molecules. For example, this process is involved when a part of the protein Notch is cleaved off and undergoes endocytosis into its neighboring cell.[3][4] Without Notch trans-endocytosis, there would be too many neurons in a developing embryo.[5] Trans-endocytosis is also involved in cell movement when the protein ephrin is bound by its receptor from a neighboring cell.[6] | https://www.wikidoc.org/index.php/Endocytosis | |
5acdac0c085a9287a8a90b3a53805b382f2d73b2 | wikidoc | Endodontics | Endodontics
# Overview
Endodontics is a specialty of dentistry, that deals with the tooth pulp and tissues surrounding the root of a tooth. The pulp (containing nerves, arterioles and venules as well as lymphatic tissue and fibrous tissue) can become diseased or injured and thus is unable to repair itself. The pulp then dies and endodontic treatment is required. The word comes from the Greek words endo meaning inside and odons meaning tooth. Literally taken, it means study of that which is "inside the tooth".
Endodontists are dentists who have specialized in this field. Typically they have completed an additional 2-3 years of training following dental school. Many endodontic residents do original research and earn a Master's degree as well as a specialty certificate. They specialize and limit their practice to root canal therapy and root canal surgery. Patients requiring root canal therapy are either referred by their general dentists to the endodontist or are self referred. Root canal therapy is also a standard procedure for general dentists.
The most common procedure done in endodontics is root-canal therapy. This procedure aims to save a tooth that would otherwise be extracted (pulled) due to infection caused by decay (a cavity in the tooth), a large filling, or trauma to the tooth. Root canal therapy involves the removal of diseased pulp tissue inside the tooth (the area inside the tooth that becomes infected due to the aforementioned reasons). The aim of treatment is to remove irreversibly inflamed, or necrotic pulp tissue before infection sets in (or after it has already set in). When the pulp tissue becomes infected, caused by bacteria from inside the tooth, the infection can leak out of the tooth's root and make the surrounding bone ill and painful or cause an abscess to form. Once the diseased pulp tissues are removed, the body's defense system can then repair the damage created by disease. Usually, this will require 2-3 visits to your dentist. The dentist will use a local anesthetic to make the procedure pain-free. In most places, it is considered a standard of care to use a rubber dam in order to isolate the tooth and provide a clean environment. An opening is made on the top of the tooth. Then the pulp chamber and root canals are cleaned and shaped for filling and sealing. Often, an intra-pulpal medicament to inhibit bacterial growth is placed and the tooth is filled with a temporary restoration until the second appointment, where the temporary restoration and medicament are removed and the canal(s) are sealed with gutta-percha--thus completing the procedure. Increasingly, however, endodontic treatment is being performed in one appointment as clinicians are finding fewer incidents of infection and pain with one-appointment vs. two appointment treatment.
Other procedures practiced in endodontics include incision for drainage and periradicular surgery. These treatments are needed in cases of abscesses, root fractures, and problematic tooth anatomy. | Endodontics
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Endodontics is a specialty of dentistry, that deals with the tooth pulp and tissues surrounding the root of a tooth. The pulp (containing nerves, arterioles and venules as well as lymphatic tissue and fibrous tissue) can become diseased or injured and thus is unable to repair itself. The pulp then dies and endodontic treatment is required. The word comes from the Greek words endo meaning inside and odons meaning tooth. Literally taken, it means study of that which is "inside the tooth".
Endodontists are dentists who have specialized in this field. Typically they have completed an additional 2-3 years of training following dental school. Many endodontic residents do original research and earn a Master's degree as well as a specialty certificate. They specialize and limit their practice to root canal therapy and root canal surgery. Patients requiring root canal therapy are either referred by their general dentists to the endodontist or are self referred. Root canal therapy is also a standard procedure for general dentists.
The most common procedure done in endodontics is root-canal therapy. This procedure aims to save a tooth that would otherwise be extracted (pulled) due to infection caused by decay (a cavity in the tooth), a large filling, or trauma to the tooth. Root canal therapy involves the removal of diseased pulp tissue inside the tooth (the area inside the tooth that becomes infected due to the aforementioned reasons). The aim of treatment is to remove irreversibly inflamed, or necrotic pulp tissue before infection sets in (or after it has already set in). When the pulp tissue becomes infected, caused by bacteria from inside the tooth, the infection can leak out of the tooth's root and make the surrounding bone ill and painful or cause an abscess to form. Once the diseased pulp tissues are removed, the body's defense system can then repair the damage created by disease. Usually, this will require 2-3 visits to your dentist. The dentist will use a local anesthetic to make the procedure pain-free. In most places, it is considered a standard of care to use a rubber dam in order to isolate the tooth and provide a clean environment. An opening is made on the top of the tooth. Then the pulp chamber and root canals are cleaned and shaped for filling and sealing. Often, an intra-pulpal medicament to inhibit bacterial growth is placed and the tooth is filled with a temporary restoration until the second appointment, where the temporary restoration and medicament are removed and the canal(s) are sealed with gutta-percha--thus completing the procedure. Increasingly, however, endodontic treatment is being performed in one appointment as clinicians are finding fewer incidents of infection and pain with one-appointment vs. two appointment treatment.
Other procedures practiced in endodontics include incision for drainage and periradicular surgery. These treatments are needed in cases of abscesses, root fractures, and problematic tooth anatomy. | https://www.wikidoc.org/index.php/Endodontic | |
b0d053315a9094b8e4784146b40aee024c56d28f | wikidoc | Endometrium | Endometrium
# Overview
The endometrium is the inner membrane of the mammalian uterus.
# Function
The endometrium functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a thick, blood vessel rich, glandular tissue layer. This represents an optimal environment for the implantation of a blastocyst upon its arrival in the uterus.
During pregnancy, the glands and blood vessels in the endometrium further increase in size and number. Vascular spaces fuse and become interconnected, forming the placenta, which supplies oxygen and nutrition to the embryo and fetus.
# Cycle
The endometrial lining undergoes cyclic regeneration. Humans and the great apes display the menstrual cycle, whereas most other mammals are subject to an estrous cycle. In both cases, the endometrium initially proliferates under the influence of estrogen. However, once ovulation occurs, in addition to estrogen, the ovary will also start to produce progesterone. This changes the proliferative pattern of the endometrium to a secretory lining. Eventually, the secretory lining provides a hospitable environment for one or more blastocysts.
If no blastocyst is detected, the progesterone level drops and the endometrial lining is either reabsorbed (estrous cycle) or shed (menstrual cycle). In the latter case, the process of shedding involves the breaking down of the lining, the tearing of small connective blood vessels, and the loss of the tissue and blood that had constituted it through the vagina. The entire process occurs over a period of several days. Menstruation may be accompanied by a series of uterine contractions; these help expel the menstrual endometrium.
In case of implantation, however, the endometrial lining is neither absorbed nor shed. Instead, it remains as decidua. The decidua becomes part of the placenta; it provides support and protection for the gestation.
If there is inadequate stimulation of the lining, due to lack of hormones, the endometrium remains thin and inactive. In humans, this will result in amenorrhea. After menopause, the lining is often described as being atrophic. In contrast, endometrium that is chronically exposed to estrogens, but not to progesterone, may become hyperplastic.
In humans, the cycle of building and shedding the endometrial lining lasts an average of 28 days. The endometrium develops at different rates in different mammals. Its formation is sometimes affected by seasons, climate, stress and other factors. The endometrium itself produces certain hormones at different points along the cycle. This affects other portions of the reproductive system.
# Histology
The endometrium consists of a single layer of columnar epithelium, resting on a layer of connective tissue which varies in thickness according to hormonal influences - the stroma. Simple tubular uterine glands reach from the endometrial surface through to the base of the stroma, which also carries a rich blood supply of spiral arteries. In a woman of reproductive age, two layers of endometrium can be distinguished. These two layers occur only in endometrium lining the cavity of the uterus, not in the lining of the Fallopian tubes:
- The functional layer is adjacent to the uterine cavity. This layer is built up after the end of menstruation during the first part of the previous menstrual cycle. Proliferation is induced by progesterone (follicular phase of menstrual cycle), and later increased by the progestrone from the corpus luteum (luteal phase). It is adapted to provide an optimum environment for the implantation and growth of the embryo. This layer is completely shed during menstruation.
- The basal layer, adjacent to the myometrium and below the functional layer, is not shed at any time during the menstrual cycle, and from it the functional layer develops.
In the absence of progesterone, the arteries supplying blood to the functional layer constrict, so that cells in that layer become ischaemic and die, leading to menstruation.
It is possible to identify the phase of the menstrual cycle by observing histological differences at each phase:
# Pathological conditions
Adenomyosis is the growth of the endometrium into the muscle layer of the uterus (the myometrium).
Endometriosis is the growth of endometrial tissue outside the uterus.
Endometrial cancer is the most common cancer of the human female genital tract. | Endometrium
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The endometrium is the inner membrane of the mammalian uterus.
# Function
The endometrium functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a thick, blood vessel rich, glandular tissue layer. This represents an optimal environment for the implantation of a blastocyst upon its arrival in the uterus.
During pregnancy, the glands and blood vessels in the endometrium further increase in size and number. Vascular spaces fuse and become interconnected, forming the placenta, which supplies oxygen and nutrition to the embryo and fetus.
# Cycle
The endometrial lining undergoes cyclic regeneration. Humans and the great apes display the menstrual cycle, whereas most other mammals are subject to an estrous cycle. In both cases, the endometrium initially proliferates under the influence of estrogen. However, once ovulation occurs, in addition to estrogen, the ovary will also start to produce progesterone. This changes the proliferative pattern of the endometrium to a secretory lining. Eventually, the secretory lining provides a hospitable environment for one or more blastocysts.
If no blastocyst is detected, the progesterone level drops and the endometrial lining is either reabsorbed (estrous cycle) or shed (menstrual cycle). In the latter case, the process of shedding involves the breaking down of the lining, the tearing of small connective blood vessels, and the loss of the tissue and blood that had constituted it through the vagina. The entire process occurs over a period of several days. Menstruation may be accompanied by a series of uterine contractions; these help expel the menstrual endometrium.
In case of implantation, however, the endometrial lining is neither absorbed nor shed. Instead, it remains as decidua. The decidua becomes part of the placenta; it provides support and protection for the gestation.
If there is inadequate stimulation of the lining, due to lack of hormones, the endometrium remains thin and inactive. In humans, this will result in amenorrhea. After menopause, the lining is often described as being atrophic. In contrast, endometrium that is chronically exposed to estrogens, but not to progesterone, may become hyperplastic.
In humans, the cycle of building and shedding the endometrial lining lasts an average of 28 days. The endometrium develops at different rates in different mammals. Its formation is sometimes affected by seasons, climate, stress and other factors. The endometrium itself produces certain hormones at different points along the cycle. This affects other portions of the reproductive system.
# Histology
The endometrium consists of a single layer of columnar epithelium, resting on a layer of connective tissue which varies in thickness according to hormonal influences - the stroma. Simple tubular uterine glands reach from the endometrial surface through to the base of the stroma, which also carries a rich blood supply of spiral arteries. In a woman of reproductive age, two layers of endometrium can be distinguished. These two layers occur only in endometrium lining the cavity of the uterus, not in the lining of the Fallopian tubes:[1]
- The functional layer is adjacent to the uterine cavity. This layer is built up after the end of menstruation during the first part of the previous menstrual cycle. Proliferation is induced by progesterone (follicular phase of menstrual cycle), and later increased by the progestrone from the corpus luteum (luteal phase). It is adapted to provide an optimum environment for the implantation and growth of the embryo. This layer is completely shed during menstruation.
- The basal layer, adjacent to the myometrium and below the functional layer, is not shed at any time during the menstrual cycle, and from it the functional layer develops.
In the absence of progesterone, the arteries supplying blood to the functional layer constrict, so that cells in that layer become ischaemic and die, leading to menstruation.
It is possible to identify the phase of the menstrual cycle by observing histological differences at each phase:
# Pathological conditions
Adenomyosis is the growth of the endometrium into the muscle layer of the uterus (the myometrium).
Endometriosis is the growth of endometrial tissue outside the uterus.
Endometrial cancer is the most common cancer of the human female genital tract. | https://www.wikidoc.org/index.php/Endometrial | |
4dfe90d0fe1442b0680596a9a8336099a9f4e21d | wikidoc | Endothelium | Endothelium
The endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary. These cells reduce friction of the flow of blood allowing the fluid to be pumped further.
Endothelial tissue is a specialized type of epithelium tissue (one of the four types of biological tissue in animals). More specifically, it is simple squamous epithelium.
Endothelium of the interior surfaces of the heart chambers are called endocardium. Both blood and lymphatic capillaries are composed of a single layer of endothelial cells.
# Function
Endothelial cells are involved in many aspects of vascular biology, including:
- vasoconstriction and vasodilation, and hence the control of blood pressure
- blood clotting (thrombosis & fibrinolysis)
- atherosclerosis
- formation of new blood vessels (angiogenesis)
- inflammation and swelling (oedema)
Endothelial cells also control the passage of materials — and the transit of white blood cells — into and out of the bloodstream.
In some organs, there are highly differentiated endothelial cells to perform specialized 'filtering' functions. Examples of such unique endothelial structures include the renal glomerulus and the blood-brain barrier.
# Pathology
Endothelial dysfunction, or the loss of proper endothelial function, is a hallmark for vascular diseases, and often leads to atherosclerosis. This is very common in patients with diabetes mellitus, hypertension or other chronic pathophysiological conditions. One of the main mechanisms of endothelial dysfunction is the diminishing of nitric oxide, often due to high levels of asymmetric dimethylarginine, which interfere with the normal L-arginine-stimulated nitric oxide synthesis. | Endothelium
Template:WikiDoc Cardiology News
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary. These cells reduce friction of the flow of blood allowing the fluid to be pumped further.
Endothelial tissue is a specialized type of epithelium tissue (one of the four types of biological tissue in animals). More specifically, it is simple squamous epithelium.
Endothelium of the interior surfaces of the heart chambers are called endocardium. Both blood and lymphatic capillaries are composed of a single layer of endothelial cells.
# Function
Endothelial cells are involved in many aspects of vascular biology, including:
- vasoconstriction and vasodilation, and hence the control of blood pressure
- blood clotting (thrombosis & fibrinolysis)
- atherosclerosis
- formation of new blood vessels (angiogenesis)
- inflammation and swelling (oedema)
Endothelial cells also control the passage of materials — and the transit of white blood cells — into and out of the bloodstream.
In some organs, there are highly differentiated endothelial cells to perform specialized 'filtering' functions. Examples of such unique endothelial structures include the renal glomerulus and the blood-brain barrier.
# Pathology
Endothelial dysfunction, or the loss of proper endothelial function, is a hallmark for vascular diseases, and often leads to atherosclerosis. This is very common in patients with diabetes mellitus, hypertension or other chronic pathophysiological conditions. One of the main mechanisms of endothelial dysfunction is the diminishing of nitric oxide, often due to high levels of asymmetric dimethylarginine, which interfere with the normal L-arginine-stimulated nitric oxide synthesis. | https://www.wikidoc.org/index.php/Endothelial | |
a2c89f541b91859ec876665802399b8e15988f84 | wikidoc | Endothermic | Endothermic
In thermodynamics, the word endothermic "within heating" describes a process or reaction that absorbs energy in the form of heat. Its etymology stems from the Greek prefix endo-, meaning “inside” and the Greek suffix –thermic, meaning “to heat”. The opposite of an endothermic process is an exothermic process, one that releases energy in the form of heat. The term “endothermic” was coined by Marcellin Berthelot.
The concept is frequently applied in physical sciences to e.g. chemical reactions, where chemical bond energy is converted to thermal energy (heat).
# Overview
Endothermic, also known as endergonic, refers to a transformation in which a system receives heat from the surroundings:
When the transformation occurs at constant pressure:
and constant volume:
If the surroundings do not supply heat (e.g., when the system is adiabatic), an endothermic transformation leads to a decrease in the temperature of the system.
## Endothermic processes
Some examples of endothermic processes are:
- Melting of ice
- Depressurising a pressure can
# Implications for chemical reactions
Chemical endothermic reactions need heat to be performed. In a thermochemical reaction that is endothermic, the heat is placed on the reactants side (heat is necessary for and absorbed during the reaction).
# Applications of endothermic processes
## Endothermic materials in passive fire protection
Endothermic substances, both natural, e.g. gypsum, and synthetic, e.g. resin-based intumescents, are popular for use in heatshielding, ablation, materials in space physics, fireproofing, e.g. fire-resistive coatings for LPG vessels, and compartmentalisation of fire in buildings, which is the cornerstone of passive fire protection. Typically, the technological basis is the conversion of hydrates, or chemically bound water into vapour, or steam. | Endothermic
In thermodynamics, the word endothermic "within heating" describes a process or reaction that absorbs energy in the form of heat. Its etymology stems from the Greek prefix endo-, meaning “inside” and the Greek suffix –thermic, meaning “to heat”. The opposite of an endothermic process is an exothermic process, one that releases energy in the form of heat. The term “endothermic” was coined by Marcellin Berthelot.
The concept is frequently applied in physical sciences to e.g. chemical reactions, where chemical bond energy is converted to thermal energy (heat).
# Overview
Endothermic, also known as endergonic, refers to a transformation in which a system receives heat from the surroundings:
When the transformation occurs at constant pressure:
and constant volume:
If the surroundings do not supply heat (e.g., when the system is adiabatic), an endothermic transformation leads to a decrease in the temperature of the system.[1]
## Endothermic processes
Some examples of endothermic processes are:[2]
- Melting of ice
- Depressurising a pressure can
# Implications for chemical reactions
Chemical endothermic reactions need heat to be performed. In a thermochemical reaction that is endothermic, the heat is placed on the reactants side (heat is necessary for and absorbed during the reaction).
# Applications of endothermic processes
## Endothermic materials in passive fire protection
Endothermic substances, both natural, e.g. gypsum, and synthetic, e.g. resin-based intumescents, are popular for use in heatshielding, ablation, materials in space physics, fireproofing, e.g. fire-resistive coatings for LPG vessels, and compartmentalisation of fire in buildings, which is the cornerstone of passive fire protection. Typically, the technological basis is the conversion of hydrates, or chemically bound water into vapour, or steam. | https://www.wikidoc.org/index.php/Endothermic | |
d67e2b9588fbb6d9f542a46f0094f0b4b7a6e6f7 | wikidoc | Energy form | Energy form
In the context of physical sciences, several forms of energy have been defined. These include:
- Thermal energy popularly known as heat
- Chemical energy
- Electrical energy
- Radiant energy commonly known as light energy
- Nuclear energy
- Magnetic energy
- Elastic energy
- Sound Energy
- Gravitational energy
- Renewable energy
- Non-renewable energy
Some basic textbooks group all these forms of energy into two broad categories: kinetic energy and potential energy. However, some forms of energy resist such easy classification, as is the case with light energy. Other familiar types of energy (such as heat in most circumstances) are a varying mix of both potential and kinetic energy.
However, the above set of the possible forms of energy is not a closed set. Whenever physical scientists discover that certain phenomenon appears to violate the law of energy conservation, new forms can be added, as is the case with dark energy.
# Notes and references
- ↑ A Glossary of Frequently Misused or Misunderstood Physics Terms and Concepts
sl:Oblike energije | Energy form
In the context of physical sciences, several forms of energy have been defined. These include:
- Thermal energy popularly known as heat
- Chemical energy
- Electrical energy
- Radiant energy commonly known as light energy
- Nuclear energy
- Magnetic energy
- Elastic energy
- Sound Energy
- Gravitational energy
- Renewable energy
- Non-renewable energy
Some basic textbooks group all these forms of energy into two broad categories:[1] kinetic energy and potential energy. However, some forms of energy resist such easy classification, as is the case with light energy. Other familiar types of energy (such as heat in most circumstances) are a varying mix of both potential and kinetic energy.
However, the above set of the possible forms of energy is not a closed set. Whenever physical scientists discover that certain phenomenon appears to violate the law of energy conservation, new forms can be added, as is the case with dark energy.
# Notes and references
- ↑ A Glossary of Frequently Misused or Misunderstood Physics Terms and Concepts
sl:Oblike energije | https://www.wikidoc.org/index.php/Energy_form | |
b3002dc19e38e34c17231b24ef77c98b587a4528 | wikidoc | Enfuvirtide | Enfuvirtide
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# Overview
Enfuvirtide is a HIV-1 fusion inhibitor that is FDA approved for the treatment of HIV-1 infection in treatment-experienced patients with HIV-1 replication despite ongoing antiretroviral therapy. Common adverse reactions include local injection site reactions, diarrhea, nausea, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site, and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial section of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars, tattoos or burn sites. Additional detailed information regarding the administration of FUZEON is described in the FUZEON Injection Instructions.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Enfuvirtide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Enfuvirtide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Insufficient data are available to establish a dose recommendation of FUZEON in pediatric patients below the age of 6 years. In pediatric patients 6 years through 16 years of age, the recommended dosage of FUZEON is 2 mg/kg twice daily up to a maximum dose of 90 mg twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected into moles, scar tissue, bruises or the navel. Table 1 contains dosing guidelines for FUZEON based on body weight. Weight should be monitored periodically and the FUZEON dose adjusted accordingly.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Enfuvirtide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Enfuvirtide in pediatric patients.
# Contraindications
- FUZEON is contraindicated in patients with known hypersensitivity to FUZEON or any of its components.
# Warnings
### Precautions
- Local Injection Site Reactions (ISRs)
- The majority of subjects (98%) receiving FUZEON in randomized, controlled, open-label, multicenter clinical trials had at least one local injection site reaction; ISRs occurred throughout treatment with FUZEON. Manifestations may include pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis. Reactions are often present at more than one injection site. Patients must be familiar with the FUZEON Injection Instructions in order to know how to inject FUZEON appropriately and how to monitor carefully for signs or symptoms of cellulitis or local infection.
- Administration with Biojector® 2000
- Nerve pain (neuralgia and/or paresthesia) lasting up to 6 months associated with administration at anatomical sites where large nerves course close to the skin, bruising and hematomas have occurred with use of the Biojector 2000 needle-free device for administration of FUZEON. Patients receiving anticoagulants or persons with hemophilia, or other coagulation disorders, may have a higher risk of post-injection bleeding.
- Pneumonia
- An increased rate of bacterial pneumonia was observed in subjects treated with FUZEON in the Phase 3 clinical trials compared to the control arm. The incidence of pneumonia was 2.7% or 3.2 events/100 patient-years in subjects receiving FUZEON+background regimen. On analysis of all diagnoses of pneumonia (pneumonia, bacterial pneumonia, bronchopneumonia, and related terms) in T20-301 and T20-302, an increased rate of bacterial pneumonia was observed in subjects treated with FUZEON compared to the control arm (6.9%, 6.7 pneumonia events per 100 patient-years versus 0.6 events per 100 patient-years, respectively). Approximately half of the study subjects with pneumonia required hospitalization. Three subject deaths in the FUZEON arm were attributed to pneumonia; all three had serious concomitant AIDS-related illnesses that contributed to their deaths. Risk factors for pneumonia included low initial CD4 lymphocyte count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease.
- Because it was unclear whether the higher incidence rate of pneumonia was related to FUZEON use, an observational study in 1850 HIV-infected patients (740 FUZEON treated patients and 1110 non-FUZEON treated patients) was conducted to evaluate the risk of pneumonia in patients treated with FUZEON. A total of 123 patients had a confirmed or probable pneumonia event in this study (62 in the FUZEON treatment arm with 1962 patient-years of observation and 61 in the non-FUZEON treatment arm with 3378 patient-years of observation). The incidence of pneumonia was 3.2 events/100 patient-years in the FUZEON treatment arm and 1.8 events/100 patient-years in the non-FUZEON treatment arm. The hazard ratio, adjusting for other baseline risk factors, was 1.34 (95% C.I. = 0.90 – 2.00). Based on this observational study, it is not possible to exclude an increased risk of pneumonia in patients treated with FUZEON compared to non-FUZEON treated patients.
- It is unclear if the increased incidence of pneumonia is related to FUZEON use. However, because of these findings, patients with HIV-1 infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions which may predispose them to pneumonia. Risk factors for pneumonia included low initial CD4 cell count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease.
- Hypersensitivity Reactions
- Systemic hypersensitivity reactions have been associated with FUZEON therapy and may recur on re-challenge. Hypersensitivity reactions have occurred in <1% of subjects studied and have included combinations of: rash, fever, nausea and vomiting, chills, rigors, hypotension, and/or elevated serum liver transaminases. Other adverse events that may be immune mediated and have been reported in subjects receiving FUZEON include primary immune complex reaction, respiratory distress, glomerulonephritis, and Guillain-Barre syndrome. Patients developing signs and symptoms suggestive of a systemic hypersensitivity reaction should discontinue FUZEON and should seek medical evaluation immediately. Therapy with FUZEON should not be restarted following systemic signs and symptoms consistent with a hypersensitivity reaction. Risk factors that may predict the occurrence or severity of hypersensitivity to FUZEON have not been identified.
- Non-HIV Infected Individuals
- There is a theoretical risk that FUZEON use may lead to the production of anti-enfuvirtide antibodies which cross react with HIV gp41. This could result in a false positive HIV test with an ELISA assay; a confirmatory western blot test would be expected to be negative. FUZEON has not been studied in non-HIV infected individuals.
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FUZEON. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The overall safety profile of FUZEON is based on 2131 subjects who received at least 1 dose of FUZEON during various clinical trials. This includes 2051 adults, 658 of whom received the recommended dose for greater than 48 weeks, and 63 pediatric subjects.
- Assessment of treatment-emergent adverse events is based on the pooled data from the two randomized, controlled, open-label, multicenter trials in treatment-experienced subjects, T20-301 (TORO 1) and T20-302 (TORO 2).
- Local Injection Site Reactions
- Local injection site reactions were the most frequent adverse events associated with the use of FUZEON. In T20-301 and T20-302, 98% of subjects had at least one local injection site reaction (ISR). A total of 7% of subjects discontinued treatment with FUZEON because of ISRs (4%) or difficulties with injecting FUZEON (3%) such as injection fatigue and inconvenience. Eighty-five percent of subjects experienced their first ISR during the initial week of treatment; ISRs continued to occur throughout treatment with FUZEON. For most subjects the severity of signs and symptoms associated with ISRs did not change during the 48 weeks of treatment. The majority of ISRs were associated with erythema, induration, the presence of nodules or cysts, and mild to moderate pain at the injection site (Table 2). In addition, the average duration of individual ISRs was between three and seven days in 41% of subjects and more than seven days in 24% of subjects. Also, the numbers of ISRs per subject at any one time was between six to 14 ISRs in 26% of subjects and more than 14 ISRs in 1.3% of subjects. Infection at the injection site (including abscess and cellulitis) was reported in 1.7% of adult subjects.
- Other Adverse Events
- In T20-301 and T20-302, after study week 8, subjects on background alone who met protocol defined criteria for virological failure were permitted to revise their background regimens and add FUZEON. Exposure on FUZEON+background was 557 patient-years, and to background alone 162 patient-years. Due to this difference in exposure, safety results are expressed as the number of patients with an adverse event per 100 patient-years of exposure. For FUZEON+background, adverse events are also displayed by percent of subjects.
- The events most frequently reported in subjects receiving FUZEON+background regimen, excluding ISRs, were diarrhea (38 per 100 patient-years or 31.7%), nausea (27 per 100 patient-years or 22.8%), and fatigue (24 per 100 patient-years or 20.2%). These events were also commonly observed in subjects that received background regimen alone: diarrhea (73 per 100 patient-years), nausea (50 per 100 patient-years), and fatigue (38 per 100 patient-years).
- Treatment-emergent adverse events, regardless of causality and excluding ISRs, from Phase 3 studies are summarized for adult subjects, in Table 3. Any Grade 2 or above events occurring at ≥2 percent of subjects and at a higher rate in subjects treated with FUZEON are summarized in Table 3; events that occurred at a higher rate in the control arms are not displayed.
- Rates of adverse events for subjects who switched to FUZEON after virological failure were similar.
- Less Common Events
- The following adverse events have been reported in 1 or more subjects; however, a causal relationship to FUZEON has not been established.
Worsening abacavir hypersensitivity reaction
Glomerulonephritis; tubular necrosis; renal insufficiency; renal failure (including fatal cases)
Thrombocytopenia; neutropenia; fever; lymphadenopathy
Hyperglycemia
Sepsis; herpes simplex
Taste disturbance; Guillain-Barre syndrome (fatal); sixth nerve palsy; peripheral neuropathy
Unstable angina pectoris
Constipation; abdominal pain upper
Asthenia
Toxic hepatitis; hepatic steatosis
Increased amylase; increased lipase; increased AST; increased GGT; increased triglycerides
Insomnia; depression; anxiety; suicide attempt
Pneumopathy; respiratory distress; cough
Pruritus
- Adverse Events in Pediatric Patients
- FUZEON has been studied in 63 pediatric subjects 5 through 16 years of age with duration of FUZEON exposure ranging from 1 dose to 134 weeks. Adverse experiences seen during clinical trials were similar to those observed in adult subjects, although infections at site of injection (cellulitis or abscess) were more frequent in adolescents than in adults, with 4 events occurring in 3 of 28 (11%) subjects.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Enfuvirtide in the drug label.
# Drug Interactions
- Potential for FUZEON to Affect Other Drugs
- Based on the results from an in vitro human microsomal study, enfuvirtide is not an inhibitor of CYP450 enzymes. In an in vivo human metabolism study (N=12), FUZEON at the recommended dose of 90 mg twice daily did not alter the metabolism of CYP3A4, CYP2D6, CYP1A2, CYP2C19 or CYP2E1 substrates.
- Potential for Other Drugs to Affect Enfuvirtide
- Based on the available data, co-administration of FUZEON and other drugs which are inducers or inhibitors of CYP450 is not expected to alter the pharmacokinetics of enfuvirtide. No dose adjustments are needed when FUZEON is co-administered with other antiretroviral and non-antiretroviral drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies have been performed in rats and rabbits at doses up to 27 times and 3.2 times the adult human dose on a m2 basis and have revealed no evidence of impaired fertility or harm to the fetus due to enfuvirtide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
- Antiretroviral Pregnancy Registry
- To monitor maternal-fetal outcomes of pregnant women exposed to FUZEON and other antiretroviral drugs, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enfuvirtide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Enfuvirtide during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breast-feed their infants to avoid the risk of postnatal transmission of HIV. It is not known whether enfuvirtide is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving FUZEON.
- Studies where radio-labeled 3H-enfuvirtide was administered to lactating rats indicated that radioactivity was present in the milk. It is not known whether the radioactivity in the milk was from radio-labeled enfuvirtide or from radio-labeled metabolites of enfuvirtide (i.e., amino acids and peptide fragments).
### Pediatric Use
- The safety and pharmacokinetics of FUZEON have been evaluated in the age groups of 6 to 16 years of age supported by evidence from adequate and well-controlled studies of FUZEON in adults. Limited efficacy data are available in pediatric subjects 6 years of age and older.
- Sixty-three HIV-1 infected pediatric subjects ages 5 through 16 years have received FUZEON in two open-label, single-arm clinical trials. Adverse experiences, including ISRs, were similar to those observed in adult subjects.
- T20-204 was an open-label, multicenter trial that evaluated the safety and antiviral activity of FUZEON in treatment-experienced pediatric subjects. Eleven subjects from 6 to 12 years were enrolled (median age of 9 years). Median baseline CD4 cell count was 495 cells/µL and the median baseline HIV-1 RNA was 4.6 log10 copies/mL.
- Ten of the 11 study subjects completed 48 weeks of chronic therapy. At week 48, 6/11 (55%) subjects had ≥1 log10 decline in HIV-1 RNA and 4/11 (36%) subjects were below 400 copies/mL of HIV-1 RNA. The median changes from baseline (for the As Treated population) in HIV-1 RNA and CD4 cell count were -1.48 log10 copies/mL and +122 cells/µL, respectively.
- T20-310 was an open-label, multicenter trial that evaluated the pharmacokinetics, safety, and antiviral activity of FUZEON in treatment-experienced pediatric subjects and adolescents. Fifty-two subjects from 5 through 16 years were enrolled (median age of 12 years). Median baseline CD4 cell count was 117 cells/µL and the median baseline HIV-1 RNA was 5.0 log10 copies/mL.
- Thirty-two of the 52 study subjects completed 48 weeks of chronic therapy. At week 48, 17/52 (33%) of subjects had ≥1 log10 decline in HIV-1 RNA, 11/52 (21%) of subjects were below 400 copies/mL of HIV-1 RNA and 5/52 (10%) were below 50 copies/mL. The median changes from baseline (for the As Treated population) in HIV-1 RNA and CD4 cell count were -1.17 log10 copies/mL and +106 cells/µL, respectively.
### Geriatic Use
- Clinical studies of FUZEON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of FUZEON in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Enfuvirtide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Enfuvirtide with respect to specific racial populations.
### Renal Impairment
- No dose adjustments of enfuvirtide are needed in patients with renal impairment.
### Hepatic Impairment
- No dose adjustments of enfuvirtide are needed in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Enfuvirtide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Enfuvirtide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Enfuvirtide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Enfuvirtide in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Enfuvirtide in the drug label.
# Pharmacology
## Mechanism of Action
- Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes. Enfuvirtide binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes.
## Structure
- FUZEON (enfuvirtide) is an inhibitor of the fusion of HIV-1 with CD4 cells. Enfuvirtide is a linear 36-amino acid synthetic peptide with the N-terminus acetylated and the C-terminus is a carboxamide. It is composed of naturally occurring L-amino acid residues.
- Enfuvirtide is a white to off-white amorphous solid. It has negligible solubility in pure water and the solubility increases in aqueous buffers (pH 7.5) to 85-142 g/100 mL. The empirical formula of enfuvirtide is C204H301N51O64, and the molecular weight is 4492. It has the following primary amino acid sequence:
- CH3CO-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH2 and the following structural formula:
- The drug product, FUZEON (enfuvirtide) for Injection, is a white to off-white, sterile, lyophilized powder. Each single-use vial contains 108 mg of enfuvirtide for the delivery of 90 mg. Prior to subcutaneous administration, the contents of the vial are reconstituted with 1 mL of Sterile Water for Injection to provide the delivery of 1 mL of the solution. Each 1 mL of the reconstituted solution contains approximately 90 mg of enfuvirtide with approximate amounts of the following excipients: 22.55 mg of mannitol, 2.39 mg of sodium carbonate (anhydrous), and sodium hydroxide and hydrochloric acid for pH adjustment as needed. The reconstituted solution has an approximate pH of 9.0.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Enfuvirtide in the drug label.
## Pharmacokinetics
- The pharmacokinetic properties of enfuvirtide were evaluated in HIV-1 infected adult and pediatric subjects.
- Absorption
- Following a 90-mg single subcutaneous injection of FUZEON into the abdomen in 12 HIV-1 infected subjects, the mean (±SD) Cmax was 4.59 ± 1.5 µg/mL, AUC was 55.8 ± 12.1 µg∙h/mL and the median Tmax was 8 hours (ranged from 3 to 12 h). The absolute bioavailability (using a 90-mg intravenous dose as a reference) was 84.3% ± 15.5%. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean (±SD) steady-state Cmax was 5.0 ± 1.7 µg/mL, Ctrough was 3.3 ± 1.6 µg/mL, AUC0-12h was 48.7 ± 19.1 µg∙h/mL, and the median Tmax was 4 hours (ranged from 4 to 8 h).
- Absorption of the 90-mg dose was comparable when injected into the subcutaneous tissue of the abdomen, thigh or arm.
- Distribution
- The mean (±SD) steady-state volume of distribution after intravenous administration of a 90-mg dose of FUZEON (N=12) was 5.5 ± 1.1 L.
- Enfuvirtide is approximately 92% bound to plasma proteins in HIV-infected plasma over a concentration range of 2 to 10 µg/mL. It is bound predominantly to albumin and to a lower extent to α-1 acid glycoprotein.
- The CSF levels of enfuvirtide (measured from 2 hours to 18 hours after administration of enfuvirtide) in 4 HIV-infected subjects were below the limit of quantification (0.025 µg/mL).
- Metabolism/Elimination
- As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool.
- Mass balance studies to determine elimination pathway(s) of enfuvirtide have not been performed in humans.
- In vitro studies with human microsomes and hepatocytes indicate that enfuvirtide undergoes hydrolysis to form a deamidated metabolite at the C-terminal phenylalanine residue, M3. The hydrolysis reaction is not NADPH dependent. The M3 metabolite is detected in human plasma following administration of enfuvirtide, with an AUC ranging from 2.4% to 15% of the enfuvirtide AUC.
- Following a 90-mg single subcutaneous dose of enfuvirtide (N=12) the mean ±SD elimination half-life of enfuvirtide is 3.8 ± 0.6 h and the mean ±SD apparent clearance was 24.8 ± 4.1 mL/h/kg. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean ±SD apparent clearance was 30.6 ± 10.6 mL/h/kg.
- Special Populations
- Hepatic Impairment
- Formal pharmacokinetic studies of enfuvirtide have not been conducted in subjects with hepatic impairment.
- Renal Impairment
- Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is not affected in patients with creatinine clearance greater than 35 mL/min. The results of a renal impairment study indicate clearance of enfuvirtide was reduced by 38% in subjects with severe renal impairment (CL = 11 – 35 mL/min; n = 4) and by 14 - 28% in subjects with end-stage renal disease maintained on dialysis (n = 8) compared to subjects with normal renal function (CL >80 mL/min; n = 8). Hemodialysis did not significantly alter enfuvirtide clearance.
- No dose adjustment is recommended for patients with impaired renal function.
- Gender and Weight
- Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is 20% lower in females than males after adjusting for body weight.
- Enfuvirtide clearance decreases with decreased body weight irrespective of gender. Relative to the clearance of a 70-kg male, a 40-kg male will have 20% lower clearance and a 110-kg male will have a 26% higher clearance. Relative to a 70-kg male, a 40-kg female will have a 36% lower clearance and a 110-kg female will have the same clearance.
- No dose adjustment is recommended for weight or gender.
- Race
- Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide was not different in Blacks compared to Caucasians. Other pharmacokinetic studies suggest no difference between Asians and Caucasians after adjusting for body weight.
- Pediatric Patients
- The pharmacokinetics of enfuvirtide have been studied in 23 pediatric subjects aged 6 through 16 years at a dose of 2 mg/kg. Enfuvirtide pharmacokinetics were determined in the presence of concomitant medications including antiretroviral agents. A dose of 2 mg/kg twice daily (maximum 90 mg twice daily) provided enfuvirtide plasma concentrations similar to those obtained in adult subjects receiving 90 mg twice daily.
- In the 23 pediatric subjects receiving the 2 mg/kg twice daily dose, the mean ±SD steady-state AUC was 56.3 ± 22.3 µg∙h/mL, Cmax was 6.3 ± 2.4 µg/mL, Ctrough was 3.1 ± 1.5 µg/mL, and apparent clearance was 40 ± 17 mL/h/kg.
- Geriatric Patients
- The pharmacokinetics of enfuvirtide have not been studied in patients over 65 years of age.
- Table 5 shows the results of the drug-drug interaction studies conducted between FUZEON and the following drugs: ritonavir, saquinavir/ritonavir, and rifampin.
## Nonclinical Toxicology
- Carcinogenesis
- Long-term animal carcinogenicity studies of enfuvirtide have not been conducted.
- Mutagenesis
- Enfuvirtide was neither mutagenic nor clastogenic in a series of in vivo and in vitro assays including the Ames bacterial reverse mutation assay, a mammalian cell forward gene mutation assay in AS52 Chinese Hamster ovary cells or an in vivo mouse micronucleus assay.
- Impairment of Fertility
- Enfuvirtide produced no adverse effects on fertility in male or female rats at doses up to 1.6 times the maximum recommended adult human daily dose on a m2 basis.
# Clinical Studies
- T20-301 and T20-302 were randomized, controlled, open-label, multicenter trials in HIV-1 infected subjects. Subjects were required to have either (1) viremia despite 3 to 6 months prior therapy with a nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI) or (2) viremia and documented resistance or intolerance to at least one member in each of the NRTI, NNRTI, and PI classes.
- All subjects received an individualized background regimen consisting of 3 to 5 antiretroviral agents selected on the basis of the subject's prior treatment history and baseline genotypic and phenotypic viral resistance measurements. Subjects were then randomized at a 2:1 ratio to FUZEON 90 mg twice daily with background regimen or background regimen alone.
- After week 8, subjects on either treatment arm who met protocol defined criteria for virological failure were permitted to revise their background regimens; those on background regimen alone were also permitted to add FUZEON.
- Demographic characteristics for studies T20-301 and T20-302 are shown in Table 6. Subjects had prior exposure to a median of 12 antiretrovirals for a median of 7 years.
- At 48 weeks, 154 (23%) of subjects in the FUZEON+background regimen and 27 (8%) in the background regimen alone had HIV-1 RNA levels <50 copies/mL, and 225 (34%) of subjects receiving FUZEON+background regimen had HIV-1 RNA levels <400 copies/mL compared to 44 (13%) in the background regimen alone. Subjects achieving HIV-1 RNA levels <50 copies/mL were included in the <400 copies/mL category and both categories were incorporated in the overall virologic responder category of achieving HIV-1 RNA at least 1 log10 below baseline.
- The mean log change in HIV-1 RNA from baseline was -1.4 log10 copies/mL in subjects receiving FUZEON+background and -0.5 in those receiving background alone. The mean change in CD4 cell count from baseline to week 48 was +91 cells/mm3 in the FUZEON+background arm and +45 cells/mm3 in the background alone arm.
- Subjects in the FUZEON+background arm achieved a better virologic and immunologic outcome than subjects in the background alone arm across all subgroups based on baseline CD4 cell count, baseline HIV-1 RNA, number of prior ARVs or number of active ARVs in the background regimen.
# How Supplied
- FUZEON (enfuvirtide) for Injection is a white to off-white, sterile, lyophilized powder and it is packaged in a single-use clear glass vial containing 108 mg of enfuvirtide for the delivery of approximately 90 mg/1 mL when reconstituted with 1 mL of Sterile Water for Injection.
- FUZEON is available in a Convenience Kit containing 60 single-use vials of FUZEON (90 mg strength), 60 vials (2 cartons of 30 each) of Sterile Water for Injection (1 mL per vial), 60 reconstitution syringes (3 cc), 60 administration syringes (1 cc), Package Insert, Patient Package Insert, and Injection Instructions (NDC 0004-0381-40).
- Storage Conditions
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
- Reconstituted solution should be stored in the original vial under refrigeration at 2° to 8°C (36° to 46°F) and used within 24 hours.
## Storage
There is limited information regarding Enfuvirtide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- To assure safe and effective use of FUZEON, the following information and instructions should be given to patients:
- Patients should be informed that injection site reactions occur in almost all patients taking FUZEON. Patients must be familiar with the FUZEON Injection Instructions for instructions on how to appropriately inject FUZEON and how to carefully monitor for signs or symptoms of cellulitis or local infection. Patients should be instructed when to contact their healthcare provider about these reactions.
- Patients should be made aware that an increased rate of bacterial pneumonia was observed in subjects treated with FUZEON in clinical trials. Patients should be advised to seek medical evaluation immediately if they develop signs or symptoms suggestive of pneumonia (cough with fever, rapid breathing, shortness of breath).
- Patients should be advised of the possibility of a systemic hypersensitivity reaction to FUZEON. Patients should be advised to discontinue therapy and immediately seek medical evaluation if they develop signs/symptoms of systemic hypersensitivity such as combinations of rash, fever, nausea and vomiting, chills, rigors, and/or hypotension.
- FUZEON is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using FUZEON.
- Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. We do not know if FUZEON can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
- FUZEON must be taken as part of a combination antiretroviral regimen. Use of FUZEON alone may lead to rapid development of virus resistant to FUZEON and possibly other agents of the same class.
- Patients and caregivers must be instructed in the use of aseptic technique when administering FUZEON in order to avoid injection site infections. Appropriate training for FUZEON reconstitution and self-injection must be given by a healthcare provider, including a careful review of the FUZEON Patient Package Insert and FUZEON Injection Instructions. The first injection should be performed under the supervision of an appropriately qualified healthcare provider. It is recommended that the patient and/or caregiver's understanding and use of aseptic injection techniques and procedures be periodically re-evaluated.
- Patients and caregivers should be instructed on the preferred anatomical sites for administration (upper arm, abdomen, anterior thigh). FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial sections of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars, tattoos or burn sites.
- Patients and caregivers should be instructed in the proper techniques for preparation, injection and disposal of needles and syringes (including not recapping needles) in order to avoid needle stick injuries. Patients should be told not to reuse needles or syringes, and be instructed in safe disposal procedures including the use of a puncture-resistant container for disposal of used needles and syringes. Patients must be instructed on the safe disposal of full containers as per local requirements. Caregivers who experience an accidental needle stick after patient injection should contact a healthcare provider immediately.
- Patients should contact their healthcare provider for any questions regarding the administration of FUZEON.
- Patients should inform their healthcare provider if they are pregnant, plan to become pregnant or become pregnant while taking this medication.
- Patients should inform their healthcare provider if they are breast-feeding.
- Patients should not change the dose or dosing schedule of FUZEON or any antiretroviral medication without consulting their healthcare provider.
- Patients should contact their healthcare provider immediately if they stop taking FUZEON or any other drug in their antiretroviral regimen.
- Patients should be told that they can obtain more information on the self-administration of FUZEON at www.FUZEON.com or by calling 1-877-4-FUZEON (1-877-438-9366).
- Patients should be advised that no studies have been conducted on the ability to drive or operate machinery while taking FUZEON. If patients experience dizziness while taking FUZEON, they should be advised to talk to their healthcare provider before driving or operating machinery.
# Precautions with Alcohol
- Alcohol-Enfuvirtide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FUZEON®
# Look-Alike Drug Names
There is limited information regarding Enfuvirtide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Enfuvirtide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Enfuvirtide is a HIV-1 fusion inhibitor that is FDA approved for the treatment of HIV-1 infection in treatment-experienced patients with HIV-1 replication despite ongoing antiretroviral therapy. Common adverse reactions include local injection site reactions, diarrhea, nausea, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site, and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial section of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars, tattoos or burn sites. Additional detailed information regarding the administration of FUZEON is described in the FUZEON Injection Instructions.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Enfuvirtide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Enfuvirtide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Insufficient data are available to establish a dose recommendation of FUZEON in pediatric patients below the age of 6 years. In pediatric patients 6 years through 16 years of age, the recommended dosage of FUZEON is 2 mg/kg twice daily up to a maximum dose of 90 mg twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected into moles, scar tissue, bruises or the navel. Table 1 contains dosing guidelines for FUZEON based on body weight. Weight should be monitored periodically and the FUZEON dose adjusted accordingly.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Enfuvirtide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Enfuvirtide in pediatric patients.
# Contraindications
- FUZEON is contraindicated in patients with known hypersensitivity to FUZEON or any of its components.
# Warnings
### Precautions
- Local Injection Site Reactions (ISRs)
- The majority of subjects (98%) receiving FUZEON in randomized, controlled, open-label, multicenter clinical trials had at least one local injection site reaction; ISRs occurred throughout treatment with FUZEON. Manifestations may include pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis. Reactions are often present at more than one injection site. Patients must be familiar with the FUZEON Injection Instructions in order to know how to inject FUZEON appropriately and how to monitor carefully for signs or symptoms of cellulitis or local infection.
- Administration with Biojector® 2000
- Nerve pain (neuralgia and/or paresthesia) lasting up to 6 months associated with administration at anatomical sites where large nerves course close to the skin, bruising and hematomas have occurred with use of the Biojector 2000 needle-free device for administration of FUZEON. Patients receiving anticoagulants or persons with hemophilia, or other coagulation disorders, may have a higher risk of post-injection bleeding.
- Pneumonia
- An increased rate of bacterial pneumonia was observed in subjects treated with FUZEON in the Phase 3 clinical trials compared to the control arm. The incidence of pneumonia was 2.7% or 3.2 events/100 patient-years in subjects receiving FUZEON+background regimen. On analysis of all diagnoses of pneumonia (pneumonia, bacterial pneumonia, bronchopneumonia, and related terms) in T20-301 and T20-302, an increased rate of bacterial pneumonia was observed in subjects treated with FUZEON compared to the control arm (6.9%, 6.7 pneumonia events per 100 patient-years versus 0.6 events per 100 patient-years, respectively). Approximately half of the study subjects with pneumonia required hospitalization. Three subject deaths in the FUZEON arm were attributed to pneumonia; all three had serious concomitant AIDS-related illnesses that contributed to their deaths. Risk factors for pneumonia included low initial CD4 lymphocyte count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease.
- Because it was unclear whether the higher incidence rate of pneumonia was related to FUZEON use, an observational study in 1850 HIV-infected patients (740 FUZEON treated patients and 1110 non-FUZEON treated patients) was conducted to evaluate the risk of pneumonia in patients treated with FUZEON. A total of 123 patients had a confirmed or probable pneumonia event in this study (62 in the FUZEON treatment arm with 1962 patient-years of observation and 61 in the non-FUZEON treatment arm with 3378 patient-years of observation). The incidence of pneumonia was 3.2 events/100 patient-years in the FUZEON treatment arm and 1.8 events/100 patient-years in the non-FUZEON treatment arm. The hazard ratio, adjusting for other baseline risk factors, was 1.34 (95% C.I. = 0.90 – 2.00). Based on this observational study, it is not possible to exclude an increased risk of pneumonia in patients treated with FUZEON compared to non-FUZEON treated patients.
- It is unclear if the increased incidence of pneumonia is related to FUZEON use. However, because of these findings, patients with HIV-1 infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions which may predispose them to pneumonia. Risk factors for pneumonia included low initial CD4 cell count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease.
- Hypersensitivity Reactions
- Systemic hypersensitivity reactions have been associated with FUZEON therapy and may recur on re-challenge. Hypersensitivity reactions have occurred in <1% of subjects studied and have included combinations of: rash, fever, nausea and vomiting, chills, rigors, hypotension, and/or elevated serum liver transaminases. Other adverse events that may be immune mediated and have been reported in subjects receiving FUZEON include primary immune complex reaction, respiratory distress, glomerulonephritis, and Guillain-Barre syndrome. Patients developing signs and symptoms suggestive of a systemic hypersensitivity reaction should discontinue FUZEON and should seek medical evaluation immediately. Therapy with FUZEON should not be restarted following systemic signs and symptoms consistent with a hypersensitivity reaction. Risk factors that may predict the occurrence or severity of hypersensitivity to FUZEON have not been identified.
- Non-HIV Infected Individuals
- There is a theoretical risk that FUZEON use may lead to the production of anti-enfuvirtide antibodies which cross react with HIV gp41. This could result in a false positive HIV test with an ELISA assay; a confirmatory western blot test would be expected to be negative. FUZEON has not been studied in non-HIV infected individuals.
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FUZEON. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP] or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The overall safety profile of FUZEON is based on 2131 subjects who received at least 1 dose of FUZEON during various clinical trials. This includes 2051 adults, 658 of whom received the recommended dose for greater than 48 weeks, and 63 pediatric subjects.
- Assessment of treatment-emergent adverse events is based on the pooled data from the two randomized, controlled, open-label, multicenter trials in treatment-experienced subjects, T20-301 (TORO 1) and T20-302 (TORO 2).
- Local Injection Site Reactions
- Local injection site reactions were the most frequent adverse events associated with the use of FUZEON. In T20-301 and T20-302, 98% of subjects had at least one local injection site reaction (ISR). A total of 7% of subjects discontinued treatment with FUZEON because of ISRs (4%) or difficulties with injecting FUZEON (3%) such as injection fatigue and inconvenience. Eighty-five percent of subjects experienced their first ISR during the initial week of treatment; ISRs continued to occur throughout treatment with FUZEON. For most subjects the severity of signs and symptoms associated with ISRs did not change during the 48 weeks of treatment. The majority of ISRs were associated with erythema, induration, the presence of nodules or cysts, and mild to moderate pain at the injection site (Table 2). In addition, the average duration of individual ISRs was between three and seven days in 41% of subjects and more than seven days in 24% of subjects. Also, the numbers of ISRs per subject at any one time was between six to 14 ISRs in 26% of subjects and more than 14 ISRs in 1.3% of subjects. Infection at the injection site (including abscess and cellulitis) was reported in 1.7% of adult subjects.
- Other Adverse Events
- In T20-301 and T20-302, after study week 8, subjects on background alone who met protocol defined criteria for virological failure were permitted to revise their background regimens and add FUZEON. Exposure on FUZEON+background was 557 patient-years, and to background alone 162 patient-years. Due to this difference in exposure, safety results are expressed as the number of patients with an adverse event per 100 patient-years of exposure. For FUZEON+background, adverse events are also displayed by percent of subjects.
- The events most frequently reported in subjects receiving FUZEON+background regimen, excluding ISRs, were diarrhea (38 per 100 patient-years or 31.7%), nausea (27 per 100 patient-years or 22.8%), and fatigue (24 per 100 patient-years or 20.2%). These events were also commonly observed in subjects that received background regimen alone: diarrhea (73 per 100 patient-years), nausea (50 per 100 patient-years), and fatigue (38 per 100 patient-years).
- Treatment-emergent adverse events, regardless of causality and excluding ISRs, from Phase 3 studies are summarized for adult subjects, in Table 3. Any Grade 2 or above events occurring at ≥2 percent of subjects and at a higher rate in subjects treated with FUZEON are summarized in Table 3; events that occurred at a higher rate in the control arms are not displayed.
- Rates of adverse events for subjects who switched to FUZEON after virological failure were similar.
- Less Common Events
- The following adverse events have been reported in 1 or more subjects; however, a causal relationship to FUZEON has not been established.
Worsening abacavir hypersensitivity reaction
Glomerulonephritis; tubular necrosis; renal insufficiency; renal failure (including fatal cases)
Thrombocytopenia; neutropenia; fever; lymphadenopathy
Hyperglycemia
Sepsis; herpes simplex
Taste disturbance; Guillain-Barre syndrome (fatal); sixth nerve palsy; peripheral neuropathy
Unstable angina pectoris
Constipation; abdominal pain upper
Asthenia
Toxic hepatitis; hepatic steatosis
Increased amylase; increased lipase; increased AST; increased GGT; increased triglycerides
Insomnia; depression; anxiety; suicide attempt
Pneumopathy; respiratory distress; cough
Pruritus
- Adverse Events in Pediatric Patients
- FUZEON has been studied in 63 pediatric subjects 5 through 16 years of age with duration of FUZEON exposure ranging from 1 dose to 134 weeks. Adverse experiences seen during clinical trials were similar to those observed in adult subjects, although infections at site of injection (cellulitis or abscess) were more frequent in adolescents than in adults, with 4 events occurring in 3 of 28 (11%) subjects.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Enfuvirtide in the drug label.
# Drug Interactions
- Potential for FUZEON to Affect Other Drugs
- Based on the results from an in vitro human microsomal study, enfuvirtide is not an inhibitor of CYP450 enzymes. In an in vivo human metabolism study (N=12), FUZEON at the recommended dose of 90 mg twice daily did not alter the metabolism of CYP3A4, CYP2D6, CYP1A2, CYP2C19 or CYP2E1 substrates.
- Potential for Other Drugs to Affect Enfuvirtide
- Based on the available data, co-administration of FUZEON and other drugs which are inducers or inhibitors of CYP450 is not expected to alter the pharmacokinetics of enfuvirtide. No dose adjustments are needed when FUZEON is co-administered with other antiretroviral and non-antiretroviral drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies have been performed in rats and rabbits at doses up to 27 times and 3.2 times the adult human dose on a m2 basis and have revealed no evidence of impaired fertility or harm to the fetus due to enfuvirtide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
- Antiretroviral Pregnancy Registry
- To monitor maternal-fetal outcomes of pregnant women exposed to FUZEON and other antiretroviral drugs, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enfuvirtide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Enfuvirtide during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breast-feed their infants to avoid the risk of postnatal transmission of HIV. It is not known whether enfuvirtide is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving FUZEON.
- Studies where radio-labeled 3H-enfuvirtide was administered to lactating rats indicated that radioactivity was present in the milk. It is not known whether the radioactivity in the milk was from radio-labeled enfuvirtide or from radio-labeled metabolites of enfuvirtide (i.e., amino acids and peptide fragments).
### Pediatric Use
- The safety and pharmacokinetics of FUZEON have been evaluated in the age groups of 6 to 16 years of age supported by evidence from adequate and well-controlled studies of FUZEON in adults. Limited efficacy data are available in pediatric subjects 6 years of age and older.
- Sixty-three HIV-1 infected pediatric subjects ages 5 through 16 years have received FUZEON in two open-label, single-arm clinical trials. Adverse experiences, including ISRs, were similar to those observed in adult subjects.
- T20-204 was an open-label, multicenter trial that evaluated the safety and antiviral activity of FUZEON in treatment-experienced pediatric subjects. Eleven subjects from 6 to 12 years were enrolled (median age of 9 years). Median baseline CD4 cell count was 495 cells/µL and the median baseline HIV-1 RNA was 4.6 log10 copies/mL.
- Ten of the 11 study subjects completed 48 weeks of chronic therapy. At week 48, 6/11 (55%) subjects had ≥1 log10 decline in HIV-1 RNA and 4/11 (36%) subjects were below 400 copies/mL of HIV-1 RNA. The median changes from baseline (for the As Treated population) in HIV-1 RNA and CD4 cell count were -1.48 log10 copies/mL and +122 cells/µL, respectively.
- T20-310 was an open-label, multicenter trial that evaluated the pharmacokinetics, safety, and antiviral activity of FUZEON in treatment-experienced pediatric subjects and adolescents. Fifty-two subjects from 5 through 16 years were enrolled (median age of 12 years). Median baseline CD4 cell count was 117 cells/µL and the median baseline HIV-1 RNA was 5.0 log10 copies/mL.
- Thirty-two of the 52 study subjects completed 48 weeks of chronic therapy. At week 48, 17/52 (33%) of subjects had ≥1 log10 decline in HIV-1 RNA, 11/52 (21%) of subjects were below 400 copies/mL of HIV-1 RNA and 5/52 (10%) were below 50 copies/mL. The median changes from baseline (for the As Treated population) in HIV-1 RNA and CD4 cell count were -1.17 log10 copies/mL and +106 cells/µL, respectively.
### Geriatic Use
- Clinical studies of FUZEON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of FUZEON in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Enfuvirtide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Enfuvirtide with respect to specific racial populations.
### Renal Impairment
- No dose adjustments of enfuvirtide are needed in patients with renal impairment.
### Hepatic Impairment
- No dose adjustments of enfuvirtide are needed in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Enfuvirtide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Enfuvirtide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Enfuvirtide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Enfuvirtide in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Enfuvirtide in the drug label.
# Pharmacology
## Mechanism of Action
- Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes. Enfuvirtide binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes.
## Structure
- FUZEON (enfuvirtide) is an inhibitor of the fusion of HIV-1 with CD4 cells. Enfuvirtide is a linear 36-amino acid synthetic peptide with the N-terminus acetylated and the C-terminus is a carboxamide. It is composed of naturally occurring L-amino acid residues.
- Enfuvirtide is a white to off-white amorphous solid. It has negligible solubility in pure water and the solubility increases in aqueous buffers (pH 7.5) to 85-142 g/100 mL. The empirical formula of enfuvirtide is C204H301N51O64, and the molecular weight is 4492. It has the following primary amino acid sequence:
- CH3CO-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH2 and the following structural formula:
- The drug product, FUZEON (enfuvirtide) for Injection, is a white to off-white, sterile, lyophilized powder. Each single-use vial contains 108 mg of enfuvirtide for the delivery of 90 mg. Prior to subcutaneous administration, the contents of the vial are reconstituted with 1 mL of Sterile Water for Injection to provide the delivery of 1 mL of the solution. Each 1 mL of the reconstituted solution contains approximately 90 mg of enfuvirtide with approximate amounts of the following excipients: 22.55 mg of mannitol, 2.39 mg of sodium carbonate (anhydrous), and sodium hydroxide and hydrochloric acid for pH adjustment as needed. The reconstituted solution has an approximate pH of 9.0.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Enfuvirtide in the drug label.
## Pharmacokinetics
- The pharmacokinetic properties of enfuvirtide were evaluated in HIV-1 infected adult and pediatric subjects.
- Absorption
- Following a 90-mg single subcutaneous injection of FUZEON into the abdomen in 12 HIV-1 infected subjects, the mean (±SD) Cmax was 4.59 ± 1.5 µg/mL, AUC was 55.8 ± 12.1 µg∙h/mL and the median Tmax was 8 hours (ranged from 3 to 12 h). The absolute bioavailability (using a 90-mg intravenous dose as a reference) was 84.3% ± 15.5%. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean (±SD) steady-state Cmax was 5.0 ± 1.7 µg/mL, Ctrough was 3.3 ± 1.6 µg/mL, AUC0-12h was 48.7 ± 19.1 µg∙h/mL, and the median Tmax was 4 hours (ranged from 4 to 8 h).
- Absorption of the 90-mg dose was comparable when injected into the subcutaneous tissue of the abdomen, thigh or arm.
- Distribution
- The mean (±SD) steady-state volume of distribution after intravenous administration of a 90-mg dose of FUZEON (N=12) was 5.5 ± 1.1 L.
- Enfuvirtide is approximately 92% bound to plasma proteins in HIV-infected plasma over a concentration range of 2 to 10 µg/mL. It is bound predominantly to albumin and to a lower extent to α-1 acid glycoprotein.
- The CSF levels of enfuvirtide (measured from 2 hours to 18 hours after administration of enfuvirtide) in 4 HIV-infected subjects were below the limit of quantification (0.025 µg/mL).
- Metabolism/Elimination
- As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool.
- Mass balance studies to determine elimination pathway(s) of enfuvirtide have not been performed in humans.
- In vitro studies with human microsomes and hepatocytes indicate that enfuvirtide undergoes hydrolysis to form a deamidated metabolite at the C-terminal phenylalanine residue, M3. The hydrolysis reaction is not NADPH dependent. The M3 metabolite is detected in human plasma following administration of enfuvirtide, with an AUC ranging from 2.4% to 15% of the enfuvirtide AUC.
- Following a 90-mg single subcutaneous dose of enfuvirtide (N=12) the mean ±SD elimination half-life of enfuvirtide is 3.8 ± 0.6 h and the mean ±SD apparent clearance was 24.8 ± 4.1 mL/h/kg. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean ±SD apparent clearance was 30.6 ± 10.6 mL/h/kg.
- Special Populations
- Hepatic Impairment
- Formal pharmacokinetic studies of enfuvirtide have not been conducted in subjects with hepatic impairment.
- Renal Impairment
- Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is not affected in patients with creatinine clearance greater than 35 mL/min. The results of a renal impairment study indicate clearance of enfuvirtide was reduced by 38% in subjects with severe renal impairment (CL = 11 – 35 mL/min; n = 4) and by 14 - 28% in subjects with end-stage renal disease maintained on dialysis (n = 8) compared to subjects with normal renal function (CL >80 mL/min; n = 8). Hemodialysis did not significantly alter enfuvirtide clearance.
- No dose adjustment is recommended for patients with impaired renal function.
- Gender and Weight
- Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is 20% lower in females than males after adjusting for body weight.
- Enfuvirtide clearance decreases with decreased body weight irrespective of gender. Relative to the clearance of a 70-kg male, a 40-kg male will have 20% lower clearance and a 110-kg male will have a 26% higher clearance. Relative to a 70-kg male, a 40-kg female will have a 36% lower clearance and a 110-kg female will have the same clearance.
- No dose adjustment is recommended for weight or gender.
- Race
- Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide was not different in Blacks compared to Caucasians. Other pharmacokinetic studies suggest no difference between Asians and Caucasians after adjusting for body weight.
- Pediatric Patients
- The pharmacokinetics of enfuvirtide have been studied in 23 pediatric subjects aged 6 through 16 years at a dose of 2 mg/kg. Enfuvirtide pharmacokinetics were determined in the presence of concomitant medications including antiretroviral agents. A dose of 2 mg/kg twice daily (maximum 90 mg twice daily) provided enfuvirtide plasma concentrations similar to those obtained in adult subjects receiving 90 mg twice daily.
- In the 23 pediatric subjects receiving the 2 mg/kg twice daily dose, the mean ±SD steady-state AUC was 56.3 ± 22.3 µg∙h/mL, Cmax was 6.3 ± 2.4 µg/mL, Ctrough was 3.1 ± 1.5 µg/mL, and apparent clearance was 40 ± 17 mL/h/kg.
- Geriatric Patients
- The pharmacokinetics of enfuvirtide have not been studied in patients over 65 years of age.
- Table 5 shows the results of the drug-drug interaction studies conducted between FUZEON and the following drugs: ritonavir, saquinavir/ritonavir, and rifampin.
## Nonclinical Toxicology
- Carcinogenesis
- Long-term animal carcinogenicity studies of enfuvirtide have not been conducted.
- Mutagenesis
- Enfuvirtide was neither mutagenic nor clastogenic in a series of in vivo and in vitro assays including the Ames bacterial reverse mutation assay, a mammalian cell forward gene mutation assay in AS52 Chinese Hamster ovary cells or an in vivo mouse micronucleus assay.
- Impairment of Fertility
- Enfuvirtide produced no adverse effects on fertility in male or female rats at doses up to 1.6 times the maximum recommended adult human daily dose on a m2 basis.
# Clinical Studies
- T20-301 and T20-302 were randomized, controlled, open-label, multicenter trials in HIV-1 infected subjects. Subjects were required to have either (1) viremia despite 3 to 6 months prior therapy with a nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI) or (2) viremia and documented resistance or intolerance to at least one member in each of the NRTI, NNRTI, and PI classes.
- All subjects received an individualized background regimen consisting of 3 to 5 antiretroviral agents selected on the basis of the subject's prior treatment history and baseline genotypic and phenotypic viral resistance measurements. Subjects were then randomized at a 2:1 ratio to FUZEON 90 mg twice daily with background regimen or background regimen alone.
- After week 8, subjects on either treatment arm who met protocol defined criteria for virological failure were permitted to revise their background regimens; those on background regimen alone were also permitted to add FUZEON.
- Demographic characteristics for studies T20-301 and T20-302 are shown in Table 6. Subjects had prior exposure to a median of 12 antiretrovirals for a median of 7 years.
- At 48 weeks, 154 (23%) of subjects in the FUZEON+background regimen and 27 (8%) in the background regimen alone had HIV-1 RNA levels <50 copies/mL, and 225 (34%) of subjects receiving FUZEON+background regimen had HIV-1 RNA levels <400 copies/mL compared to 44 (13%) in the background regimen alone. Subjects achieving HIV-1 RNA levels <50 copies/mL were included in the <400 copies/mL category and both categories were incorporated in the overall virologic responder category of achieving HIV-1 RNA at least 1 log10 below baseline.
- The mean log change in HIV-1 RNA from baseline was -1.4 log10 copies/mL in subjects receiving FUZEON+background and -0.5 in those receiving background alone. The mean change in CD4 cell count from baseline to week 48 was +91 cells/mm3 in the FUZEON+background arm and +45 cells/mm3 in the background alone arm.
- Subjects in the FUZEON+background arm achieved a better virologic and immunologic outcome than subjects in the background alone arm across all subgroups based on baseline CD4 cell count, baseline HIV-1 RNA, number of prior ARVs or number of active ARVs in the background regimen.
# How Supplied
- FUZEON (enfuvirtide) for Injection is a white to off-white, sterile, lyophilized powder and it is packaged in a single-use clear glass vial containing 108 mg of enfuvirtide for the delivery of approximately 90 mg/1 mL when reconstituted with 1 mL of Sterile Water for Injection.
- FUZEON is available in a Convenience Kit containing 60 single-use vials of FUZEON (90 mg strength), 60 vials (2 cartons of 30 each) of Sterile Water for Injection (1 mL per vial), 60 reconstitution syringes (3 cc), 60 administration syringes (1 cc), Package Insert, Patient Package Insert, and Injection Instructions (NDC 0004-0381-40).
- Storage Conditions
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
- Reconstituted solution should be stored in the original vial under refrigeration at 2° to 8°C (36° to 46°F) and used within 24 hours.
## Storage
There is limited information regarding Enfuvirtide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- To assure safe and effective use of FUZEON, the following information and instructions should be given to patients:
- Patients should be informed that injection site reactions occur in almost all patients taking FUZEON. Patients must be familiar with the FUZEON Injection Instructions for instructions on how to appropriately inject FUZEON and how to carefully monitor for signs or symptoms of cellulitis or local infection. Patients should be instructed when to contact their healthcare provider about these reactions.
- Patients should be made aware that an increased rate of bacterial pneumonia was observed in subjects treated with FUZEON in clinical trials. Patients should be advised to seek medical evaluation immediately if they develop signs or symptoms suggestive of pneumonia (cough with fever, rapid breathing, shortness of breath).
- Patients should be advised of the possibility of a systemic hypersensitivity reaction to FUZEON. Patients should be advised to discontinue therapy and immediately seek medical evaluation if they develop signs/symptoms of systemic hypersensitivity such as combinations of rash, fever, nausea and vomiting, chills, rigors, and/or hypotension.
- FUZEON is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using FUZEON.
- Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. We do not know if FUZEON can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
- FUZEON must be taken as part of a combination antiretroviral regimen. Use of FUZEON alone may lead to rapid development of virus resistant to FUZEON and possibly other agents of the same class.
- Patients and caregivers must be instructed in the use of aseptic technique when administering FUZEON in order to avoid injection site infections. Appropriate training for FUZEON reconstitution and self-injection must be given by a healthcare provider, including a careful review of the FUZEON Patient Package Insert and FUZEON Injection Instructions. The first injection should be performed under the supervision of an appropriately qualified healthcare provider. It is recommended that the patient and/or caregiver's understanding and use of aseptic injection techniques and procedures be periodically re-evaluated.
- Patients and caregivers should be instructed on the preferred anatomical sites for administration (upper arm, abdomen, anterior thigh). FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial sections of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars, tattoos or burn sites.
- Patients and caregivers should be instructed in the proper techniques for preparation, injection and disposal of needles and syringes (including not recapping needles) in order to avoid needle stick injuries. Patients should be told not to reuse needles or syringes, and be instructed in safe disposal procedures including the use of a puncture-resistant container for disposal of used needles and syringes. Patients must be instructed on the safe disposal of full containers as per local requirements. Caregivers who experience an accidental needle stick after patient injection should contact a healthcare provider immediately.
- Patients should contact their healthcare provider for any questions regarding the administration of FUZEON.
- Patients should inform their healthcare provider if they are pregnant, plan to become pregnant or become pregnant while taking this medication.
- Patients should inform their healthcare provider if they are breast-feeding.
- Patients should not change the dose or dosing schedule of FUZEON or any antiretroviral medication without consulting their healthcare provider.
- Patients should contact their healthcare provider immediately if they stop taking FUZEON or any other drug in their antiretroviral regimen.
- Patients should be told that they can obtain more information on the self-administration of FUZEON at www.FUZEON.com or by calling 1-877-4-FUZEON (1-877-438-9366).
- Patients should be advised that no studies have been conducted on the ability to drive or operate machinery while taking FUZEON. If patients experience dizziness while taking FUZEON, they should be advised to talk to their healthcare provider before driving or operating machinery.
# Precautions with Alcohol
- Alcohol-Enfuvirtide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FUZEON®[1]
# Look-Alike Drug Names
There is limited information regarding Enfuvirtide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Enfuvirtide | |
ed33c2fd72f2f0978696e68172cf0febf9205ff5 | wikidoc | Enterotoxin | Enterotoxin
# Overview
An enterotoxin is a protein toxin released by a micro-organism in the lower intestine. Enterotoxins are frequently cytotoxic and kill cells by altering the permeability of the epithelial cells of the intestinal wall. They are mostly pore forming toxins, secreted by bacteria, that assemble to form pores in cell membranes. This causes the cells to die.
The death of cells that form the barrier between the intestinal lumen and the surrounding tissue causes interstitial fluid, composed of water and electrolytes to leak into the intestinal tract, causing diarrhea.
# Organisms secreting enterotoxins
Examples of organisms secreting enterotoxins are: Escherichia coli O157:H7, Clostridium perfringens, Vibrio cholerae, Staphylococcus aureus, Rotavirus and Yersinia enterocolitica. These toxins have A and B subunits. The A subunit is responsible for the loss of permeability of the intestinal endothelial cells. The B subunit acts as a syringe, injecting the A subunit into the cytoplasm. | Enterotoxin
# Overview
An enterotoxin is a protein toxin released by a micro-organism in the lower intestine. Enterotoxins are frequently cytotoxic and kill cells by altering the permeability of the epithelial cells of the intestinal wall. They are mostly pore forming toxins, secreted by bacteria, that assemble to form pores in cell membranes. This causes the cells to die.
The death of cells that form the barrier between the intestinal lumen and the surrounding tissue causes interstitial fluid, composed of water and electrolytes to leak into the intestinal tract, causing diarrhea.
# Organisms secreting enterotoxins
Examples of organisms secreting enterotoxins are: Escherichia coli O157:H7, Clostridium perfringens, Vibrio cholerae, Staphylococcus aureus, Rotavirus and Yersinia enterocolitica. These toxins have A and B subunits. The A subunit is responsible for the loss of permeability of the intestinal endothelial cells. The B subunit acts as a syringe, injecting the A subunit into the cytoplasm. | https://www.wikidoc.org/index.php/Enterotoxin | |
1ef81ccd1d46f5ea129a3deb75ce228337cb9cc9 | wikidoc | Enterovirus | Enterovirus
# Overview
Enteroviruses are a genus of (+)ssRNA viruses associated with several human and mammalian diseases. Serologic studies have distinguished 66 human enterovirus serotypes on the basis of antibody neutralization tests. Additional antigenic variants have been defined within several of the serotypes on the basis of reduced or nonreciprocal cross-neutralization between variant strains. On the basis of their pathogenesis in humans and animals, the enteroviruses were originally classified into four groups, polioviruses, Coxsackie A viruses (CA), Coxsackie B viruses (CB), and echoviruses, but it was quickly realized that there were significant overlaps in the biological properties of viruses in the different groups. Enteroviruses isolated more recently are named with a system of consecutive numbers: EV68, EV69, EV70, and EV71, etc.
Enteroviruses affect millions of people worldwide each year, and are often found in the respiratory secretions (e.g., saliva, sputum, or nasal mucus) and stool of an infected person. Historically, poliomyelitis was the most significant disease caused by an enterovirus, Poliovirus. There are 62 non-polio enteroviruses that can cause disease in humans: 23 Coxsackie A viruses, 6 Coxsackie B viruses, 28 echoviruses, and 5 other enteroviruses. Poliovirus, as well as coxsackie and echovirus are spread through the fecal-oral route. Infection can result in a wide variety of symptoms ranging from mild respiratory illness (common cold), hand, foot and mouth disease, acute hemorrhagic conjunctivitis, aseptic meningitis, myocarditis, severe neonatal sepsis-like disease, and acute flaccid paralysis.
# Species and genetics
Enteroviruses are members of the picornavirus family, a large and diverse group of small RNA viruses characterized by a single positive-strand genomic RNA. All enteroviruses contain a genome of approximately 7,500 bases and are known to have a high mutation rate due to low-fidelity replication and frequent recombination. After infection of the host cell, the genome is translated in a cap-independent manner into a single polyprotein, which is subsequently processed by virus-encoded proteases into the structural capsid proteins and the nonstructural proteins, which are mainly involved in the replication of the virus.
The enterovirus genus includes the following ten species:
- Bovine enterovirus
- Human enterovirus A
- Human enterovirus B
- Human enterovirus C
- Human enterovirus D
- Human rhinovirus A
- Human rhinovirus B
- Human rhinovirus C
- Porcine enterovirus B
- Simian enterovirus A
Within these ten species are the serotypes:
- Coxsackievirus
serotypes CV-A2, CV-A3, CV-A4, CV-A5, CV-A6, CV-A7, CV-A8, CV-A10, CV-A12, CV-A14, & CV-A16 found under the species: Human enterovirus A.
serotypes CV-B1, CV-B2, CV-B3, CV-B4, CV-B5, CV-B6, CV-A9, & CV-A23 found under the species: Human enterovirus B.
serotypes CV-A1, CV-A11, CV-A13, CV-A17, CV-A19, CV-A20, CV-A21, CV-A22, & CV-A24 found under the species: Human enterovirus C.
- Echovirus
serotypes E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-19, E20, E-21, E-24, E-25, E-26, E-27, E-29, E-30, E-31, E-32, & E-33 found under the species: Human enterovirus B.
- Enterovirus
serotypes EV-71, EV-76, EV-89, EV-90, EV-91, & EV-92 found under the species: Human enterovirus A.
serotypes EV-69, EV-73, EV-74, EV-75, EV-77, EV-78, EV-79, EV-80, EV-81, EV-82, EV-83, EV-84, EV-85, EV-86, EV-87, EV-88, EV-93, EV-97, EV-98, EV-100, EV-101, EV-106, & EV-107 found under the species: Human enterovirus B.
serotypes EV-95, EV-96, EV-99, EV-102, EV-104, EV-105, & EV-109 found under the species: Human enterovirus C.
serotypes EV-68, EV-70, & EV-94 found under the species: Human enterovirus D.
# Treatment
## Antimicrobial therapy
- Enterovirus D68 treatment
- Preferred regimen: supportive therapy
- Note: A new drug Pleconaril designed to affect Rhinovirus is being suggested to be effective against Enterovirus D68 but further investigation is required
- Human rhinovirus
serotypes HRV-1, HRV-2, HRV-7, HRV-8, HRV-9, HRV-10, HRV-11, HRV-12, HRV-13, HRV-15, HRV-16, HRV-18, HRV-19, HRV-20, HRV-21, HRV-22, HRV-23, HRV-24, HRV-25, HRV-28, HRV-29, HRV-30, HRV-31, HRV-32, HRV-33, HRV-34, HRV-36, HRV-38, HRV-39, HRV-40, HRV-41, HRV-43, HRV-44, HRV-45, HRV-46, HRV-47, HRV-49, HRV-50, HRV-51, HRV-53, HRV-54, HRV-55, HRV-56, HRV-57, HRV-58, HRV-59, HRV-60, HRV-61, HRV-62, HRV-63, HRV-64, HRV-65, HRV-66, HRV-67, HRV-68, HRV-71, HRV-73, HRV-74, HRV-75, HRV-76, HRV-77, HRV-78, HRV-80, HRV-81, HRV-82, HRV-85, HRV-88, HRV-89, HRV-90, HRV-94, HRV-95, HRV-96, HRV-98, & HRV-100 found under the species: Human rhinovirus A.
serotypes HRV-3, HRV-4, HRV-5, HRV-6, HRV-14, HRV-17, HRV-26, HRV-27, HRV-35, HRV-37, HRV-42, HRV-48, HRV-52, HRV-69, HRV-70, HRV-72, HRV-79, HRV-83, HRV-84, HRV-86, HRV-91, HRV-92, HRV-93, HRV-97, & HRV-99 found under the species: Human rhinovirus B.
- Poliovirus
serotypes PV-1, PV-2, & PV-3 found under the species: Human enterovirus C.
## Coxsackie and echovirus
Coxsackie viruses are a non-phylogenetic group. Coxsackie A viruses are mainly associated with human hand, foot and mouth disease. Coxsackie B viruses can cause mild signs and symptoms, similar to a "cold", but these viruses also can lead to more serious diseases, including myocarditis (inflammation of the heart); pericarditis (inflammation of the sac lining the heart); meningitis (inflammation of the membranes that line the brain and spinal cord); and pancreatitis (inflammation of the pancreas).
Echoviruses are a cause of many of the nonspecific viral infections. It is mainly found in the intestine, and can cause nervous disorders. The usual symptoms of Coxsackie and echovirus are fever, mild rash, and mild upper respiratory tract (URT) illness.
## Enterovirus 71
Enterovirus 71 (EV-71) is notable as one of the major causative agents for hand, foot and mouth disease (HFMD), and is sometimes associated with severe central nervous system diseases. EV71 was first isolated and characterized from cases of neurological disease in California in 1969. To date, little is known about the molecular mechanisms of host response to EV71 infection, but increases in the level of mRNAs encoding chemokines, proteins involved in protein degradation, complement proteins, and proapoptotis proteins have been implicated.
## Poliovirus
There are three serotypes of poliovirus, PV1, PV2, and PV3; each with a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV1 is the most common form encountered in nature; however, all three forms are extremely infectious. Poliovirus can affect the spinal cord and cause poliomyelitis.
Polioviruses were formerly classified as a species belonging to the genus Enterovirus in the family Picornaviridae. The Poliovirus species has been eliminated from the genus Enterovirus. The following serotypes, Human poliovirus 1, Human poliovirus 2, and Human poliovirus 3, were assigned to the species Human enterovirus C, in the genus Enterovirus in the family Picornaviridae. The type species of the genus Enterovirus was changed from Poliovirus to Human enterovirus C. This has been ratified in April 2008.
The 39th Executive Committee (EC39) of the International Committee on Taxonomy of Viruses (ICTV) met in Canada during June 2007 with new taxonomic proposals.
Two of the proposals with three changes were:
- Code 2005.261V.04: To remove the following species Poliovirus from the existing genus Enterovirus in the family Picornaviridae.
- Code 2005.262V.04: To assign the viruses; PV-1, PV-2, PV-3 to the existing species Human enterovirus C in the genus Enterovirus in the family Picornaviridae.
- Code 2005.263V.04: To change the type species Poliovirus from the existing genus Enterovirus in the family Picornaviridae to the type species Human enterovirus C.
Proposals approved at the (EC39) meeting of 2007, were sent to members of ICTV via email for ratification and have become official taxonomy. There have been a total of 215 taxonomic proposals, which have been approved and ratified since the 8th ICTV Report of 2005.
The ratification process was performed by email. The proposals were sent electronically via email on March 18, 2008 to ICTV members with a request to vote on whether to ratify the taxonomic proposals, with a 1-month deadline.
The following are two of the taxonomic proposals with three changes that were ratified by ICTV members in April 2008:
Picornaviruses
- 2005.261V.04: To remove the following species from the existing genus Enterovirus in the family Picornaviridae: Poliovirus.(Note: Poliovirus hereby loses its status as a virus species).
- 2005.262V.04: To assign the following viruses to the species Human enterovirus C in the existing genus Enterovirus in the family Picornaviridae: Human poliovirus 1, Human poliovirus 2, Human poliovirus 3. (This is not strictly necessary as a taxonomic proposal because it concerns entities below the species level, but it is left in to clarify this reorganization of the Picornaviridae).
- 2005.263V.04: To change the type species of the genus Enterovirus in the family Picornaviridae, from Poliovirus to Human enterovirus C.
The ICTVdb, International Committee on Taxonomy of Viruses data base, based on the ICTV Master Species List, 8th Report, June 2005 is obsolete.
## Rhinovirus
There are three species of Rhinoviruses: Human Rhinovirus A, Human Rhinovirus B, and Human Rhinovirus C which contain over 100 serotypes. Rhinoviruses are the most suspected causative agents of the common cold. This makes it difficult to develop a single vaccine against so many serotypes.
# Treatment
## Antimicrobial therapy
- Rhinovirus treatment (commom cold)
- Supportive therapy
- Symptomatic treatment-Ipratropium bromide intranasal (2 sprays tid) AND Clemastine 1.34 mg 1–2 tab PO bid–tid (over the counter)
- Symptomatic relief by Ipratropium nasal spray decreases rhinorrhea and sneezing vs placebo. AND Clemastine (an antihistamine) decreases sneezing, rhinorrhea but associated with dry nose, mouth & throat in 6–19%.OR Oral pleconaril given within 24 hrs of onset reduced duration (1 day) & severity of “cold symptoms” in DBPCT (p < .001).
- Note (1): No antiviral treatment indicated.
# Diseases caused by enterovirus infection
- Poliomyelitis is the most notable disease caused by enterovirus infection.
- Nonspecific febrile illness is the most common presentation of enterovirus infection. Other than fever, symptoms include muscle pain, sore throat, gastrointestinal distress, and headache. Abdominal discomfort may also be reported in some patients.
- Enteroviruses are by far the most common causes of aseptic meningitis in children. In the United States, enteroviruses are responsible for 30,000 to 50,000 meningitis hospitalizations per year as a result of 30 million to 50 million infections.
- Pleurodynia is characerized by severe paroxysmal pain in the chest and abdomen, along with fever, and sometimes nausea, headache, and emesis.
- Pericarditis and/or myocarditis are typically caused by enteroviruses; symptoms consist of fever with dyspnea and chest pain. Arrhythmias, heart failure, and myocardial infarction have also been reported.
- Acute hemorrhagic conjunctivitis can be caused by enteroviruses.
- Herpangina is caused by Coxsackie A virus, and causes a vesicular rash in the oral cavity and on the pharynx, along with high fever, sore throat, malaise, and often dysphagia, loss of appetite, back pain, and headache. It is also self limiting, with symptoms typically ending in 3–4 days.
- Hand, foot and mouth disease is a childhood illness most commonly caused by infection by Coxsackie A virus or EV71.
- Encephalitis is rare manifestation of enterovirus infection; when it occurs, the most frequent enterovirus found to be causing it is echovirus 9.
- Bornholm disease is enteroviral in origin.
- A 2007 study suggested that acute respiratory or gastrointestinal infections associated with enterovirus may be a factor in chronic fatigue syndrome.
## Treatment
Treatment for enteroviral infection is mainly supportive. In cases of pleurodynia, treatment consists of analgesics to relieve the severe pain that occurs in patients with the disease; in some severe cases, opiates may be needed. Treatment for aseptic meningitis caused by enteroviruses is also mainly symptomatic. In patients with enteroviral carditis, treatment consists of the prevention and treatment of complications, such as arrhythmias, pericardial effusion, and cardiac failure. Other treatments that have been investigated for enteroviral carditis include intravenous immunoglobulin.
# Gallery
- Electron micrograph of the poliovirus, a species of Enterovirus. From Public Health Image Library (PHIL).
- Girl with skin lesions on the face due to echovirus type 9. From Public Health Image Library (PHIL).
- Child displays a deformity of her right lower extremity due to polio caused by the poliovirus, an enterovirus member. From Public Health Image Library (PHIL).
Child displays a deformity of her right lower extremity due to polio caused by the poliovirus, an enterovirus member. From Public Health Image Library (PHIL).
- Immunoelectron microscopic technique able to discern the morphologic traits of the Coxsackie B4 virus virions. From Public Health Image Library (PHIL).
- Immunoelectron microscopic technique able to discern the morphologic traits of the Coxsackie B4 virus virions. From Public Health Image Library (PHIL).
- Transmission electron micrograph (TEM) reveals the presence of coxsackie B3 virus particles, found within a specimen of muscle tissue. From Public Health Image Library (PHIL).
- Transmission electron micrograph (TEM) depicts a number of virions found responsible for a case of acute hemorrhagic conjunctivitis (AHC). From Public Health Image Library (PHIL).
- ransmission electron micrograph (TEM) depicts a number of virions found responsible for a case of acute hemorrhagic conjunctivitis (AHC).From Public Health Image Library (PHIL).
- Transmission electron micrograph (TEM) reveals numerous, spheroid-shaped Enterovirus-D68 (EV-D68) virions. From Public Health Image Library (PHIL).
- Transmission electron micrograph (TEM) reveals numerous, spheroid-shaped Enterovirus-D68 (EV-D68) virions. From Public Health Image Library (PHIL). | Enterovirus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Enteroviruses are a genus of (+)ssRNA viruses associated with several human and mammalian diseases. Serologic studies have distinguished 66 human enterovirus serotypes on the basis of antibody neutralization tests. Additional antigenic variants have been defined within several of the serotypes on the basis of reduced or nonreciprocal cross-neutralization between variant strains. On the basis of their pathogenesis in humans and animals, the enteroviruses were originally classified into four groups, polioviruses, Coxsackie A viruses (CA), Coxsackie B viruses (CB), and echoviruses, but it was quickly realized that there were significant overlaps in the biological properties of viruses in the different groups. Enteroviruses isolated more recently are named with a system of consecutive numbers: EV68, EV69, EV70, and EV71, etc.[1]
Enteroviruses affect millions of people worldwide each year, and are often found in the respiratory secretions (e.g., saliva, sputum, or nasal mucus) and stool of an infected person. Historically, poliomyelitis was the most significant disease caused by an enterovirus, Poliovirus. There are 62 non-polio enteroviruses that can cause disease in humans: 23 Coxsackie A viruses, 6 Coxsackie B viruses, 28 echoviruses, and 5 other enteroviruses.[2] Poliovirus, as well as coxsackie and echovirus are spread through the fecal-oral route. Infection can result in a wide variety of symptoms ranging from mild respiratory illness (common cold), hand, foot and mouth disease, acute hemorrhagic conjunctivitis, aseptic meningitis, myocarditis, severe neonatal sepsis-like disease, and acute flaccid paralysis.[2]
# Species and genetics
Enteroviruses are members of the picornavirus family, a large and diverse group of small RNA viruses characterized by a single positive-strand genomic RNA. All enteroviruses contain a genome of approximately 7,500 bases and are known to have a high mutation rate due to low-fidelity replication and frequent recombination.[3] After infection of the host cell, the genome is translated in a cap-independent manner into a single polyprotein, which is subsequently processed by virus-encoded proteases into the structural capsid proteins and the nonstructural proteins, which are mainly involved in the replication of the virus.[4]
The enterovirus genus includes the following ten species:[5]
- Bovine enterovirus
- Human enterovirus A
- Human enterovirus B
- Human enterovirus C
- Human enterovirus D
- Human rhinovirus A
- Human rhinovirus B
- Human rhinovirus C
- Porcine enterovirus B
- Simian enterovirus A
Within these ten species are the serotypes:
- Coxsackievirus
serotypes CV-A2, CV-A3, CV-A4, CV-A5, CV-A6, CV-A7, CV-A8, CV-A10, CV-A12, CV-A14, & CV-A16 found under the species: Human enterovirus A.
serotypes CV-B1, CV-B2, CV-B3, CV-B4, CV-B5, CV-B6, CV-A9, & CV-A23 found under the species: Human enterovirus B.
serotypes CV-A1, CV-A11, CV-A13, CV-A17, CV-A19, CV-A20, CV-A21, CV-A22, & CV-A24 found under the species: Human enterovirus C.
- Echovirus
serotypes E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-19, E20, E-21, E-24, E-25, E-26, E-27, E-29, E-30, E-31, E-32, & E-33 found under the species: Human enterovirus B.
- Enterovirus
serotypes EV-71, EV-76, EV-89, EV-90, EV-91, & EV-92 found under the species: Human enterovirus A.
serotypes EV-69, EV-73, EV-74, EV-75, EV-77, EV-78, EV-79, EV-80, EV-81, EV-82, EV-83, EV-84, EV-85, EV-86, EV-87, EV-88, EV-93, EV-97, EV-98, EV-100, EV-101, EV-106, & EV-107 found under the species: Human enterovirus B.
serotypes EV-95, EV-96, EV-99, EV-102, EV-104, EV-105, & EV-109 found under the species: Human enterovirus C.
serotypes EV-68, EV-70, & EV-94 found under the species: Human enterovirus D.
# Treatment
## Antimicrobial therapy
- Enterovirus D68 treatment[6]
- Preferred regimen: supportive therapy
- Note: A new drug Pleconaril designed to affect Rhinovirus is being suggested to be effective against Enterovirus D68 but further investigation is required[7]
- Human rhinovirus
serotypes HRV-1, HRV-2, HRV-7, HRV-8, HRV-9, HRV-10, HRV-11, HRV-12, HRV-13, HRV-15, HRV-16, HRV-18, HRV-19, HRV-20, HRV-21, HRV-22, HRV-23, HRV-24, HRV-25, HRV-28, HRV-29, HRV-30, HRV-31, HRV-32, HRV-33, HRV-34, HRV-36, HRV-38, HRV-39, HRV-40, HRV-41, HRV-43, HRV-44, HRV-45, HRV-46, HRV-47, HRV-49, HRV-50, HRV-51, HRV-53, HRV-54, HRV-55, HRV-56, HRV-57, HRV-58, HRV-59, HRV-60, HRV-61, HRV-62, HRV-63, HRV-64, HRV-65, HRV-66, HRV-67, HRV-68, HRV-71, HRV-73, HRV-74, HRV-75, HRV-76, HRV-77, HRV-78, HRV-80, HRV-81, HRV-82, HRV-85, HRV-88, HRV-89, HRV-90, HRV-94, HRV-95, HRV-96, HRV-98, & HRV-100 found under the species: Human rhinovirus A.
serotypes HRV-3, HRV-4, HRV-5, HRV-6, HRV-14, HRV-17, HRV-26, HRV-27, HRV-35, HRV-37, HRV-42, HRV-48, HRV-52, HRV-69, HRV-70, HRV-72, HRV-79, HRV-83, HRV-84, HRV-86, HRV-91, HRV-92, HRV-93, HRV-97, & HRV-99 found under the species: Human rhinovirus B.
- Poliovirus
serotypes PV-1, PV-2, & PV-3 found under the species: Human enterovirus C.[8]
## Coxsackie and echovirus
Coxsackie viruses are a non-phylogenetic group.[9] Coxsackie A viruses are mainly associated with human hand, foot and mouth disease. Coxsackie B viruses can cause mild signs and symptoms, similar to a "cold", but these viruses also can lead to more serious diseases, including myocarditis (inflammation of the heart); pericarditis (inflammation of the sac lining the heart); meningitis (inflammation of the membranes that line the brain and spinal cord); and pancreatitis (inflammation of the pancreas).
Echoviruses are a cause of many of the nonspecific viral infections. It is mainly found in the intestine, and can cause nervous disorders.[citation needed] The usual symptoms of Coxsackie and echovirus are fever, mild rash, and mild upper respiratory tract (URT) illness.[citation needed]
## Enterovirus 71
Enterovirus 71 (EV-71) is notable as one of the major causative agents for hand, foot and mouth disease (HFMD), and is sometimes associated with severe central nervous system diseases.[10] EV71 was first isolated and characterized from cases of neurological disease in California in 1969.[11][12] To date, little is known about the molecular mechanisms of host response to EV71 infection, but increases in the level of mRNAs encoding chemokines, proteins involved in protein degradation, complement proteins, and proapoptotis proteins have been implicated.[13]
## Poliovirus
There are three serotypes of poliovirus, PV1, PV2, and PV3; each with a slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV1 is the most common form encountered in nature; however, all three forms are extremely infectious.[14] Poliovirus can affect the spinal cord and cause poliomyelitis.
Polioviruses were formerly classified as a species belonging to the genus Enterovirus in the family Picornaviridae. The Poliovirus species has been eliminated from the genus Enterovirus. The following serotypes, Human poliovirus 1, Human poliovirus 2, and Human poliovirus 3, were assigned to the species Human enterovirus C, in the genus Enterovirus in the family Picornaviridae. The type species of the genus Enterovirus was changed from Poliovirus to Human enterovirus C. This has been ratified in April 2008.[15]
The 39th Executive Committee (EC39) of the International Committee on Taxonomy of Viruses (ICTV) met in Canada during June 2007 with new taxonomic proposals.[16]
Two of the proposals with three changes were:
- Code 2005.261V.04: To remove the following species Poliovirus from the existing genus Enterovirus in the family Picornaviridae.
- Code 2005.262V.04: To assign the viruses; PV-1, PV-2, PV-3 to the existing species Human enterovirus C in the genus Enterovirus in the family Picornaviridae.[17]
- Code 2005.263V.04: To change the type species Poliovirus from the existing genus Enterovirus in the family Picornaviridae to the type species Human enterovirus C.[18]
Proposals approved at the (EC39) meeting of 2007, were sent to members of ICTV via email for ratification and have become official taxonomy. There have been a total of 215 taxonomic proposals, which have been approved and ratified since the 8th ICTV Report of 2005.[19]
The ratification process was performed by email. The proposals were sent electronically via email on March 18, 2008 to ICTV members with a request to vote on whether to ratify the taxonomic proposals, with a 1-month deadline.
The following are two of the taxonomic proposals with three changes that were ratified by ICTV members in April 2008:
Picornaviruses
- 2005.261V.04: To remove the following species from the existing genus Enterovirus in the family Picornaviridae: Poliovirus.(Note: Poliovirus hereby loses its status as a virus species).
- 2005.262V.04: To assign the following viruses to the species Human enterovirus C in the existing genus Enterovirus in the family Picornaviridae: Human poliovirus 1, Human poliovirus 2, Human poliovirus 3. (This is not strictly necessary as a taxonomic proposal because it concerns entities below the species level, but it is left in to clarify this reorganization of the Picornaviridae).
- 2005.263V.04: To change the type species of the genus Enterovirus in the family Picornaviridae, from Poliovirus to Human enterovirus C.[15]
The ICTVdb, International Committee on Taxonomy of Viruses data base, based on the ICTV Master Species List, 8th Report, June 2005 is obsolete.[20]
## Rhinovirus
There are three species of Rhinoviruses: Human Rhinovirus A, Human Rhinovirus B, and Human Rhinovirus C which contain over 100 serotypes. Rhinoviruses are the most suspected causative agents of the common cold. This makes it difficult to develop a single vaccine against so many serotypes.
# Treatment
## Antimicrobial therapy
- Rhinovirus treatment (commom cold)
- Supportive therapy
- Symptomatic treatment-Ipratropium bromide intranasal (2 sprays tid) AND Clemastine 1.34 mg 1–2 tab PO bid–tid (over the counter)
- Symptomatic relief by Ipratropium nasal spray decreases rhinorrhea and sneezing vs placebo.[21] AND Clemastine (an antihistamine) decreases sneezing, rhinorrhea but associated with dry nose, mouth & throat in 6–19%.[22]OR Oral pleconaril given within 24 hrs of onset reduced duration (1 day) & severity of “cold symptoms” in DBPCT (p < .001).[23]
- Note (1): No antiviral treatment indicated.[24]
# Diseases caused by enterovirus infection
- Poliomyelitis is the most notable disease caused by enterovirus infection.
- Nonspecific febrile illness is the most common presentation of enterovirus infection. Other than fever, symptoms include muscle pain, sore throat, gastrointestinal distress, and headache. Abdominal discomfort may also be reported in some patients.
- Enteroviruses are by far the most common causes of aseptic meningitis in children. In the United States, enteroviruses are responsible for 30,000 to 50,000 meningitis hospitalizations per year as a result of 30 million to 50 million infections.[2]
- Pleurodynia is characerized by severe paroxysmal pain in the chest and abdomen, along with fever, and sometimes nausea, headache, and emesis.
- Pericarditis and/or myocarditis are typically caused by enteroviruses; symptoms consist of fever with dyspnea and chest pain. Arrhythmias, heart failure, and myocardial infarction have also been reported.
- Acute hemorrhagic conjunctivitis can be caused by enteroviruses.
- Herpangina is caused by Coxsackie A virus, and causes a vesicular rash in the oral cavity and on the pharynx, along with high fever, sore throat, malaise, and often dysphagia, loss of appetite, back pain, and headache. It is also self limiting, with symptoms typically ending in 3–4 days.
- Hand, foot and mouth disease is a childhood illness most commonly caused by infection by Coxsackie A virus or EV71.
- Encephalitis is rare manifestation of enterovirus infection; when it occurs, the most frequent enterovirus found to be causing it is echovirus 9.
- Bornholm disease is enteroviral in origin.
- A 2007 study suggested that acute respiratory or gastrointestinal infections associated with enterovirus may be a factor in chronic fatigue syndrome.[25]
## Treatment
Treatment for enteroviral infection is mainly supportive. In cases of pleurodynia, treatment consists of analgesics to relieve the severe pain that occurs in patients with the disease; in some severe cases, opiates may be needed. Treatment for aseptic meningitis caused by enteroviruses is also mainly symptomatic. In patients with enteroviral carditis, treatment consists of the prevention and treatment of complications, such as arrhythmias, pericardial effusion, and cardiac failure. Other treatments that have been investigated for enteroviral carditis include intravenous immunoglobulin.[26]
# Gallery
- Electron micrograph of the poliovirus, a species of Enterovirus. From Public Health Image Library (PHIL). [27]
- Girl with skin lesions on the face due to echovirus type 9. From Public Health Image Library (PHIL). [27]
- Child displays a deformity of her right lower extremity due to polio caused by the poliovirus, an enterovirus member. From Public Health Image Library (PHIL). [27]
Child displays a deformity of her right lower extremity due to polio caused by the poliovirus, an enterovirus member. From Public Health Image Library (PHIL). [27]
- Immunoelectron microscopic technique able to discern the morphologic traits of the Coxsackie B4 virus virions. From Public Health Image Library (PHIL). [27]
- Immunoelectron microscopic technique able to discern the morphologic traits of the Coxsackie B4 virus virions. From Public Health Image Library (PHIL). [27]
- Transmission electron micrograph (TEM) reveals the presence of coxsackie B3 virus particles, found within a specimen of muscle tissue. From Public Health Image Library (PHIL). [27]
- Transmission electron micrograph (TEM) depicts a number of virions found responsible for a case of acute hemorrhagic conjunctivitis (AHC). From Public Health Image Library (PHIL). [27]
- ransmission electron micrograph (TEM) depicts a number of virions found responsible for a case of acute hemorrhagic conjunctivitis (AHC).From Public Health Image Library (PHIL). [27]
- Transmission electron micrograph (TEM) reveals numerous, spheroid-shaped Enterovirus-D68 (EV-D68) virions. From Public Health Image Library (PHIL). [27]
- Transmission electron micrograph (TEM) reveals numerous, spheroid-shaped Enterovirus-D68 (EV-D68) virions. From Public Health Image Library (PHIL). [27] | https://www.wikidoc.org/index.php/Enteroviral | |
504ffaa30084ffd4138967607a2e95ec321977c5 | wikidoc | Vedolizumab | Vedolizumab
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# Overview
Vedolizumab is a monoclonal antibody that is FDA approved for the treatment of Adult Ulcerative Colitis and Crohn’s disease. Common adverse reactions include nasopharyngitis and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Ulcerative Colitis or Crohn’s Disease
The recommended dosage of vedolizumab in adults with ulcerative colitis or Crohn's disease is 300 mg administered by intravenous infusion at zero, two and six weeks and then every eight weeks thereafter.
Discontinue therapy in patients who show no evidence of therapeutic benefit by Week 14.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vedolizumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vedolizumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Vedolizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vedolizumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vedolizumab in pediatric patients.
# Contraindications
Vedolizumab is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to vedolizumab or any of its excipients (such as dyspnea, bronchospasm, urticaria, flushing, rash and increased heart rate)
# Warnings
### Infusion-Related Reactions and Hypersensitivity Reactions
- In UC Trials I and II and CD Trials I and III, hypersensitivity reactions occurred including a case of anaphylaxis (one out of 1434 patients ).
- Allergic reactions including dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have also been observed.
- The majority were mild to moderate in severity as assessed by the investigator.
- Experience with other biologic medications suggests that hypersensitivity reactions and anaphylaxis to vedolizumab may vary in their time of onset from during infusion or immediately post-infusion to occurring up to several hours post-infusion.
- If anaphylaxis or other serious allergic reactions occur, discontinue administration of vedolizumab immediately and initiate appropriate treatment (e.g., epinephrine and antihistamines).
### Infections
- Patients treated with vedolizumab are at increased risk for developing infections.
- The most commonly reported infections in clinical trials occurring at a rate greater on vedolizumab than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection).
- Serious infections have also been reported in patients treated with vedolizumab, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.
- Vedolizumab is not recommended in patients with active, severe infections until the infections are controlled.
- Consider withholding treatment in patients who develop a severe infection while on treatment with vedolizumab.
- Exercise caution when considering the use of vedolizumab in patients with a history of recurring severe infections.
- Consider screening for tuberculosis (TB) according to the local practice.
- For progressive multifocal leukoencephalopathy (PML),
### Progressive Multifocal Leukoencephalopathy
- Another integrin receptor antagonist has been associated with progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS). PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised.
- In vedolizumab clinical trials, patients were actively monitored for PML with frequent and regular screenings, and evaluations of any new, unexplained neurological symptoms, as necessary.
- While zero cases of PML were identified among patients with at least 24 months of exposure, a risk of PML cannot be ruled out.
- No claims of comparative safety to other integrin receptor antagonists can be made based on this data.
- Monitor patients on vedolizumab for any new onset, or worsening, of neurological signs and symptoms.
- Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
- The progression of deficits usually leads to death or severe disability over weeks or months. If PML is suspected, withhold dosing with vedolizumab and refer to a neurologist; if confirmed, discontinue dosing permanently.
### Liver Injury
- There have been reports of elevations of transaminase and/or bilirubin in patients receiving vedolizumab. In general, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. vedolizumab should be discontinued in patients with jaundice or other evidence of significant liver injury.
### Live and Oral Vaccines
- Prior to initiating treatment with vedolizumab, all patients should be brought up to date with all immunizations according to current immunization guidelines.
- Patients receiving vedolizumab may receive non-live vaccines (e.g., influenza vaccine injection) and may receive live vaccines if the benefits outweigh the risks.
- There are no data on the secondary transmission of infection by live vaccines in patients receiving vedolizumab.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to vedolizumab in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years.
The safety data described in Table 1 are derived from four controlled Phase 3 trials (UC Trials I and II, and CD Trials I and III); data from patients receiving open-label vedolizumab treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included.
In these trials, 1,434 patients received vedolizumab 300 mg for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohn’s disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III).
Adverse reactions were reported in 52% of patients treated with vedolizumab and 45% of patients treated with placebo (UC Trials I and II: 49% with vedolizumab and 37% with placebo; CD Trials I and III: 55% with vedolizumab and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with vedolizumab compared to 4% of patients treated with placebo (UC Trials I and II: 8% with vedolizumab and 7% with placebo; CD Trials I and III: 12% with vedolizumab and 9%, with placebo).
The most common adverse reactions (reported by ≥3% of patients treated with vedolizumab in the UC Trials I and II and CD Trials I and III combined group and ≥1% higher than in combined placebo group) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in extremities (Table 1).
Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received vedolizumab at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10 week Crohn’s disease trial, are similar to those listed in Table 1.
Infusion-Related Reactions and Hypersensitivity Reactions
Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following vedolizumab administration in clinical trials. In UC Trials I and II and Crohn’s Trials I and III, one case of anaphylaxis was reported by a Crohn’s disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash and increased blood pressure and heart rate) and was managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone.
In UC Trials I and II and CD Trials I and III, 4% of patients treated with vedolizumab and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with vedolizumab (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria and vomiting (each of these adverse reactions occurred in <1% in all patients treated with vedolizumab) and no individual adverse reaction reported occurred at a rate above 1%. These reactions generally occurred within the first two hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment. Less than 1% of patients treated with vedolizumab had IRRs assessed by the investigator as severe, and IRRs requiring discontinuation of study treatment occurred in <1%.
In clinical trials, for patients with mild IRRs or hypersensitivity reactions, physicians were allowed to pretreat with standard medical treatment (e.g., antihistamine, hydrocortisone and/or acetaminophen) prior to next infusion.
Infections
In UC Trials I and II and CD Trials I and III, the rate of infections was 0.85 per patient-year in the patients treated with vedolizumab and 0.7 per patient-year in the patients treated with placebo. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infection. Two percent of patients discontinued vedolizumab due to infections.
In UC Trials I and II and CD Trials I and III, the rate of serious infections was 0.07 per patient-year in patients treated with vedolizumab and 0.06 per patient-year in patients treated with placebo. Serious infections were more common in Crohn’s disease patients than ulcerative colitis patients, and anal abscesses were the most frequently reported serious adverse reaction in Crohn’s disease patients. Over 48 months, there was no increase in the rate of serious infections.
In controlled- and open-label long-term extension trials in adults treated with vedolizumab, serious infections have been reported, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.
In UC Trials I and II and CD Trials I and III, sepsis, including bacterial sepsis and septic shock, was reported in four of 1434 (0.3%) patients treated with vedolizumab and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohn’s disease patients treated with vedolizumab died due to reported sepsis or septic shock; both of these patients had significant comorbidities and a complicated hospital course that contributed to the deaths. In an open label long-term extension trial, additional cases of sepsis (some fatal), including bacterial sepsis and septic shock, were reported. The rate of sepsis in patients with ulcerative colitis or Crohn’s disease receiving vedolizumab was two per 1000 patient-years.
In clinical trials, all patients were screened for tuberculosis. One case of latent, pulmonary tuberculosis was diagnosed during the controlled trials with vedolizumab. Additional cases of pulmonary tuberculosis were diagnosed during the open-label trial. All of these observed cases occurred outside the United States, and none of the patients had extrapulmonary manifestations.
Liver Injury
There have been reports of elevations of transaminase and/or bilirubin in patients receiving vedolizumab. In UC Trials I and II and CD Trials I and III, three patients reported serious adverse reactions of hepatitis, manifested as elevated transaminases with or without elevated bilirubin and symptoms consistent with hepatitis (e.g., malaise, nausea, vomiting, abdominal pain, anorexia). These adverse reactions occurred following two to five vedolizumab doses; however, based on case report information it is unclear if the reactions indicated drug-induced or autoimmune etiology. All patients recovered following discontinuation of therapy with some requiring corticosteroid treatment. In controlled trials, the incidence of ALT and AST elevations ≥3 x ULN was <2% in patients treated with vedolizumab and in patients treated with placebo. In the open-label trial, one additional case of serious hepatitis was observed.
Malignancies
In UC Trials I and II and CD Trials I and III, malignancies (excluding dysplasia and basal cell carcinoma) were reported in six of 1434 (0.4%) patients treated with vedolizumab, including colon cancer (n=2), transitional cell carcinoma (n=1), breast cancer (n=1), carcinoid tumor of the appendix (n=1) and squamous cell carcinoma (n=1). Malignancy was reported in one of 297 (0.3%) patients treated with placebo (squamous cell carcinoma).
Malignancies (excluding dysplasia and basal cell carcinoma) observed during the ongoing open-label long-term extension trial included B-cell lymphoma, breast cancer, colon cancer, malignant hepatic neoplasm, malignant lung neoplasm, malignant melanoma, lung cancer of primary neuroendocrine carcinoma, renal cancer and squamous cell carcinoma. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited.
Live and Oral Vaccines
There are no data on the secondary transmission of infection by live vaccines in patients receiving vedolizumab.
In a placebo-controlled study of healthy volunteers, 61 subjects were given a single vedolizumab 750 mg dose (2.5 times the recommended dose), and 62 subjects received placebo followed by intramuscular vaccination with Hepatitis B surface antigen and oral cholera vaccine. After intramuscular vaccination with three doses of recombinant Hepatitis B surface antigen, those treated with vedolizumab did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to vedolizumab did have lower seroconversion rates and anti-cholera titers relative to placebo after receiving the two doses of a killed, oral cholera vaccine. The impact on other oral vaccines and on nasal vaccines in patients is unknown.
### Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. In UC Trials I and II and CD Trials I and III, in patients who received vedolizumab, the frequency of antibodies detected in patients was 13% at 24 weeks after the last dose of study drug (greater than five half-lives after last dose). During treatment, 56 of 1434 (4%) of patients treated with vedolizumab had detectable anti-vedolizumab antibody at any time during the 52 weeks of continuous treatment. Nine of 56 patients were persistently positive (at two or more study visits) for anti-vedolizumab antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab. Among eight of these nine subjects with persistently positive anti-vedolizumab antibody and available vedolizumab concentration data, six had undetectable and two had reduced vedolizumab concentrations. None of the nine subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, presence of vedolizumab, and underlying disease. For these reasons, comparison of the incidence of antibodies to vedolizumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Vedolizumab Postmarketing Experience in the drug label.
# Drug Interactions
### Natalizumab
- Because of the potential for increased risk of PML and other infections, avoid the concomitant use of vedolizumab with natalizumab.
### TNF Blockers
- Because of the potential for increased risk of infections, avoid the concomitant use of vedolizumab with TNF blockers.
### Live Vaccines
- Live vaccines may be administered concurrently with vedolizumab only if the benefits outweigh the risks
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no studies with vedolizumab in pregnant women.
- No fetal harm was observed in animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage. *Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the benefits to the mother outweigh the risk to the unborn child.
### Clinical Considerations
Any adverse pregnancy effect from vedolizumab would likely be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
### Animal Data
A reproduction study has been performed in pregnant rabbits at single intravenous doses up to 100 mg/kg administered on gestation Day 7 (about 20 times the recommended human dosage) and has revealed no evidence of impaired fertility or harm to the fetus due to vedolizumab. A pre- and post-natal development study in monkeys showed no evidence of any adverse effect on pre- and post-natal development at intravenous doses up to 100 mg/kg (about 20 times the recommended human dosage).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vedolizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vedolizumab during labor and delivery.
### Nursing Mothers
- It is unknown whether vedolizumab is present in human milk.
- Vedolizumab was detected in the milk of lactating monkeys.
- Exercise caution when administering vedolizumab to a nursing woman.
### Pediatric Use
- Safety and effectiveness of vedolizumab in pediatric patients have not been established.
### Geriatic Use
- Clinical trials of vedolizumab did not include sufficient numbers of subjects aged 65 and over (46 Crohn’s and ulcerative colitis patients aged 65 and over were treated with vedolizumab during controlled Phase 3 trials) to determine whether they respond differently from younger subjects. However, no overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Vedolizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vedolizumab with respect to specific racial populations.
### Renal Impairment
- Pharmacokinetics of vedolizumab in patients with renal insufficiency have not been studied.
### Hepatic Impairment
- Pharmacokinetics of vedolizumab in patients with hepatic insufficiency have not been studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vedolizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vedolizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer vedolizumab as an intravenous infusion over 30 minutes.
- Do not administer as an intravenous push or bolus.
- Vedolizumab lyophilized powder must be reconstituted with Sterile Water for injection and diluted in 250 mL of sterile 0.9% Sodium Chloride injection prior to administration.
- After the infusion is complete, flush with 30 mL of sterile 0.9% Sodium Chloride injection.
- Vedolizumab should be administered by a healthcare professional prepared to manage hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use. Observe patients during infusion and until the infusion is complete.
### Prior to Administration of vedolizumab
- Prior to initiating treatment with vedolizumab, all patients should be brought up to date with all immunizations according to current immunization guidelines.
### Monitoring
- Monitor for PML with frequent and regular screenings, and evaluations of any new, unexplained neurological symptoms, as necessary.
# IV Compatibility
### Reconstitution Instructions
- Reconstitute vedolizumab at room temperature. Vedolizumab should be reconstituted and prepared by a trained medical professional using aseptic technique by the following procedure:
- Remove the flip-off cap from the single-dose vial and wipe with alcohol swab. Reconstitute vedolizumab vial containing lyophilized powder with 4.8 mL of Sterile Water for injection, using a syringe with a 21 to 25 gauge needle.
- Insert the syringe needle into the vial through the center of the stopper and direct the stream of Sterile Water for injection to the glass wall of the vial to avoid excessive foaming.
- Gently swirl the vial for at least 15 seconds to dissolve the lyophilized powder. Do not vigorously shake or invert.
- Allow the solution to sit for up to 20 minutes at room temperature to allow for reconstitution and for any foam to settle; the vial can be swirled and inspected for dissolution during this time. If not fully dissolved after 20 minutes, allow another 10 minutes for dissolution. Do not use the vial if the drug product is not dissolved within 30 minutes.
- Visually inspect the reconstituted vedolizumab solution for particulate matter and discoloration prior to administration. Solution should be clear or opalescent, colorless to light brownish yellow and free of visible particulates. Do not administer reconstituted solution showing uncharacteristic color or containing particulates.
- Prior to withdrawing the reconstituted vedolizumab solution from the vial, gently invert vial three times.
- Withdraw 5 mL (300 mg) of reconstituted vedolizumab solution using a syringe with a 21 to 25 gauge needle. Discard any remaining portion of the reconstituted solution in the vial.
Dilution Instructions
Add the 5 mL (300 mg) of reconstituted vedolizumab solution to 250 mL of sterile 0.9% Sodium Chloride and gently mix the infusion bag. Do not add other medicinal products to the prepared infusion solution or intravenous infusion set. Once reconstituted and diluted, use the infusion solution as soon as possible.
Storage
Do not freeze. Discard any unused portion of the infusion solution.
# Overdosage
There is limited information regarding Vedolizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. Vedolizumab does not bind to or inhibit function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1).
The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T-lymphocytes to gut lymph tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn’s disease.
## Structure
Vedolizumab, an integrin receptor antagonist, is a humanized IgG1 monoclonal antibody produced in Chinese hamster ovary cells that binds to the human α4β7 integrin. Vedolizumab has an approximate molecular weight of 147 kilodaltons.
## Pharmacodynamics
In clinical trials with vedolizumab at doses ranging from 0.2 to 10 mg/kg (which includes doses outside of the recommended dose), saturation of α4β7 receptors on subsets of circulating lymphocytes involved in gut-immune surveillance was observed.
In clinical trials with vedolizumab at doses ranging from 0.2 to 10 mg/kg and 180 to 750 mg (which include doses outside of the recommended dose) in healthy subjects and in patients with ulcerative colitis or Crohn’s disease, vedolizumab did not elevate neutrophils, basophils, eosinophils, B-helper and cytotoxic T-lymphocytes, total memory helper T-lymphocytes, monocytes or natural killer cells.
A reduction in gastrointestinal inflammation was observed in rectal biopsy specimens from Phase 2 ulcerative colitis patients exposed to vedolizumab for four or six weeks compared to placebo control as assessed by histopathology.
In a study of 14 healthy subjects, vedolizumab did not affect the CD4+ lymphocyte cell counts, CD8+ lymphocyte cell counts, or the CD4+:CD8+ ratios in the CSF
## Pharmacokinetics
Similar pharmacokinetics were observed in ulcerative colitis and Crohn’s disease patients administered 300 mg vedolizumab as a 30 minute intravenous infusion on Weeks 0 and 2, followed by 300 mg vedolizumab every eight weeks starting from Week 6 (Table 2).
The presence of persistent anti-vedolizumab antibody was observed to substantially reduce serum concentrations of vedolizumab, either to undetectable or negligible levels at Weeks 6 and 52 (n=8).
Vedolizumab clearance depends on both linear and nonlinear pathways; the nonlinear clearance decreases with increasing concentrations. Population pharmacokinetic analyses indicated that the linear clearance was approximately 0.157 L/day, the serum half-life was approximately 25 days at 300 mg dosage, and the distribution volume was approximately 5 L.
Vedolizumab was not detected in the cerebrospinal fluid (CSF) of 14 healthy subjects at five weeks after a single intravenous administration of 450 mg vedolizumab (1.5 times the recommended dosage).
### Special Populations
Population pharmacokinetic analysis showed that the severity of disease state, body weight, prior treatment with TNF blocker therapy, age (18 to 78 years), serum albumin, co-administered immunomodulators (including azathioprine, 6-mercaptopurine, methotrexate), and co-administered aminosalicylates did not have a clinically meaningful effect on the pharmacokinetics of vedolizumab.
Pharmacokinetics of vedolizumab in patients with renal or hepatic insufficiency have not been studied.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of vedolizumab. Studies to evaluate the possible impairment of fertility or mutagenic potential of vedolizumab have not been performed.
# Clinical Studies
### Clinical Studies in Ulcerative Colitis
The safety and efficacy of vedolizumab were evaluated in two randomized, double-blind, placebo-controlled trials (UC Trials I and II) in adult patients with moderately to severely active ulcerative colitis (UC) defined as Mayo score of six to 12 with endoscopy subscore of two or three. The Mayo score ranges from zero to 12 and has four subscales that are each scored from zero (normal) to three (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of two is defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of three is defined by spontaneous bleeding and ulceration.
Enrolled patients in the United States (US) had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine or 6-mercaptopurine) and/or an inadequate response, loss of response, or intolerance to a TNF blocker. Outside the US, prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of UC) or had an inadequate response or intolerance to corticosteroids.
Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed.
### UC Trial I
In UC Trial I, 374 patients were randomized in a double-blind fashion (3:2) to receive vedolizumab 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage ≤30 mg/day or equivalent), and immunomodulators (azathioprine or 6‑mercaptopurine) were permitted through Week 6.
At baseline, patients received corticosteroids (54%), immunomodulators (azathioprine or 6-mercaptopurine) (30%), and/or aminosalicylates (74%). Thirty-nine percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Eighteen percent of patients had an inadequate response, inability to taper or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline Mayo score was nine in the vedolizumab group and eight in the placebo group.
In UC Trial I, a greater percentage of patients treated with vedolizumab compared to patients treated with placebo achieved clinical response at Week 6 (defined in Table 3). A greater percentage of patients treated with vedolizumab compared to patients treated with placebo also achieved clinical remission at Week 6 (defined in Table 3). In addition, a greater percentage of patients treated with vedolizumab had improvement of endoscopic appearance of the mucosa at Week 6 (defined in Table 3).
### UC Trial II
In order to be randomized to treatment in UC Trial II, patients had to have received vedolizumab and be in clinical response at Week 6. Patients could have come from either UC Trial I or from a group who received vedolizumab open-label.
In UC Trial II, 373 patients were randomized in a double‑blind fashion (1:1:1) to one of the following regimens beginning at Week 6: vedolizumab 300 mg every eight weeks, vedolizumab 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine or 6-mercaptopurine) were permitted outside the US but were not permitted beyond Week 6 in the US.
At Week 6, patients were receiving corticosteroids (61%), immunomodulators (azathioprine or 6-mercaptopurine) (32%) and aminosalicylates (75%). Thirty-two percent of patients had an inadequate response, loss of response or intolerance to a TNF blocker therapy. At Week 6, the median Mayo score was eight in the vedolizumab every eight week group, the vedolizumab every four week group, and the placebo group. Patients who had achieved clinical response at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6.
In UC Trial II, a greater percentage of patients in groups treated with vedolizumab as compared to placebo achieved clinical remission at Week 52, and maintained clinical response (clinical response at both Weeks 6 and 52) (Table 4). In addition, a greater percentage of patients in groups treated with vedolizumab as compared to placebo were in clinical remission at both Weeks 6 and 52, and had improvement of endoscopic appearance of the mucosa at Week 52 (Table 4). In the subgroup of patients who achieved clinical response at Week 6 and were receiving corticosteroid medication at baseline, a greater proportion of patients in groups treated with vedolizumab as compared to placebo discontinued corticosteroids and were in clinical remission at Week 52 (Table 4).
The vedolizumab every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen.
### Clinical Studies in Crohn’s Disease
The safety and efficacy of vedolizumab were evaluated in three randomized, double-blind, placebo-controlled clinical trials (CD Trials I, II, and III) in adult patients with moderately to severely active Crohn’s disease (CD) (Crohn’s Disease Activity Index score of 220 to 450).1
Enrolled patients in the United States (US) had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine, 6-mercaptopurine, or methotrexate) and/or an inadequate response, loss of response, or intolerance to one or more TNF blockers. Outside the US, prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of CD) or had an inadequate response or intolerance to corticosteroids.
Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 30 to 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed.
### CD Trial I
In CD Trial I, 368 patients were randomized in a double-blind fashion (3:2) to receive vedolizumab 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage ≤30 mg/day or equivalent), and immunomodulators (azathioprine, 6-mercaptopurine or methotrexate) were permitted through Week 6.
At baseline, patients were receiving corticosteroids (49%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (35%), and/or aminosalicylates (46%). Forty-eight percent of the patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Seventeen percent of patients had inadequate response, inability to taper, or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline CDAI score was 324 in the vedolizumab group and 319 in the placebo group.
In CD Trial I, a statistically significantly higher percentage of patients treated with vedolizumab achieved clinical remission (defined as CDAI ≤150) as compared to placebo at Week 6 (Table 5). The difference in the percentage of patients who demonstrated clinical response (defined as a ≥100-point decrease in CDAI score from baseline), was however, not statistically significant at Week 6.
### CD Trial II
Compared to CD Trial I, CD Trial II enrolled a higher number of patients who had over the previous five-year period had an inadequate response, loss of response, or intolerance to one or more TNF blockers (76%); this was the primary analysis population. In CD Trial II, 416 patients were randomized in a double-blind fashion (1:1) to receive either vedolizumab 300 mg or placebo at Weeks 0, 2 and 6. Efficacy assessments were at Weeks 6 and 10. Concomitant aminosalicylates, corticosteroids, and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted through Week 10.
At baseline, patients were receiving corticosteroids (54%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (34%), and aminosalicylates (31%). The median baseline CDAI score was 317 in the vedolizumab group and 301 in the placebo group.
For the primary endpoint (clinical remission at Week 6), treatment with vedolizumab did not result in statistically significant improvement over placebo (Table 5). Secondary endpoints including assessments at Week 10 were not tested because the primary endpoint was not statistically significant
### CD Trial III
In order to be randomized to treatment in CD Trial III, patients had to have received vedolizumab and be in clinical response (defined as a ≥70-point decrease in CDAI score from baseline) at Week 6. Patients could have come from either CD Trial I or from a group who received vedolizumab open-label.
In CD Trial III, 461 patients were randomized in a double‑blind fashion (1:1:1) to one of the following regimens beginning at Week 6: vedolizumab 300 mg every eight weeks, vedolizumab 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted outside the US but were not permitted beyond Week 6 in the US.
At Week 6, patients were receiving corticosteroids (59%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (31%), and aminosalicylates (41%). Fifty-one percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. At Week 6, the median CDAI score was 322 in the vedolizumab every eight week group, 316 in the vedolizumab every four week group, and 315 in the placebo group. Patients who had achieved clinical response (≥70 decrease in CDAI score from baseline) at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6.
In CD Trial III a greater percentage of patients in groups treated with vedolizumab as compared to placebo were in clinical remission (defined as CDAI score ≤150) at Week 52. A greater percentage of patients in groups treated with vedolizumab as compared to placebo had a clinical response (defined as ≥100 decrease in CDAI score from baseline) at Week 52 (Table 6). In the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response at Week 6 (defined as ≥70 decrease in CDAI score from baseline), a greater proportion of patients in groups treated with vedolizumab as compared to placebo discontinued corticosteroids by Week 52 and were in clinical remission at Week 52 (Table 6).
The vedolizumab every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen.
# How Supplied
- Vedolizumab (vedolizumab) is supplied in sterile 20 mL single-use glass vials, containing 300 mg of vedolizumab as a white to off-white cake.
## Storage
- Refrigerate unopened vials at 2° to 8°C (36º to 46ºF). Retain in original package to protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Hypersensitivity Reactions
Instruct patients to report immediately if they experience symptoms consistent with a hypersensitivity reaction during or following an infusion of vedolizumab.
### Infections
Inform patients that they may be more likely to develop infections when taking vedolizumab. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection.
### Progressive Multifocal Leukoencephalopathy
Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in patients who received a different integrin receptor antagonist product. Instruct patients to report if they experience any new onset or worsening of neurological signs and symptoms immediately, as these could be indicative of PML
### Liver Injury
- Inform patients that elevated transaminase levels with or without elevated bilirubin has occurred in patients who received vedolizumab. Instruct patients to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice
# Precautions with Alcohol
Alcohol-Vedolizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Entyvio
# Look-Alike Drug Names
There is limited information regarding Vedolizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Vedolizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]
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# Overview
Vedolizumab is a monoclonal antibody that is FDA approved for the treatment of Adult Ulcerative Colitis and Crohn’s disease. Common adverse reactions include nasopharyngitis and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Ulcerative Colitis or Crohn’s Disease
The recommended dosage of vedolizumab in adults with ulcerative colitis or Crohn's disease is 300 mg administered by intravenous infusion at zero, two and six weeks and then every eight weeks thereafter.
Discontinue therapy in patients who show no evidence of therapeutic benefit by Week 14.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vedolizumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vedolizumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Vedolizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vedolizumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vedolizumab in pediatric patients.
# Contraindications
Vedolizumab is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to vedolizumab or any of its excipients (such as dyspnea, bronchospasm, urticaria, flushing, rash and increased heart rate)
# Warnings
### Infusion-Related Reactions and Hypersensitivity Reactions
- In UC Trials I and II and CD Trials I and III, hypersensitivity reactions occurred including a case of anaphylaxis (one out of 1434 patients [0.07%]).
- Allergic reactions including dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have also been observed.
- The majority were mild to moderate in severity as assessed by the investigator.
- Experience with other biologic medications suggests that hypersensitivity reactions and anaphylaxis to vedolizumab may vary in their time of onset from during infusion or immediately post-infusion to occurring up to several hours post-infusion.
- If anaphylaxis or other serious allergic reactions occur, discontinue administration of vedolizumab immediately and initiate appropriate treatment (e.g., epinephrine and antihistamines).
### Infections
- Patients treated with vedolizumab are at increased risk for developing infections.
- The most commonly reported infections in clinical trials occurring at a rate greater on vedolizumab than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection).
- Serious infections have also been reported in patients treated with vedolizumab, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.
- Vedolizumab is not recommended in patients with active, severe infections until the infections are controlled.
- Consider withholding treatment in patients who develop a severe infection while on treatment with vedolizumab.
- Exercise caution when considering the use of vedolizumab in patients with a history of recurring severe infections.
- Consider screening for tuberculosis (TB) according to the local practice.
- For progressive multifocal leukoencephalopathy (PML),
### Progressive Multifocal Leukoencephalopathy
- Another integrin receptor antagonist has been associated with progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS). PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised.
- In vedolizumab clinical trials, patients were actively monitored for PML with frequent and regular screenings, and evaluations of any new, unexplained neurological symptoms, as necessary.
- While zero cases of PML were identified among patients with at least 24 months of exposure, a risk of PML cannot be ruled out.
- No claims of comparative safety to other integrin receptor antagonists can be made based on this data.
- Monitor patients on vedolizumab for any new onset, or worsening, of neurological signs and symptoms.
- Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
- The progression of deficits usually leads to death or severe disability over weeks or months. If PML is suspected, withhold dosing with vedolizumab and refer to a neurologist; if confirmed, discontinue dosing permanently.
### Liver Injury
- There have been reports of elevations of transaminase and/or bilirubin in patients receiving vedolizumab. In general, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. vedolizumab should be discontinued in patients with jaundice or other evidence of significant liver injury.
### Live and Oral Vaccines
- Prior to initiating treatment with vedolizumab, all patients should be brought up to date with all immunizations according to current immunization guidelines.
- Patients receiving vedolizumab may receive non-live vaccines (e.g., influenza vaccine injection) and may receive live vaccines if the benefits outweigh the risks.
- There are no data on the secondary transmission of infection by live vaccines in patients receiving vedolizumab.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to vedolizumab in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years.
The safety data described in Table 1 are derived from four controlled Phase 3 trials (UC Trials I and II, and CD Trials I and III); data from patients receiving open-label vedolizumab treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included.
In these trials, 1,434 patients received vedolizumab 300 mg for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohn’s disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III).
Adverse reactions were reported in 52% of patients treated with vedolizumab and 45% of patients treated with placebo (UC Trials I and II: 49% with vedolizumab and 37% with placebo; CD Trials I and III: 55% with vedolizumab and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with vedolizumab compared to 4% of patients treated with placebo (UC Trials I and II: 8% with vedolizumab and 7% with placebo; CD Trials I and III: 12% with vedolizumab and 9%, with placebo).
The most common adverse reactions (reported by ≥3% of patients treated with vedolizumab in the UC Trials I and II and CD Trials I and III combined group and ≥1% higher than in combined placebo group) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in extremities (Table 1).
Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received vedolizumab at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10 week Crohn’s disease trial, are similar to those listed in Table 1.
Infusion-Related Reactions and Hypersensitivity Reactions
Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following vedolizumab administration in clinical trials. In UC Trials I and II and Crohn’s Trials I and III, one case of anaphylaxis [one out of 1434 patients treated with vedolizumab (0.07%)] was reported by a Crohn’s disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash and increased blood pressure and heart rate) and was managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone.
In UC Trials I and II and CD Trials I and III, 4% of patients treated with vedolizumab and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with vedolizumab (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria and vomiting (each of these adverse reactions occurred in <1% in all patients treated with vedolizumab) and no individual adverse reaction reported occurred at a rate above 1%. These reactions generally occurred within the first two hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment. Less than 1% of patients treated with vedolizumab had IRRs assessed by the investigator as severe, and IRRs requiring discontinuation of study treatment occurred in <1%.
In clinical trials, for patients with mild IRRs or hypersensitivity reactions, physicians were allowed to pretreat with standard medical treatment (e.g., antihistamine, hydrocortisone and/or acetaminophen) prior to next infusion.
Infections
In UC Trials I and II and CD Trials I and III, the rate of infections was 0.85 per patient-year in the patients treated with vedolizumab and 0.7 per patient-year in the patients treated with placebo. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infection. Two percent of patients discontinued vedolizumab due to infections.
In UC Trials I and II and CD Trials I and III, the rate of serious infections was 0.07 per patient-year in patients treated with vedolizumab and 0.06 per patient-year in patients treated with placebo. Serious infections were more common in Crohn’s disease patients than ulcerative colitis patients, and anal abscesses were the most frequently reported serious adverse reaction in Crohn’s disease patients. Over 48 months, there was no increase in the rate of serious infections.
In controlled- and open-label long-term extension trials in adults treated with vedolizumab, serious infections have been reported, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.
In UC Trials I and II and CD Trials I and III, sepsis, including bacterial sepsis and septic shock, was reported in four of 1434 (0.3%) patients treated with vedolizumab and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohn’s disease patients treated with vedolizumab died due to reported sepsis or septic shock; both of these patients had significant comorbidities and a complicated hospital course that contributed to the deaths. In an open label long-term extension trial, additional cases of sepsis (some fatal), including bacterial sepsis and septic shock, were reported. The rate of sepsis in patients with ulcerative colitis or Crohn’s disease receiving vedolizumab was two per 1000 patient-years.
In clinical trials, all patients were screened for tuberculosis. One case of latent, pulmonary tuberculosis was diagnosed during the controlled trials with vedolizumab. Additional cases of pulmonary tuberculosis were diagnosed during the open-label trial. All of these observed cases occurred outside the United States, and none of the patients had extrapulmonary manifestations.
Liver Injury
There have been reports of elevations of transaminase and/or bilirubin in patients receiving vedolizumab. In UC Trials I and II and CD Trials I and III, three patients reported serious adverse reactions of hepatitis, manifested as elevated transaminases with or without elevated bilirubin and symptoms consistent with hepatitis (e.g., malaise, nausea, vomiting, abdominal pain, anorexia). These adverse reactions occurred following two to five vedolizumab doses; however, based on case report information it is unclear if the reactions indicated drug-induced or autoimmune etiology. All patients recovered following discontinuation of therapy with some requiring corticosteroid treatment. In controlled trials, the incidence of ALT and AST elevations ≥3 x ULN was <2% in patients treated with vedolizumab and in patients treated with placebo. In the open-label trial, one additional case of serious hepatitis was observed.
Malignancies
In UC Trials I and II and CD Trials I and III, malignancies (excluding dysplasia and basal cell carcinoma) were reported in six of 1434 (0.4%) patients treated with vedolizumab, including colon cancer (n=2), transitional cell carcinoma (n=1), breast cancer (n=1), carcinoid tumor of the appendix (n=1) and squamous cell carcinoma (n=1). Malignancy was reported in one of 297 (0.3%) patients treated with placebo (squamous cell carcinoma).
Malignancies (excluding dysplasia and basal cell carcinoma) observed during the ongoing open-label long-term extension trial included B-cell lymphoma, breast cancer, colon cancer, malignant hepatic neoplasm, malignant lung neoplasm, malignant melanoma, lung cancer of primary neuroendocrine carcinoma, renal cancer and squamous cell carcinoma. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited.
Live and Oral Vaccines
There are no data on the secondary transmission of infection by live vaccines in patients receiving vedolizumab.
In a placebo-controlled study of healthy volunteers, 61 subjects were given a single vedolizumab 750 mg dose (2.5 times the recommended dose), and 62 subjects received placebo followed by intramuscular vaccination with Hepatitis B surface antigen and oral cholera vaccine. After intramuscular vaccination with three doses of recombinant Hepatitis B surface antigen, those treated with vedolizumab did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to vedolizumab did have lower seroconversion rates and anti-cholera titers relative to placebo after receiving the two doses of a killed, oral cholera vaccine. The impact on other oral vaccines and on nasal vaccines in patients is unknown.
### Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. In UC Trials I and II and CD Trials I and III, in patients who received vedolizumab, the frequency of antibodies detected in patients was 13% at 24 weeks after the last dose of study drug (greater than five half-lives after last dose). During treatment, 56 of 1434 (4%) of patients treated with vedolizumab had detectable anti-vedolizumab antibody at any time during the 52 weeks of continuous treatment. Nine of 56 patients were persistently positive (at two or more study visits) for anti-vedolizumab antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab. Among eight of these nine subjects with persistently positive anti-vedolizumab antibody and available vedolizumab concentration data, six had undetectable and two had reduced vedolizumab concentrations. None of the nine subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, presence of vedolizumab, and underlying disease. For these reasons, comparison of the incidence of antibodies to vedolizumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Vedolizumab Postmarketing Experience in the drug label.
# Drug Interactions
### Natalizumab
- Because of the potential for increased risk of PML and other infections, avoid the concomitant use of vedolizumab with natalizumab.
### TNF Blockers
- Because of the potential for increased risk of infections, avoid the concomitant use of vedolizumab with TNF blockers.
### Live Vaccines
- Live vaccines may be administered concurrently with vedolizumab only if the benefits outweigh the risks
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no studies with vedolizumab in pregnant women.
- No fetal harm was observed in animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage. *Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the benefits to the mother outweigh the risk to the unborn child.
### Clinical Considerations
Any adverse pregnancy effect from vedolizumab would likely be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
### Animal Data
A reproduction study has been performed in pregnant rabbits at single intravenous doses up to 100 mg/kg administered on gestation Day 7 (about 20 times the recommended human dosage) and has revealed no evidence of impaired fertility or harm to the fetus due to vedolizumab. A pre- and post-natal development study in monkeys showed no evidence of any adverse effect on pre- and post-natal development at intravenous doses up to 100 mg/kg (about 20 times the recommended human dosage).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vedolizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vedolizumab during labor and delivery.
### Nursing Mothers
- It is unknown whether vedolizumab is present in human milk.
- Vedolizumab was detected in the milk of lactating monkeys.
- Exercise caution when administering vedolizumab to a nursing woman.
### Pediatric Use
- Safety and effectiveness of vedolizumab in pediatric patients have not been established.
### Geriatic Use
- Clinical trials of vedolizumab did not include sufficient numbers of subjects aged 65 and over (46 Crohn’s and ulcerative colitis patients aged 65 and over were treated with vedolizumab during controlled Phase 3 trials) to determine whether they respond differently from younger subjects. However, no overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Vedolizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vedolizumab with respect to specific racial populations.
### Renal Impairment
- Pharmacokinetics of vedolizumab in patients with renal insufficiency have not been studied.
### Hepatic Impairment
- Pharmacokinetics of vedolizumab in patients with hepatic insufficiency have not been studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vedolizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vedolizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer vedolizumab as an intravenous infusion over 30 minutes.
- Do not administer as an intravenous push or bolus.
- Vedolizumab lyophilized powder must be reconstituted with Sterile Water for injection and diluted in 250 mL of sterile 0.9% Sodium Chloride injection prior to administration.
- After the infusion is complete, flush with 30 mL of sterile 0.9% Sodium Chloride injection.
- Vedolizumab should be administered by a healthcare professional prepared to manage hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use. Observe patients during infusion and until the infusion is complete.
### Prior to Administration of vedolizumab
- Prior to initiating treatment with vedolizumab, all patients should be brought up to date with all immunizations according to current immunization guidelines.
### Monitoring
- Monitor for PML with frequent and regular screenings, and evaluations of any new, unexplained neurological symptoms, as necessary.
# IV Compatibility
### Reconstitution Instructions
- Reconstitute vedolizumab at room temperature. Vedolizumab should be reconstituted and prepared by a trained medical professional using aseptic technique by the following procedure:
- Remove the flip-off cap from the single-dose vial and wipe with alcohol swab. Reconstitute vedolizumab vial containing lyophilized powder with 4.8 mL of Sterile Water for injection, using a syringe with a 21 to 25 gauge needle.
- Insert the syringe needle into the vial through the center of the stopper and direct the stream of Sterile Water for injection to the glass wall of the vial to avoid excessive foaming.
- Gently swirl the vial for at least 15 seconds to dissolve the lyophilized powder. Do not vigorously shake or invert.
- Allow the solution to sit for up to 20 minutes at room temperature to allow for reconstitution and for any foam to settle; the vial can be swirled and inspected for dissolution during this time. If not fully dissolved after 20 minutes, allow another 10 minutes for dissolution. Do not use the vial if the drug product is not dissolved within 30 minutes.
- Visually inspect the reconstituted vedolizumab solution for particulate matter and discoloration prior to administration. Solution should be clear or opalescent, colorless to light brownish yellow and free of visible particulates. Do not administer reconstituted solution showing uncharacteristic color or containing particulates.
- Prior to withdrawing the reconstituted vedolizumab solution from the vial, gently invert vial three times.
- Withdraw 5 mL (300 mg) of reconstituted vedolizumab solution using a syringe with a 21 to 25 gauge needle. Discard any remaining portion of the reconstituted solution in the vial.
Dilution Instructions
Add the 5 mL (300 mg) of reconstituted vedolizumab solution to 250 mL of sterile 0.9% Sodium Chloride and gently mix the infusion bag. Do not add other medicinal products to the prepared infusion solution or intravenous infusion set. Once reconstituted and diluted, use the infusion solution as soon as possible.
Storage
Do not freeze. Discard any unused portion of the infusion solution.
# Overdosage
There is limited information regarding Vedolizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. Vedolizumab does not bind to or inhibit function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1).
The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T-lymphocytes to gut lymph tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn’s disease.
## Structure
Vedolizumab, an integrin receptor antagonist, is a humanized IgG1 monoclonal antibody produced in Chinese hamster ovary cells that binds to the human α4β7 integrin. Vedolizumab has an approximate molecular weight of 147 kilodaltons.
## Pharmacodynamics
In clinical trials with vedolizumab at doses ranging from 0.2 to 10 mg/kg (which includes doses outside of the recommended dose), saturation of α4β7 receptors on subsets of circulating lymphocytes involved in gut-immune surveillance was observed.
In clinical trials with vedolizumab at doses ranging from 0.2 to 10 mg/kg and 180 to 750 mg (which include doses outside of the recommended dose) in healthy subjects and in patients with ulcerative colitis or Crohn’s disease, vedolizumab did not elevate neutrophils, basophils, eosinophils, B-helper and cytotoxic T-lymphocytes, total memory helper T-lymphocytes, monocytes or natural killer cells.
A reduction in gastrointestinal inflammation was observed in rectal biopsy specimens from Phase 2 ulcerative colitis patients exposed to vedolizumab for four or six weeks compared to placebo control as assessed by histopathology.
In a study of 14 healthy subjects, vedolizumab did not affect the CD4+ lymphocyte cell counts, CD8+ lymphocyte cell counts, or the CD4+:CD8+ ratios in the CSF
## Pharmacokinetics
Similar pharmacokinetics were observed in ulcerative colitis and Crohn’s disease patients administered 300 mg vedolizumab as a 30 minute intravenous infusion on Weeks 0 and 2, followed by 300 mg vedolizumab every eight weeks starting from Week 6 (Table 2).
The presence of persistent anti-vedolizumab antibody was observed to substantially reduce serum concentrations of vedolizumab, either to undetectable or negligible levels at Weeks 6 and 52 (n=8).
Vedolizumab clearance depends on both linear and nonlinear pathways; the nonlinear clearance decreases with increasing concentrations. Population pharmacokinetic analyses indicated that the linear clearance was approximately 0.157 L/day, the serum half-life was approximately 25 days at 300 mg dosage, and the distribution volume was approximately 5 L.
Vedolizumab was not detected in the cerebrospinal fluid (CSF) of 14 healthy subjects at five weeks after a single intravenous administration of 450 mg vedolizumab (1.5 times the recommended dosage).
### Special Populations
Population pharmacokinetic analysis showed that the severity of disease state, body weight, prior treatment with TNF blocker therapy, age (18 to 78 years), serum albumin, co-administered immunomodulators (including azathioprine, 6-mercaptopurine, methotrexate), and co-administered aminosalicylates did not have a clinically meaningful effect on the pharmacokinetics of vedolizumab.
Pharmacokinetics of vedolizumab in patients with renal or hepatic insufficiency have not been studied.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of vedolizumab. Studies to evaluate the possible impairment of fertility or mutagenic potential of vedolizumab have not been performed.
# Clinical Studies
### Clinical Studies in Ulcerative Colitis
The safety and efficacy of vedolizumab were evaluated in two randomized, double-blind, placebo-controlled trials (UC Trials I and II) in adult patients with moderately to severely active ulcerative colitis (UC) defined as Mayo score of six to 12 with endoscopy subscore of two or three. The Mayo score ranges from zero to 12 and has four subscales that are each scored from zero (normal) to three (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of two is defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of three is defined by spontaneous bleeding and ulceration.
Enrolled patients in the United States (US) had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine or 6-mercaptopurine) and/or an inadequate response, loss of response, or intolerance to a TNF blocker. Outside the US, prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of UC) or had an inadequate response or intolerance to corticosteroids.
Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed.
### UC Trial I
In UC Trial I, 374 patients were randomized in a double-blind fashion (3:2) to receive vedolizumab 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage ≤30 mg/day or equivalent), and immunomodulators (azathioprine or 6‑mercaptopurine) were permitted through Week 6.
At baseline, patients received corticosteroids (54%), immunomodulators (azathioprine or 6-mercaptopurine) (30%), and/or aminosalicylates (74%). Thirty-nine percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Eighteen percent of patients had an inadequate response, inability to taper or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline Mayo score was nine in the vedolizumab group and eight in the placebo group.
In UC Trial I, a greater percentage of patients treated with vedolizumab compared to patients treated with placebo achieved clinical response at Week 6 (defined in Table 3). A greater percentage of patients treated with vedolizumab compared to patients treated with placebo also achieved clinical remission at Week 6 (defined in Table 3). In addition, a greater percentage of patients treated with vedolizumab had improvement of endoscopic appearance of the mucosa at Week 6 (defined in Table 3).
### UC Trial II
In order to be randomized to treatment in UC Trial II, patients had to have received vedolizumab and be in clinical response at Week 6. Patients could have come from either UC Trial I or from a group who received vedolizumab open-label.
In UC Trial II, 373 patients were randomized in a double‑blind fashion (1:1:1) to one of the following regimens beginning at Week 6: vedolizumab 300 mg every eight weeks, vedolizumab 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine or 6-mercaptopurine) were permitted outside the US but were not permitted beyond Week 6 in the US.
At Week 6, patients were receiving corticosteroids (61%), immunomodulators (azathioprine or 6-mercaptopurine) (32%) and aminosalicylates (75%). Thirty-two percent of patients had an inadequate response, loss of response or intolerance to a TNF blocker therapy. At Week 6, the median Mayo score was eight in the vedolizumab every eight week group, the vedolizumab every four week group, and the placebo group. Patients who had achieved clinical response at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6.
In UC Trial II, a greater percentage of patients in groups treated with vedolizumab as compared to placebo achieved clinical remission at Week 52, and maintained clinical response (clinical response at both Weeks 6 and 52) (Table 4). In addition, a greater percentage of patients in groups treated with vedolizumab as compared to placebo were in clinical remission at both Weeks 6 and 52, and had improvement of endoscopic appearance of the mucosa at Week 52 (Table 4). In the subgroup of patients who achieved clinical response at Week 6 and were receiving corticosteroid medication at baseline, a greater proportion of patients in groups treated with vedolizumab as compared to placebo discontinued corticosteroids and were in clinical remission at Week 52 (Table 4).
The vedolizumab every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen.
### Clinical Studies in Crohn’s Disease
The safety and efficacy of vedolizumab were evaluated in three randomized, double-blind, placebo-controlled clinical trials (CD Trials I, II, and III) in adult patients with moderately to severely active Crohn’s disease (CD) (Crohn’s Disease Activity Index [CDAI] score of 220 to 450).1
Enrolled patients in the United States (US) had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine, 6-mercaptopurine, or methotrexate) and/or an inadequate response, loss of response, or intolerance to one or more TNF blockers. Outside the US, prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of CD) or had an inadequate response or intolerance to corticosteroids.
Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 30 to 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed.
### CD Trial I
In CD Trial I, 368 patients were randomized in a double-blind fashion (3:2) to receive vedolizumab 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage ≤30 mg/day or equivalent), and immunomodulators (azathioprine, 6-mercaptopurine or methotrexate) were permitted through Week 6.
At baseline, patients were receiving corticosteroids (49%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (35%), and/or aminosalicylates (46%). Forty-eight percent of the patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Seventeen percent of patients had inadequate response, inability to taper, or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline CDAI score was 324 in the vedolizumab group and 319 in the placebo group.
In CD Trial I, a statistically significantly higher percentage of patients treated with vedolizumab achieved clinical remission (defined as CDAI ≤150) as compared to placebo at Week 6 (Table 5). The difference in the percentage of patients who demonstrated clinical response (defined as a ≥100-point decrease in CDAI score from baseline), was however, not statistically significant at Week 6.
### CD Trial II
Compared to CD Trial I, CD Trial II enrolled a higher number of patients who had over the previous five-year period had an inadequate response, loss of response, or intolerance to one or more TNF blockers (76%); this was the primary analysis population. In CD Trial II, 416 patients were randomized in a double-blind fashion (1:1) to receive either vedolizumab 300 mg or placebo at Weeks 0, 2 and 6. Efficacy assessments were at Weeks 6 and 10. Concomitant aminosalicylates, corticosteroids, and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted through Week 10.
At baseline, patients were receiving corticosteroids (54%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (34%), and aminosalicylates (31%). The median baseline CDAI score was 317 in the vedolizumab group and 301 in the placebo group.
For the primary endpoint (clinical remission at Week 6), treatment with vedolizumab did not result in statistically significant improvement over placebo (Table 5). Secondary endpoints including assessments at Week 10 were not tested because the primary endpoint was not statistically significant
### CD Trial III
In order to be randomized to treatment in CD Trial III, patients had to have received vedolizumab and be in clinical response (defined as a ≥70-point decrease in CDAI score from baseline) at Week 6. Patients could have come from either CD Trial I or from a group who received vedolizumab open-label.
In CD Trial III, 461 patients were randomized in a double‑blind fashion (1:1:1) to one of the following regimens beginning at Week 6: vedolizumab 300 mg every eight weeks, vedolizumab 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted outside the US but were not permitted beyond Week 6 in the US.
At Week 6, patients were receiving corticosteroids (59%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (31%), and aminosalicylates (41%). Fifty-one percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. At Week 6, the median CDAI score was 322 in the vedolizumab every eight week group, 316 in the vedolizumab every four week group, and 315 in the placebo group. Patients who had achieved clinical response (≥70 decrease in CDAI score from baseline) at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6.
In CD Trial III a greater percentage of patients in groups treated with vedolizumab as compared to placebo were in clinical remission (defined as CDAI score ≤150) at Week 52. A greater percentage of patients in groups treated with vedolizumab as compared to placebo had a clinical response (defined as ≥100 decrease in CDAI score from baseline) at Week 52 (Table 6). In the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response at Week 6 (defined as ≥70 decrease in CDAI score from baseline), a greater proportion of patients in groups treated with vedolizumab as compared to placebo discontinued corticosteroids by Week 52 and were in clinical remission at Week 52 (Table 6).
The vedolizumab every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen.
# How Supplied
- Vedolizumab (vedolizumab) is supplied in sterile 20 mL single-use glass vials, containing 300 mg of vedolizumab as a white to off-white cake.
## Storage
- Refrigerate unopened vials at 2° to 8°C (36º to 46ºF). Retain in original package to protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Hypersensitivity Reactions
Instruct patients to report immediately if they experience symptoms consistent with a hypersensitivity reaction during or following an infusion of vedolizumab.
### Infections
Inform patients that they may be more likely to develop infections when taking vedolizumab. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection.
### Progressive Multifocal Leukoencephalopathy
Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in patients who received a different integrin receptor antagonist product. Instruct patients to report if they experience any new onset or worsening of neurological signs and symptoms immediately, as these could be indicative of PML
### Liver Injury
- Inform patients that elevated transaminase levels with or without elevated bilirubin has occurred in patients who received vedolizumab. Instruct patients to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice
# Precautions with Alcohol
Alcohol-Vedolizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Entyvio[1]
# Look-Alike Drug Names
There is limited information regarding Vedolizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Entyvio | |
75bab00ed38d8a28325bc9fb97d7d5868de443ab | wikidoc | Enucleation | Enucleation
# Overview
Enucleation is removal of the eye, leaving the eye muscles and remaining orbital contents intact. This type of ocular surgery is indicated for a number of different ocular tumors, in eyes that have suffered severe trauma, and in eyes that are blind and painful due to other disease.
Auto-enucleation is a form of severe self-harm which may occur in sufferers of psychosis.
# Classification
There are three types of eye removal
- Evisceration - removal of the internal eye contents, but the sclera is left behind with the extraocular muscles still attached.
- Enucleation - removal of the eyeball, but the adjacent structures of the eye socket and eyelids remain. An intraocular tumor excision requires an enucleation, not an evisceration.
- Exenteration - removal of the contents of the eye socket (orbit) including the eyeball, fat, muscles and other adjacent structures of the eye. The eyelids may also be removed in cases of cutaneous cancers and unrelenting infection. Exenteration is sometimes done together with Maxillectomy which is removal of the maxilla or the upper jaw bone/cheekbone
# Reasons for eye removal
- Cancer of the eye (retinoblastoma, melanomas, any other cancers of the eye or orbit)
- Severe injury of the eye when the eye cannot be saved or attempts to save the eye have failed
- End stage glaucoma
- Painful, blind eye
- In cases of sympathetic ophthalmia (inflammation of the eye) to prevent travel to other eye, in which, if untreated can cause blindness
- Congenital cystic eye
- Torture
- Punishment
- In a deceased person, for their cornea so their cornea can be used for when a next living person needs a corneal transplant
# Orbital implants and ocular prostheses
Removal of the eye by enucleation or evisceration can relieve pain and minimize further risk to life and well-being of an individual with the above noted conditions. In addition, procedures to remove the eye should address the resulting appearance of the orbit. Orbital implants and ocular prostheses are used by the surgeon to restore a more natural appearance.
An orbital implant is placed after removal of the eye to restore volume to the eye socket and enhance movement or motility of an ocular prosthesis and eyelids. The eyeball is a slightly elongated sphere with a diameter of approximately 24 millimetres. To avoid a sunken appearance to the eye socket, an implant approximating this volume can be placed into the space of the removed eye, secured, and covered with
Tenon's capsule and conjunctiva (the mucous membrane covering the natural sclera). Implants can be made of many materials with the most common being plastic, hydroxylapatite, metal alloy or glass.
Later, once the conjunctiva has healed and post-operative swelling has subsided, an ocular prosthesis can be placed to provide the appearance of a natural eye. The prosthesis is fabricated by an ocularist. Its form is that of a cupped disc so that it can fit comfortably in the pocket behind the eyelids overlying the conjunctiva that covers the orbital implant. The external portion of the ocular prosthesis is painted and finished to mimic a natural eye color, shape and luster. It can be removed and cleaned periodically by the individual or a care giver.
The two part system of orbital implant and ocular prosthesis provides a stable, and well tolerated aesthetic restoration of the eye socket. Although vision is not restored by removal of the eye with placement of an orbital implant and ocular prosthesis, a natural appearance can result. The implant can be moved by intact extraocular muscles that will track or move simultaneously with the other eye. The visible ocular prosthesis can couple with the orbital implant and thus move simultaneously with the other eye. The eyelids can move and blink over the prosthesis as well.
Patient #1: MR images of a patient status post enucleation | Enucleation
Template:Interventions infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Enucleation is removal of the eye, leaving the eye muscles and remaining orbital contents intact. This type of ocular surgery is indicated for a number of different ocular tumors, in eyes that have suffered severe trauma, and in eyes that are blind and painful due to other disease.[1]
Auto-enucleation is a form of severe self-harm which may occur in sufferers of psychosis.
# Classification
There are three types of eye removal
- Evisceration - removal of the internal eye contents, but the sclera is left behind with the extraocular muscles still attached.
- Enucleation - removal of the eyeball, but the adjacent structures of the eye socket and eyelids remain. An intraocular tumor excision requires an enucleation, not an evisceration.
- Exenteration - removal of the contents of the eye socket (orbit) including the eyeball, fat, muscles and other adjacent structures of the eye. The eyelids may also be removed in cases of cutaneous cancers and unrelenting infection. Exenteration is sometimes done together with Maxillectomy which is removal of the maxilla or the upper jaw bone/cheekbone
# Reasons for eye removal
- Cancer of the eye (retinoblastoma, melanomas, any other cancers of the eye or orbit)
- Severe injury of the eye when the eye cannot be saved or attempts to save the eye have failed
- End stage glaucoma
- Painful, blind eye
- In cases of sympathetic ophthalmia (inflammation of the eye) to prevent travel to other eye, in which, if untreated can cause blindness
- Congenital cystic eye
- Torture
- Punishment
- In a deceased person, for their cornea so their cornea can be used for when a next living person needs a corneal transplant
# Orbital implants and ocular prostheses
Removal of the eye by enucleation or evisceration can relieve pain and minimize further risk to life and well-being of an individual with the above noted conditions. In addition, procedures to remove the eye should address the resulting appearance of the orbit. Orbital implants and ocular prostheses are used by the surgeon to restore a more natural appearance.
An orbital implant is placed after removal of the eye to restore volume to the eye socket and enhance movement or motility of an ocular prosthesis and eyelids. The eyeball is a slightly elongated sphere with a diameter of approximately 24 millimetres. To avoid a sunken appearance to the eye socket, an implant approximating this volume can be placed into the space of the removed eye, secured, and covered with
Tenon's capsule and conjunctiva (the mucous membrane covering the natural sclera). Implants can be made of many materials with the most common being plastic, hydroxylapatite, metal alloy or glass.
Later, once the conjunctiva has healed and post-operative swelling has subsided, an ocular prosthesis can be placed to provide the appearance of a natural eye. The prosthesis is fabricated by an ocularist. Its form is that of a cupped disc so that it can fit comfortably in the pocket behind the eyelids overlying the conjunctiva that covers the orbital implant. The external portion of the ocular prosthesis is painted and finished to mimic a natural eye color, shape and luster. It can be removed and cleaned periodically by the individual or a care giver.
The two part system of orbital implant and ocular prosthesis provides a stable, and well tolerated aesthetic restoration of the eye socket. Although vision is not restored by removal of the eye with placement of an orbital implant and ocular prosthesis, a natural appearance can result. The implant can be moved by intact extraocular muscles that will track or move simultaneously with the other eye. The visible ocular prosthesis can couple with the orbital implant and thus move simultaneously with the other eye. The eyelids can move and blink over the prosthesis as well.
Patient #1: MR images of a patient status post enucleation
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-
-
- | https://www.wikidoc.org/index.php/Enucleation | |
152b36be6412cb8597d9daba6100306874b35e8b | wikidoc | Enzyme unit | Enzyme unit
The enzyme unit (U) is a unit for the amount of a particular enzyme.
One U is defined as that amount of the enzyme that catalyzes the conversion of 1 micro mole of substrate per minute. The conditions also have to be specified: one usually takes a temperature of 30°C and the pH value and substrate concentration that yield the maximal substrate conversion rate.
The enzyme unit was adopted by the International Union of Biochemistry in 1964. Since the minute is not an SI unit, the enzyme unit is discouraged in favour of the katal, the unit recommended by the General Conference on Weights and Measures in 1978 and officially adopted in 1999. One katal is the amount of enzyme that converts 1 mole of substrate per second, so
The enzyme unit should not be confused with the International Unit (IU), an unrelated measure of biologically active substances. | Enzyme unit
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The enzyme unit (U) is a unit for the amount of a particular enzyme.[1]
One U is defined as that amount of the enzyme that catalyzes the conversion of 1 micro mole of substrate per minute. The conditions also have to be specified: one usually takes a temperature of 30°C and the pH value and substrate concentration that yield the maximal substrate conversion rate.
The enzyme unit was adopted by the International Union of Biochemistry in 1964. Since the minute is not an SI unit, the enzyme unit is discouraged in favour of the katal, the unit recommended by the General Conference on Weights and Measures in 1978 and officially adopted in 1999. One katal is the amount of enzyme that converts 1 mole of substrate per second, so
The enzyme unit should not be confused with the International Unit (IU), an unrelated measure of biologically active substances. | https://www.wikidoc.org/index.php/Enzyme_unit | |
376c8502fcf8034609983d5e38f96f2c22c0b3b2 | wikidoc | Epiboxidine | Epiboxidine
Epiboxidine is a chemical compound which acts as a partial agonist at neural nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes. It was developed as a less toxic analogue of the potent frog-derived alkaloid epibatidine, which is around 200 times stronger than morphine as an analgesic but produces extremely dangerous toxic side effects.
Epiboxidine is around ten times less potent than epibatidine as an α4β2 agonist, but has around the same potency as an α3β4 agonist. It has only one-tenth of the analgesic power of epibatidine, but is also much less toxic.
# Uses
Despite its decreased potency and toxicity compared to epibatidine, epiboxidine itself is still too toxic to be developed as a drug for use in humans. It is used in scientific research and as a parent compound to derive newer analogues which may be safer and have greater potential for clinical development. | Epiboxidine
Template:Chembox new
Epiboxidine is a chemical compound which acts as a partial agonist at neural nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes. It was developed as a less toxic analogue of the potent frog-derived alkaloid epibatidine, which is around 200 times stronger than morphine as an analgesic but produces extremely dangerous toxic side effects.
Epiboxidine is around ten times less potent than epibatidine as an α4β2 agonist, but has around the same potency as an α3β4 agonist. It has only one-tenth of the analgesic power of epibatidine, but is also much less toxic.[1]
# Uses
Despite its decreased potency and toxicity compared to epibatidine, epiboxidine itself is still too toxic to be developed as a drug for use in humans. It is used in scientific research[2] and as a parent compound to derive newer analogues which may be safer and have greater potential for clinical development.[3][4][5]
Template:Pharm-stub | https://www.wikidoc.org/index.php/Epiboxidine | |
eeaf0299e39fd4800db73757b42f6886446d509a | wikidoc | Epigenetics | Epigenetics
Epigenetics is a term in biology used today to refer to features such as chromatin and DNA modifications that are stable over rounds of cell division but do not involve changes in the underlying DNA sequence of the organism. These epigenetic changes play a role in the process of cellular differentiation, allowing cells to stably maintain different characteristics despite containing the same genomic material. Epigenetic features are inherited when cells divide despite a lack of change in the DNA sequence itself and, although most of these features are considered dynamic over the course of development in multicellular organisms, some epigenetic features show transgenerational inheritance and are inherited from one generation to the next.
Specific epigenetic processes of interest include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.
# Etymology and Definitions
The word "epigenetics" has been associated with many different definitions, and much of the confusion surrounding the use of the word "epigenetics" relates to the fact that it was originally defined to explain phenomena without knowing their molecular basis and with time became narrowly linked to certain phenomena as their molecular basis was discovered.
Originally, the word "epigenetics" (as in "epigenetic landscape") was coined by C. H. Waddington in 1942 as a portmanteau of the words "genetics" and "epigenesis". Epigenesis is an older word used to describe the differentiation of cells from a totipotent state in embryonic development (used in contrast to "preformationism"). At the time Waddington first used the term "epigenetics" the physical nature of genes and their role in heredity was not known. Epigenetics was Waddington's model of how genes within a multicellular organism interact with their surroundings to produce a phenotype. Because all cells within an organism inherit the same DNA sequences, cellular differentiation processes crucial for epigenesis rely strongly on epigenetic rather than genetic inheritance. Robin Holliday defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms."
Another usage of the word "epigenetics" was employed by the psychologist Erik Erikson, who developed an "epigenetic theory of human development" which focuses on psycho-social crises.
The modern usage of the word "epigenetic" is more narrow, referring to heritable traits (over rounds of cell division and sometimes transgenerationally) that do not involve changes to the underlying DNA sequence. The Greek "epi-" prefix of the word "epigenetics" implies features that are "on top of" or "in addition to" genetics, and the current usage of the word reflects this—epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance.
The similarity of the word to "genetics" has generated many parallel usages. The "epigenome" is a parallel to the word "genome" and refers to the overall epigenetic state of a cell. The phrase "genetic code" has also been adapted—the "epigenetic code" has been used to describe the set of epigenetic features that create different phenotypes in different cells. Taken to its extreme, the "epigenetic code" could represent the total state of the cell, with the position of each molecule accounted for; more typically, the term is used in reference to systematic efforts to measure specific, relevant forms of epigenetic information such as the histone code or DNA methylation patterns.
# Mechanisms
Several types of epigenetic inheritance systems may play a role in what has become known as cell memory:
## DNA methylation and chromatin remodelling
Because the phenotype of a cell or individual is affected by which of its genes are transcribed, heritable transcription states can give rise to epigenetic effects. There are several layers of regulation of gene expression, one of which is remodelling of chromatin, the complex of DNA and the histone proteins with which it associates. Chromatin remodelling is initiated by one of two things:
- posttranslational modification of the amino acids that make up histone proteins,
- or the addition of methyl groups to the DNA, at CpG sites, to convert cytosine to 5-methylcytosine.
Whereas DNA is not completely stripped of nucleosomes during replication, it is possible that the remaining modified histones may act as templates, initiating identical modification of surrounding new histones after deposition. DNA methylation has a more clear method of propagation through the preferential methylation of hemimethylated symmetric sites by enzymes like Dnmt 1.
Although modifications occur throughout the histone sequence, the unstructured termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation, methylation and ubiquitylation. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 lysines of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally correlated with transcriptional competence.
One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because lysine normally has a positive charge on the nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone and prevent them from repelling each other. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge causing the DNA to repel itself. When this occurs, complexes like SWI/SNF and other transcriptional factors can bind to the DNA, thus opening it up and exposing it to enzymes like RNA polymerase so transcription of the gene can occur.
In addition, the positively charged tails of histone proteins from one nucleosome may interact with the histone proteins on a neighboring nucleosome, causing them to pack closely. Lysine acetylation may interfere with these interactions, causing the chromatin structure to open up.
Lysine acetylation may also act as a beacon to recruit other activating chromatin modifying enzymes (and basal transcription machinery as well). Indeed, the bromodomain—a protein segment (domain) that specifically binds acetyl-lysine—is found in many enzymes that help activate transcription including the SWI/SNF complex (on the protein polybromo). It may be that acetylation acts in this and the previous way to aid in transcriptional activation.
The idea that modifications act as docking modules for related factors is borne out by histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive heterochromatin). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein HP1 recruits HP1 to K9 methylated regions. One example that seems to refute the biophysical model for acetylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional activation. Tri-methylation in this case would introduce a fixed positive charge on the tail.
It should be emphasized that differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently than acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the histone code.
DNA methylation frequently occurs in repeated sequences, and may help to suppress 'junk DNA': Because 5-methylcytosine is chemically very similar to thymidine, CpG sites are frequently mutated and become rare in the genome, except at CpG islands where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. DNA methylation patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent DNA methyltransferases, DNMT1, DNMT3A and DNMT3B, the loss of any of which is lethal in mice. DNMT1 is the most abundant methyltransferase in somatic cells, localizes to replication foci, has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA). By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after DNA replication, and therefore is often referred to as the ‘maintenance' methyltransferase. DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.
Because DNA methylation and chromatin remodelling play such a central role in many types of epigenic inheritance, the word "epigenetics" is sometimes used as a synonym for these processes. However, this can be misleading. Chromatin remodelling is not always inherited, and not all epigenetic inheritance involves chromatin remodelling.
## RNA transcripts and their encoded proteins
Sometimes a gene, after being turned on, transcribes a product that (either directly or indirectly) maintains the activity of that gene. For example, Hnf4 and MyoD enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factor activity of the proteins they encode. Other epigenetic changes are mediated by the production of different splice forms of RNA, or by formation of double-stranded RNA (RNAi). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are most often turned on or off by signal transduction, although in some systems where syncytia or gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion. A large amount of RNA and protein is contributed to the zygote by the mother during oogenesis or via nurse cells, resulting in maternal effect phenotypes. A smaller quantity of sperm RNA is transmitted from the father, but there is recent evidence that this epigenetic information can lead to visible changes in several generations of offspring.
## Prions
Prions are infectious forms of proteins. Proteins generally fold into discrete units which perform distinct cellular functions, but some proteins are also capable of forming an infectious conformational state known as a prion. Although often viewed in the context of infectious disease, prions are more loosely defined by their ability to catalytically convert other native state versions of the same protein to an infectious conformational state. It is in this latter sense that they can be viewed as epigenetic agents capable of inducing a phenotypic change without a modification of the genome.
Fungal prions are considered epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. PSI+ and URE3, discovered in yeast in 1965 and 1971, are the two most well studied of this type of prion. Prions can have a phenotypic effect through the sequestration of protein in aggregates, thereby reducing that protein's activity. In PSI+ cells, the loss of the Sup35 protein (which is involved in termination of translation) causes ribosomes to have a higher rate of read-through of stop codons, an effect which results in suppression of nonsense mutations in other genes. The ability of Sup35 to form prions may be a conserved trait. It could confer an adaptive advantage by giving cells the ability to switch into a PSI+ state and express dormant genetic features normally terminated by premature stop codon mutations.
## Structural inheritance systems
In ciliates such as Tetrahymena and Paramecium, genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.
# Functions and consequences
## Development
Somatic epigenetic inheritance, particularly through DNA methylation and chromatin remodelling, is very important in the development of multicellular eukaryotic organisms. The genome sequence is static (with some notable exceptions), but cells differentiate in many different types, which perform different functions, and respond differently to the environment and intercellular signalling. Thus, as individuals develop, morphogens activate or silence genes in an epigenetically heritable fashion, giving cells a "memory". In mammals, most cells terminally differentiate, with only stem cells retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In mammals, some stem cells continue producing new differentiated cells throughout life, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin remodelling, it has been hypothesised that plant cells do not have "memories", resetting their gene expression patterns at each cell division using positional information from the environment and surrounding cells to determine their fate.
## Medicine
Epigenetics has many and varied potential medical applications. Congenital genetic disease is well understood, and it is also clear that epigenetics can play a role, for example, in the case of Angelman syndrome and Prader-Willi syndrome. These are normal genetic diseases caused by gene deletions, but are unusually common because individuals are essentially hemizygous because of genomic imprinting, and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.
## Evolution
Although epigenetics in multicellular organisms is generally thought to be a mechanism involved in differentiation, with epigenetic patterns "reset" when organisms reproduce, there have been some observations of transgenerational epigenetic inheritance (e.g., the phenomenon of paramutation observed in maize). Although most of these multigenerational epigenetic traits are gradually lost over several generations, the possibility remains that multigenerational epigenetics could be another aspect to evolution and adaptation. These effects may require enhancements to the standard conceptual framework of Neo-Darwinism.
Epigenetic features may play a role in short-term adaptation of species by allowing for reversible phenotype variability. The modification of epigenetic features associated with a region of DNA allows organisms, on a multigenerational time scale, to switch between phenotypes that express and repress that particular gene. Whereas the DNA sequence of the region is not mutated, this change is reversible. It has also been speculated that organisms may take advantage of differential mutation rates associated with epigenetic features to control the mutation rates of particular genes.
Epigenetic changes have also been observed to occur in response to environmental exposure—for example, mice given some dietary supplements have epigenetic changes affecting expression of the agouti gene, which affects their fur color, weight, and propensity to develop cancer.
Although this change isn't adaptive since the underlying mutation is agouti gene was developed artificially, the observation of epigenetic change occurring in response to environmental factors opens up the possibility of organismal adaptive inheritance—a sort of Lamarckian inheritance. Although this remains speculative, if this does occur some instances of evolution would indeed be separate from standard genetic inheritance.
# Epigenetic effects in humans
## Genomic imprinting and related disorders
Some human disorders are associated with genomic imprinting, a phenomenon in mammals where the father and mother contribute different epigenetic patterns for specific genomic loci in their germ cells. The most well known case of imprinting in human disorders is that of Angelman syndrome and Prader-Willi syndrome—both can be produced by the same genetic mutation, chromosome 15q partial deletion, and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father. This is due to the presence of genomic imprinting in the region, a phenomenon in mammals where the father and mother contribute different epigenetic patterns in their germ cells. Beckwith-Wiedemann syndrome is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.
## Transgenerational epigenetic observations
Pembrey and colleagues also observed that the paternal (but not maternal) grandsons of Swedish boys who were exposed to famine in the 19th Century were more likely to get diabetes, suggesting that this was a transgenerational epigenetic inheritance
## Cancer and developmental abnormalities
A variety of compounds are considered as epigenetic carcinogens—they result in an increased incidence of tumors, but they do not show mutagen activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include diethylstilbestrol, arsenite, hexachlorobenzene, and nickel compounds.
Many teratogens exert specific effects on the fetus by epigenetic mechanisms. While epigenetic effects may preserve the effect of a teratogen such as diethylstilbestrol throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence. However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist. FDA label information for Vidaza(tm), a formulation of 5-azacitidine (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased embryo loss, and abnormal embryo development. In rats, endocrine differences were observed in offspring of males exposed to morphine. In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms. | Epigenetics
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Epigenetics is a term in biology used today to refer to features such as chromatin and DNA modifications that are stable over rounds of cell division but do not involve changes in the underlying DNA sequence of the organism.[1] These epigenetic changes play a role in the process of cellular differentiation, allowing cells to stably maintain different characteristics despite containing the same genomic material. Epigenetic features are inherited when cells divide despite a lack of change in the DNA sequence itself and, although most of these features are considered dynamic over the course of development in multicellular organisms, some epigenetic features show transgenerational inheritance and are inherited from one generation to the next.[2]
Specific epigenetic processes of interest include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.
# Etymology and Definitions
The word "epigenetics" has been associated with many different definitions, and much of the confusion surrounding the use of the word "epigenetics" relates to the fact that it was originally defined to explain phenomena without knowing their molecular basis and with time became narrowly linked to certain phenomena as their molecular basis was discovered.[3]
Originally, the word "epigenetics" (as in "epigenetic landscape") was coined by C. H. Waddington in 1942 as a portmanteau of the words "genetics" and "epigenesis".[4] Epigenesis is an older word used to describe the differentiation of cells from a totipotent state in embryonic development (used in contrast to "preformationism"). At the time Waddington first used the term "epigenetics" the physical nature of genes and their role in heredity was not known. Epigenetics was Waddington's model of how genes within a multicellular organism interact with their surroundings to produce a phenotype. Because all cells within an organism inherit the same DNA sequences, cellular differentiation processes crucial for epigenesis rely strongly on epigenetic rather than genetic inheritance. Robin Holliday defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms."[5]
Another usage of the word "epigenetics" was employed by the psychologist Erik Erikson, who developed an "epigenetic theory of human development" which focuses on psycho-social crises.
The modern usage of the word "epigenetic" is more narrow, referring to heritable traits (over rounds of cell division and sometimes transgenerationally) that do not involve changes to the underlying DNA sequence.[6] The Greek "epi-" prefix of the word "epigenetics" implies features that are "on top of" or "in addition to" genetics, and the current usage of the word reflects this—epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance.
The similarity of the word to "genetics" has generated many parallel usages. The "epigenome" is a parallel to the word "genome" and refers to the overall epigenetic state of a cell. The phrase "genetic code" has also been adapted—the "epigenetic code" has been used to describe the set of epigenetic features that create different phenotypes in different cells. Taken to its extreme, the "epigenetic code" could represent the total state of the cell, with the position of each molecule accounted for; more typically, the term is used in reference to systematic efforts to measure specific, relevant forms of epigenetic information such as the histone code or DNA methylation patterns.
# Mechanisms
Several types of epigenetic inheritance systems may play a role in what has become known as cell memory:[7]
## DNA methylation and chromatin remodelling
Because the phenotype of a cell or individual is affected by which of its genes are transcribed, heritable transcription states can give rise to epigenetic effects. There are several layers of regulation of gene expression, one of which is remodelling of chromatin, the complex of DNA and the histone proteins with which it associates. Chromatin remodelling is initiated by one of two things:
- posttranslational modification of the amino acids that make up histone proteins,
- or the addition of methyl groups to the DNA, at CpG sites, to convert cytosine to 5-methylcytosine.
Whereas DNA is not completely stripped of nucleosomes during replication, it is possible that the remaining modified histones may act as templates, initiating identical modification of surrounding new histones after deposition. DNA methylation has a more clear method of propagation through the preferential methylation of hemimethylated symmetric sites by enzymes like Dnmt 1.
Although modifications occur throughout the histone sequence, the unstructured termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation, methylation and ubiquitylation. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 lysines of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally correlated with transcriptional competence.
One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because lysine normally has a positive charge on the nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone and prevent them from repelling each other. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge causing the DNA to repel itself. When this occurs, complexes like SWI/SNF and other transcriptional factors can bind to the DNA, thus opening it up and exposing it to enzymes like RNA polymerase so transcription of the gene can occur.
In addition, the positively charged tails of histone proteins from one nucleosome may interact with the histone proteins on a neighboring nucleosome, causing them to pack closely. Lysine acetylation may interfere with these interactions, causing the chromatin structure to open up.
Lysine acetylation may also act as a beacon to recruit other activating chromatin modifying enzymes (and basal transcription machinery as well). Indeed, the bromodomain—a protein segment (domain) that specifically binds acetyl-lysine—is found in many enzymes that help activate transcription including the SWI/SNF complex (on the protein polybromo). It may be that acetylation acts in this and the previous way to aid in transcriptional activation.
The idea that modifications act as docking modules for related factors is borne out by histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive heterochromatin). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein HP1 recruits HP1 to K9 methylated regions. One example that seems to refute the biophysical model for acetylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional activation. Tri-methylation in this case would introduce a fixed positive charge on the tail.
It should be emphasized that differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently than acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the histone code.
DNA methylation frequently occurs in repeated sequences, and may help to suppress 'junk DNA':[8] Because 5-methylcytosine is chemically very similar to thymidine, CpG sites are frequently mutated and become rare in the genome, except at CpG islands where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. DNA methylation patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent DNA methyltransferases, DNMT1, DNMT3A and DNMT3B, the loss of any of which is lethal in mice.[9] DNMT1 is the most abundant methyltransferase in somatic cells,[10] localizes to replication foci,[11] has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).[12] By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after DNA replication, and therefore is often referred to as the ‘maintenance' methyltransferase.[13] DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.[9][14]
Because DNA methylation and chromatin remodelling play such a central role in many types of epigenic inheritance, the word "epigenetics" is sometimes used as a synonym for these processes. However, this can be misleading. Chromatin remodelling is not always inherited, and not all epigenetic inheritance involves chromatin remodelling.[15]
## RNA transcripts and their encoded proteins
Sometimes a gene, after being turned on, transcribes a product that (either directly or indirectly) maintains the activity of that gene. For example, Hnf4 and MyoD enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factor activity of the proteins they encode. Other epigenetic changes are mediated by the production of different splice forms of RNA, or by formation of double-stranded RNA (RNAi). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are most often turned on or off by signal transduction, although in some systems where syncytia or gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion. A large amount of RNA and protein is contributed to the zygote by the mother during oogenesis or via nurse cells, resulting in maternal effect phenotypes. A smaller quantity of sperm RNA is transmitted from the father, but there is recent evidence that this epigenetic information can lead to visible changes in several generations of offspring.[16]
## Prions
Prions are infectious forms of proteins. Proteins generally fold into discrete units which perform distinct cellular functions, but some proteins are also capable of forming an infectious conformational state known as a prion. Although often viewed in the context of infectious disease, prions are more loosely defined by their ability to catalytically convert other native state versions of the same protein to an infectious conformational state. It is in this latter sense that they can be viewed as epigenetic agents capable of inducing a phenotypic change without a modification of the genome.[17]
Fungal prions are considered epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. PSI+ and URE3, discovered in yeast in 1965 and 1971, are the two most well studied of this type of prion.[18][19] Prions can have a phenotypic effect through the sequestration of protein in aggregates, thereby reducing that protein's activity. In PSI+ cells, the loss of the Sup35 protein (which is involved in termination of translation) causes ribosomes to have a higher rate of read-through of stop codons, an effect which results in suppression of nonsense mutations in other genes.[20] The ability of Sup35 to form prions may be a conserved trait. It could confer an adaptive advantage by giving cells the ability to switch into a PSI+ state and express dormant genetic features normally terminated by premature stop codon mutations.[21][22]
## Structural inheritance systems
In ciliates such as Tetrahymena and Paramecium, genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.
# Functions and consequences
## Development
Somatic epigenetic inheritance, particularly through DNA methylation and chromatin remodelling, is very important in the development of multicellular eukaryotic organisms. The genome sequence is static (with some notable exceptions), but cells differentiate in many different types, which perform different functions, and respond differently to the environment and intercellular signalling. Thus, as individuals develop, morphogens activate or silence genes in an epigenetically heritable fashion, giving cells a "memory". In mammals, most cells terminally differentiate, with only stem cells retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In mammals, some stem cells continue producing new differentiated cells throughout life, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin remodelling, it has been hypothesised that plant cells do not have "memories", resetting their gene expression patterns at each cell division using positional information from the environment and surrounding cells to determine their fate.[23]
## Medicine
Epigenetics has many and varied potential medical applications. Congenital genetic disease is well understood, and it is also clear that epigenetics can play a role, for example, in the case of Angelman syndrome and Prader-Willi syndrome. These are normal genetic diseases caused by gene deletions, but are unusually common because individuals are essentially hemizygous because of genomic imprinting, and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.[24]
## Evolution
Although epigenetics in multicellular organisms is generally thought to be a mechanism involved in differentiation, with epigenetic patterns "reset" when organisms reproduce, there have been some observations of transgenerational epigenetic inheritance (e.g., the phenomenon of paramutation observed in maize). Although most of these multigenerational epigenetic traits are gradually lost over several generations, the possibility remains that multigenerational epigenetics could be another aspect to evolution and adaptation. These effects may require enhancements to the standard conceptual framework of Neo-Darwinism.[25][26]
Epigenetic features may play a role in short-term adaptation of species by allowing for reversible phenotype variability. The modification of epigenetic features associated with a region of DNA allows organisms, on a multigenerational time scale, to switch between phenotypes that express and repress that particular gene.[27] Whereas the DNA sequence of the region is not mutated, this change is reversible. It has also been speculated that organisms may take advantage of differential mutation rates associated with epigenetic features to control the mutation rates of particular genes.[27]
Epigenetic changes have also been observed to occur in response to environmental exposure—for example, mice given some dietary supplements have epigenetic changes affecting expression of the agouti gene, which affects their fur color, weight, and propensity to develop cancer.[28][29]
Although this change isn't adaptive since the underlying mutation is agouti gene was developed artificially, the observation of epigenetic change occurring in response to environmental factors opens up the possibility of organismal adaptive inheritance—a sort of Lamarckian inheritance. Although this remains speculative, if this does occur some instances of evolution would indeed be separate from standard genetic inheritance.[30]
# Epigenetic effects in humans
## Genomic imprinting and related disorders
Some human disorders are associated with genomic imprinting, a phenomenon in mammals where the father and mother contribute different epigenetic patterns for specific genomic loci in their germ cells.[31] The most well known case of imprinting in human disorders is that of Angelman syndrome and Prader-Willi syndrome—both can be produced by the same genetic mutation, chromosome 15q partial deletion, and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father.[32] This is due to the presence of genomic imprinting in the region, a phenomenon in mammals where the father and mother contribute different epigenetic patterns in their germ cells.[33] Beckwith-Wiedemann syndrome is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.
## Transgenerational epigenetic observations
Pembrey and colleagues also observed that the paternal (but not maternal) grandsons of Swedish boys who were exposed to famine in the 19th Century were more likely to get diabetes, suggesting that this was a transgenerational epigenetic inheritance[34]
## Cancer and developmental abnormalities
A variety of compounds are considered as epigenetic carcinogens—they result in an increased incidence of tumors, but they do not show mutagen activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include diethylstilbestrol, arsenite, hexachlorobenzene, and nickel compounds.
Many teratogens exert specific effects on the fetus by epigenetic mechanisms.[35][36] While epigenetic effects may preserve the effect of a teratogen such as diethylstilbestrol throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence.[37] However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.[38] FDA label information for Vidaza(tm), a formulation of 5-azacitidine (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased embryo loss, and abnormal embryo development. In rats, endocrine differences were observed in offspring of males exposed to morphine.[39] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.[40] | https://www.wikidoc.org/index.php/Epigenetic | |
25cd8ea98c33eeb8a492d558ae0a7d233753b693 | wikidoc | Meprobamate | Meprobamate
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Meprobamate is an anti anxiety drug that is FDA approved for the treatment of anxiety disorders. Common adverse reactions include nausea, vomiting, diarrhea. drowsiness, ataxia, dizziness, slurred speech, headache, vertigo, weakness, paresthesias.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Meprobamate tablets are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually do not require treatment with an anxiolytic.
- The effectiveness of meprobamate tablets in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.
# Dosage
- Meprobamate Tablets USP: The usual adult daily dosage is 1200mg to 1600 mg, in three or four divided doses; a daily dosage above 2400 mg is not recommended.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Meprobamate in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Meprobamate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
- Meprobamate tablets are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually do not require treatment with an anxiolytic.
- The effectiveness of meprobamate tablets in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.
# Dosing
- The usual daily dosage for children ages six to twelve years is 200 mg to 600 mg, in two or three divided doses.
- Not recommended for children under age 6 (see Usage in Children).
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Meprobamate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Meprobamate in pediatric patients.
# Contraindications
- Acute intermittent porphyria as well as allergic or idiosyncratic reactions to meprobamate or related compounds such as carisoprodol, mebutamate, tybamate, or carbromal.
# Warnings
Drug Dependence
- Physical dependence, psychological dependence, and abuse have occurred. When chronic intoxication from prolonged use occurs, it usually involves ingestion of greater than recommended doses and is manifested by ataxia, slurred speech, and vertigo.
- Therefore, careful supervision of dose and amounts prescribed is advised, as well as avoidance of prolonged administration, especially for alcoholics and other patients with a known propensity for taking excessive quantities of drugs.
- Sudden withdrawal of the drug after prolonged and excessive use may precipitate recurrence of pre-existing symptoms such as anxiety, anorexia, insomnia, or withdrawal reactions such as vomiting, ataxia, tremors, muscle twitching, confusional states, hallucinosis, and rarely, convulsive seizures. Such seizures are more likely to occur in persons with central nervous system damage or pre-existent or latent convulsive disorders. Onset of withdrawal symptoms occurs usually within 12 to 48 hours after discontinuation of meprobamate; symptoms usually cease within the next 12 to 48 hours.
- When excessive dosage has continued for weeks or months, dosage should be reduced gradually over a period of one or two weeks rather than abruptly stopped. Alternatively, a long-acting barbiturate may be substituted, then gradually withdrawn.
Potentially Hazardous Tasks
- Patients should be warned that meprobamate may impair the mental and/or physical abilities required for performance of potentially hazardous tasks such as driving or operating machinery.
Additive Effects
- Since the effects of meprobamate and alcohol or meprobamate and other CNS depressants or psychotropic drugs may be additive, appropriate caution should be exercised with patients who take more than one of these agents simultaneously.
Usage in Pregnancy and Lactation
- An increased risk of congenital malformations associated with the use of minor tranquilizers (meprobamate, chlordiazepoxide and diazepam) during the first trimester of pregnancy has been suggested in several studies. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug.
- Meprobamate passes the placental barrier. It is present both in umbilical cord blood at or near maternal plasma levels and in breast milk of lactating mothers at concentrations two to four times that of maternal plasma. When use of meprobamate is contemplated in breastfeeding patients, the drug's higher concentration in breast milk as compared to maternal plasma should be considered.
Usage in Children
- Meprobamate tablets should not be administered to children under age six, since there is a lack of documented evidence for safety and effectiveness in this age group.
# PRECAUTIONS
- The lowest effective dose should be administered, particularly to elderly and/or debilitated patients, in order to preclude oversedation.
- The possibility of suicide attempts should be considered and the least amount of drug feasible should be dispensed at any one time.
- Meprobamate is metabolized in the liver and excreted by the kidney; to avoid its excess accumulation, caution should be exercised in administration to patients with compromised liver or kidney function.
- Meprobamate occasionally may precipitate seizures in epileptic patients.
# Adverse Reactions
## Clinical Trials Experience
Central Nervous System
- Drowsiness, ataxia, dizziness, slurred speech, headache, vertigo, weakness, paresthesias, impairment of visual accommodation, euphoria, overstimulation, paradoxical excitement, fast EEG activity.
Gastrointestinal
- Nausea, vomiting, diarrhea.
Cardiovascular
- Palpitation, tachycardia, various forms of arrhythmia, transient ECG changes, syncope; also hypotensive crisis (including one fatal case).
Allergic or Idiosyncratic
- Allergic or idiosyncratic reactions are usually seen within the period of the first to fourth dose in patients having had no previous contact with the drug. Milder reactions are characterized by an itchy, urticarial, or erythematous maculopapular rash which may be generalized or confined to the groin. Other reactions have included leukopenia, acute nonthrombocytopenic purpura, petechiae, ecchymoses, eosinophilia, peripheral edema, adenopathy, fever, fixed drug eruption with cross reaction to carisoprodol, and cross sensitivity between meprobamate/mebutamate and meprobamate/carbromal.
- More severe hypersensitivity reactions, rarely reported, include hyperpyrexia chills, angioneurotic edema, bronchospasm, oliguria and anuria. Also, anaphylaxis, erythema multiforme, exfoliative dermatitis, stomatitis, proctitis, Stevens-Johnson syndrome and bullous dermatitis, including one fatal case of the latter following administration of meprobamate in combination with prednisolone.
- In case of allergic or idiosyncratic reactions to meprobamate, discontinue the drug and initiate appropriate symptomatic therapy, which may include epinephrine,antihistamines, and in severe cases, corticosteroids. In evaluating possible allergic reactions, also consider allergy to excipients.
Hematologic
- Agranulocytosis and aplastic anemia have been reported. These cases rarely were fatal. Rare cases of thrombocytopenic Purpura have been reported.
Other
- Exacerbation of porphyric symptoms.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Meprobamate in the drug label.
# Drug Interactions
There is limited information regarding Meprobamate Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Meprobamate in women who are pregnant.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Meprobamate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Meprobamate during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Meprobamate with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Meprobamate with respect to pediatric patients.
### Geriatic Use
- Clinical studies of meprobamate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Meprobamate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Meprobamate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Meprobamate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Meprobamate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Meprobamate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Meprobamate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Meprobamate in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Meprobamate in the drug label.
# Overdosage
- Suicidal attempts with meprobamate have resulted in drowsiness, lethargy, stupor, ataxia, coma, shock, vasomotor, and respiratory collapse. Some suicidal attempts have been fatal.
- The following data on meprobamate tablets have been reported in the literature and from other sources. These data are not expected to correlate with each case (considering factors such as individual susceptibility and length of time from ingestion to treatment), but represent the usual ranges reported.
Acute simple overdose (meprobamate alone): Death has been reported with ingestion of as little as 12 g meprobamate and survival with as much as 40 g.
Blood Levels
- 0.5-2 mg% represents the usual blood level range of meprobamate after therapeutic doses. The level may occasionally be as high as 3 mg%.
- 3-10 mg% usually corresponds to findings of mild to moderate symptoms of overdosage, such as stupor or light coma.
- 10-20 mg% usually corresponds to deeper coma, requiring more intensive treatment. Some fatalities occur.
- At levels greater than 20 mg%, more fatalities than survivals can be expected.
Acute combined overdose (meprobamate with alcohol or other CNS depressants or psychotropic drugs): Since effects can be additive, a history of ingestion of a low dose of meprobamate plus any of these compounds (or of a relative low blood or tissue level) cannot be used as a prognostic indicator.
- In cases where excessive doses have been taken, sleep ensues rapidly and blood pressure, pulse, and respiratory rates are reduced to basal levels. Any drug remaining in the stomach should be removed and symptomatic therapy given. Should respiration or blood pressure become compromised, respiratory assistance, central nervous system stimulants, and pressor agents should be administered cautiously as indicated. Meprobamate is metabolized in the liver and excreted by the kidney. Diuresis, osmotic (mannitol) diuresis, peritoneal dialysis, and hemodialysis have been used successfully. Careful monitoring of urinary output is necessary and caution should be taken to avoid overhydration. Relapse and death, after initial recovery, have been attributed to incomplete gastric emptying and delayed absorption. Meprobamate can be measured in biological fluids by two methods: colorimetric (Hoffman, A.J. and Ludwig, B.J.: J Amer Pharm Assn 48: 740, 1959) and gas chromatographic (Douglas, J.F. et al: Anal Chem 39: 956, 1967).
# Pharmacology
## Mechanism of Action
There is limited information regarding Meprobamate Mechanism of Action in the drug label.
## Structure
Meprobamate is a white powder with a characteristic odor and a bitter taste. It is slightly soluble in water, freely soluble in acetone and alcohol, and sparingly soluble in ether. The structural formula of meprobamate is:
Meprobamate Tablets USP 200 mg and 400 mg for oral administration contain the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and pregelatinised starch.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Meprobamate in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Meprobamate in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Meprobamate in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Meprobamate in the drug label.
# How Supplied
- Meprobamate Tablets USP 200 mg are white to off white, round, biconvex, uncoated tablets debossed with “L125” on one side and break line on other side.
- NDC 23155-128-03 Bottle of 30
- NDC 23155-128-01 Bottle of 100
- NDC 23155-128-10 Bottle of 1000
- Meprobamate Tablets USP 400 mg are white to off white, round, biconvex, uncoated tablets debossed with “L105” on one side and break line on other side.
- NDC 23155-129-03 Bottle of 30
- NDC 23155-129-01 Bottle of 100
- NDC 23155-129-10 Bottle of 1000
- Dispense in well-closed container with child-resistant closure.
## Storage
- Store at controlled room temperature, excursions permitted to 15°C-30°C (59°F-86°F).
- Preserve in well closed container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Meprobamate in the drug label.
# Precautions with Alcohol
- Alcohol-Meprobamate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
MEPROBAMATE
# Look-Alike Drug Names
There is limited information regarding Meprobamate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Meprobamate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Meprobamate is an anti anxiety drug that is FDA approved for the treatment of anxiety disorders. Common adverse reactions include nausea, vomiting, diarrhea. drowsiness, ataxia, dizziness, slurred speech, headache, vertigo, weakness, paresthesias.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Meprobamate tablets are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually do not require treatment with an anxiolytic.
- The effectiveness of meprobamate tablets in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.
# Dosage
- Meprobamate Tablets USP: The usual adult daily dosage is 1200mg to 1600 mg, in three or four divided doses; a daily dosage above 2400 mg is not recommended.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Meprobamate in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Meprobamate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
- Meprobamate tablets are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually do not require treatment with an anxiolytic.
- The effectiveness of meprobamate tablets in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.
# Dosing
- The usual daily dosage for children ages six to twelve years is 200 mg to 600 mg, in two or three divided doses.
- Not recommended for children under age 6 (see Usage in Children).
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Meprobamate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Meprobamate in pediatric patients.
# Contraindications
- Acute intermittent porphyria as well as allergic or idiosyncratic reactions to meprobamate or related compounds such as carisoprodol, mebutamate, tybamate, or carbromal.
# Warnings
Drug Dependence
- Physical dependence, psychological dependence, and abuse have occurred. When chronic intoxication from prolonged use occurs, it usually involves ingestion of greater than recommended doses and is manifested by ataxia, slurred speech, and vertigo.
- Therefore, careful supervision of dose and amounts prescribed is advised, as well as avoidance of prolonged administration, especially for alcoholics and other patients with a known propensity for taking excessive quantities of drugs.
- Sudden withdrawal of the drug after prolonged and excessive use may precipitate recurrence of pre-existing symptoms such as anxiety, anorexia, insomnia, or withdrawal reactions such as vomiting, ataxia, tremors, muscle twitching, confusional states, hallucinosis, and rarely, convulsive seizures. Such seizures are more likely to occur in persons with central nervous system damage or pre-existent or latent convulsive disorders. Onset of withdrawal symptoms occurs usually within 12 to 48 hours after discontinuation of meprobamate; symptoms usually cease within the next 12 to 48 hours.
- When excessive dosage has continued for weeks or months, dosage should be reduced gradually over a period of one or two weeks rather than abruptly stopped. Alternatively, a long-acting barbiturate may be substituted, then gradually withdrawn.
Potentially Hazardous Tasks
- Patients should be warned that meprobamate may impair the mental and/or physical abilities required for performance of potentially hazardous tasks such as driving or operating machinery.
Additive Effects
- Since the effects of meprobamate and alcohol or meprobamate and other CNS depressants or psychotropic drugs may be additive, appropriate caution should be exercised with patients who take more than one of these agents simultaneously.
Usage in Pregnancy and Lactation
- An increased risk of congenital malformations associated with the use of minor tranquilizers (meprobamate, chlordiazepoxide and diazepam) during the first trimester of pregnancy has been suggested in several studies. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug.
- Meprobamate passes the placental barrier. It is present both in umbilical cord blood at or near maternal plasma levels and in breast milk of lactating mothers at concentrations two to four times that of maternal plasma. When use of meprobamate is contemplated in breastfeeding patients, the drug's higher concentration in breast milk as compared to maternal plasma should be considered.
Usage in Children
- Meprobamate tablets should not be administered to children under age six, since there is a lack of documented evidence for safety and effectiveness in this age group.
# PRECAUTIONS
- The lowest effective dose should be administered, particularly to elderly and/or debilitated patients, in order to preclude oversedation.
- The possibility of suicide attempts should be considered and the least amount of drug feasible should be dispensed at any one time.
- Meprobamate is metabolized in the liver and excreted by the kidney; to avoid its excess accumulation, caution should be exercised in administration to patients with compromised liver or kidney function.
- Meprobamate occasionally may precipitate seizures in epileptic patients.
# Adverse Reactions
## Clinical Trials Experience
Central Nervous System
- Drowsiness, ataxia, dizziness, slurred speech, headache, vertigo, weakness, paresthesias, impairment of visual accommodation, euphoria, overstimulation, paradoxical excitement, fast EEG activity.
Gastrointestinal
- Nausea, vomiting, diarrhea.
Cardiovascular
- Palpitation, tachycardia, various forms of arrhythmia, transient ECG changes, syncope; also hypotensive crisis (including one fatal case).
Allergic or Idiosyncratic
- Allergic or idiosyncratic reactions are usually seen within the period of the first to fourth dose in patients having had no previous contact with the drug. Milder reactions are characterized by an itchy, urticarial, or erythematous maculopapular rash which may be generalized or confined to the groin. Other reactions have included leukopenia, acute nonthrombocytopenic purpura, petechiae, ecchymoses, eosinophilia, peripheral edema, adenopathy, fever, fixed drug eruption with cross reaction to carisoprodol, and cross sensitivity between meprobamate/mebutamate and meprobamate/carbromal.
- More severe hypersensitivity reactions, rarely reported, include hyperpyrexia chills, angioneurotic edema, bronchospasm, oliguria and anuria. Also, anaphylaxis, erythema multiforme, exfoliative dermatitis, stomatitis, proctitis, Stevens-Johnson syndrome and bullous dermatitis, including one fatal case of the latter following administration of meprobamate in combination with prednisolone.
- In case of allergic or idiosyncratic reactions to meprobamate, discontinue the drug and initiate appropriate symptomatic therapy, which may include epinephrine,antihistamines, and in severe cases, corticosteroids. In evaluating possible allergic reactions, also consider allergy to excipients.
Hematologic
- Agranulocytosis and aplastic anemia have been reported. These cases rarely were fatal. Rare cases of thrombocytopenic Purpura have been reported.
Other
- Exacerbation of porphyric symptoms.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Meprobamate in the drug label.
# Drug Interactions
There is limited information regarding Meprobamate Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Meprobamate in women who are pregnant.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Meprobamate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Meprobamate during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Meprobamate with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Meprobamate with respect to pediatric patients.
### Geriatic Use
- Clinical studies of meprobamate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Meprobamate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Meprobamate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Meprobamate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Meprobamate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Meprobamate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Meprobamate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Meprobamate in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Meprobamate in the drug label.
# Overdosage
- Suicidal attempts with meprobamate have resulted in drowsiness, lethargy, stupor, ataxia, coma, shock, vasomotor, and respiratory collapse. Some suicidal attempts have been fatal.
- The following data on meprobamate tablets have been reported in the literature and from other sources. These data are not expected to correlate with each case (considering factors such as individual susceptibility and length of time from ingestion to treatment), but represent the usual ranges reported.
Acute simple overdose (meprobamate alone): Death has been reported with ingestion of as little as 12 g meprobamate and survival with as much as 40 g.
Blood Levels
- 0.5-2 mg% represents the usual blood level range of meprobamate after therapeutic doses. The level may occasionally be as high as 3 mg%.
- 3-10 mg% usually corresponds to findings of mild to moderate symptoms of overdosage, such as stupor or light coma.
- 10-20 mg% usually corresponds to deeper coma, requiring more intensive treatment. Some fatalities occur.
- At levels greater than 20 mg%, more fatalities than survivals can be expected.
Acute combined overdose (meprobamate with alcohol or other CNS depressants or psychotropic drugs): Since effects can be additive, a history of ingestion of a low dose of meprobamate plus any of these compounds (or of a relative low blood or tissue level) cannot be used as a prognostic indicator.
- In cases where excessive doses have been taken, sleep ensues rapidly and blood pressure, pulse, and respiratory rates are reduced to basal levels. Any drug remaining in the stomach should be removed and symptomatic therapy given. Should respiration or blood pressure become compromised, respiratory assistance, central nervous system stimulants, and pressor agents should be administered cautiously as indicated. Meprobamate is metabolized in the liver and excreted by the kidney. Diuresis, osmotic (mannitol) diuresis, peritoneal dialysis, and hemodialysis have been used successfully. Careful monitoring of urinary output is necessary and caution should be taken to avoid overhydration. Relapse and death, after initial recovery, have been attributed to incomplete gastric emptying and delayed absorption. Meprobamate can be measured in biological fluids by two methods: colorimetric (Hoffman, A.J. and Ludwig, B.J.: J Amer Pharm Assn 48: 740, 1959) and gas chromatographic (Douglas, J.F. et al: Anal Chem 39: 956, 1967).
# Pharmacology
## Mechanism of Action
There is limited information regarding Meprobamate Mechanism of Action in the drug label.
## Structure
Meprobamate is a white powder with a characteristic odor and a bitter taste. It is slightly soluble in water, freely soluble in acetone and alcohol, and sparingly soluble in ether. The structural formula of meprobamate is:
Meprobamate Tablets USP 200 mg and 400 mg for oral administration contain the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and pregelatinised starch.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Meprobamate in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Meprobamate in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Meprobamate in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Meprobamate in the drug label.
# How Supplied
- Meprobamate Tablets USP 200 mg are white to off white, round, biconvex, uncoated tablets debossed with “L125” on one side and break line on other side.
- NDC 23155-128-03 Bottle of 30
- NDC 23155-128-01 Bottle of 100
- NDC 23155-128-10 Bottle of 1000
- Meprobamate Tablets USP 400 mg are white to off white, round, biconvex, uncoated tablets debossed with “L105” on one side and break line on other side.
- NDC 23155-129-03 Bottle of 30
- NDC 23155-129-01 Bottle of 100
- NDC 23155-129-10 Bottle of 1000
- Dispense in well-closed container with child-resistant closure.
## Storage
- Store at controlled room temperature, excursions permitted to 15°C-30°C (59°F-86°F).
- Preserve in well closed container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Meprobamate in the drug label.
# Precautions with Alcohol
- Alcohol-Meprobamate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
MEPROBAMATE
# Look-Alike Drug Names
There is limited information regarding Meprobamate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Equanil | |
102a0c7769a2f8601c6b652b908cf8e428332110 | wikidoc | Erb's palsy | Erb's palsy
# Overview
Duchenne-Erb's palsy or simply Erb's palsy, is a lesion to the C5-C6 brachial roots; it can be a form of brachial plexus birth palsy (BPBP) or can be acquired in adulthood. It occurs when there is a stretching of the superior brachial plexus (neuropraxia, neuroma, neurotmesis), leading in most of the cases to a temporal weakness and loss of sensation in certain muscles of the upper extremity.
# Historical Perspective
- Erb's palsy, was first described by William Smellie, a British obstetrician, in 1754 on his midwifery book, "Traité de la theorie et pratique des accouchemens".
- In 1861, French neurologist, Guillaume Benjamin Amand Duchenne was the first to discover the association of paralysis in the same muscles (deltoid, biceps, and subscapularis) of arms and shoulders of infants delivered vaginally, naming it "obstetric palsy of the brachial plexus".
- In 1874, German neurologist, Wilhelm Heinrich Erb concluded that paralysis was associated with a radicular lesion at the level of the superior plexus, C5-C6, and not from isolated peripheral nerve lesions.
- In 1985, Narakas made a classification for Erb's palsy grading the severity and determining the prognosis.
# Classification
- Erb's palsy may be classified according to the severity of damage produced to the brachial plexus nerves as:
- Neurapraxia: Mild, temporal disruption, or compression of the myelin sheath, with no structural damage to the axon.
- Axonotmesis: Anatomic interruption of the myelin sheath and the axon of the nerve, but perineurium and epineurium remain intact.
- Neurotmesis: Complete tear of the nerve, including the axon with his endoneurium, perineurium, and epineurium.
- Erb's palsy, in turn, is also classified within the Narakas system, which categorizes Brachial Plexus Birth Palsy (BPBP) according to the roots involved, and its directly linked to its prognosis:
Group I: Classic Erb's palsy (C5-C6 roots). Good spontaneous recovery in > 80% of cases.
Group II: Extended Erb's palsy (C5-C7 roots). Good spontaneous recovery in > 60% of cases.
Group III: Global palsy without Horner syndrome (C5-C8 roots). Good spontaneous recovery of shoulder/elbow in > 30–50% of cases. Functional hand frequently noted.
Group IV: Global palsy with Horner syndrome (C5-T1). Without surgery, severe arm deficits are expected.
- Group I: Classic Erb's palsy (C5-C6 roots). Good spontaneous recovery in > 80% of cases.
- Group II: Extended Erb's palsy (C5-C7 roots). Good spontaneous recovery in > 60% of cases.
- Group III: Global palsy without Horner syndrome (C5-C8 roots). Good spontaneous recovery of shoulder/elbow in > 30–50% of cases. Functional hand frequently noted.
- Group IV: Global palsy with Horner syndrome (C5-T1). Without surgery, severe arm deficits are expected.
# Pathophysiology
- Erb's palsy is caused by damage to the upper brachial plexus, cervical roots C5-C6, and in 50% of the cases, involving C7.
- Although, damage can occur at any time, this usually happens during a delivery complicated by shoulder dystocia.
- Excessive upper traction to the baby's head in opposite direction from the shoulder produces stretching to the nerve fibers that can lead to a simple temporal disruption or compression, to a complete tear of the entire plexus.
- Another way of damage to upper brachial plexus can be made by excessive pressure on the baby's raised arm during a breech delivery.
- The superior trunk of the brachial plexus has a motor and sensory fibers. Palsy of C5 and C6 roots affects the movement of deltoid, biceps, brachialis, infraspinatus, supraspinatus, and serratus anterior muscles, as well as the sensation of the skin of the shoulder, anterolateral forearm, index and thumb fingers.
- Consequently, the patient is unable to abduct or externally rotate the shoulder, as well as supinate the forearm because of weakness.
# Causes
- The most common cause of Erb's palsy is a difficult extraction during vaginal delivery due to shoulder dystocia. To review the risk factors that aim into a difficult extraction, and ultimately promote Erb's palsy, click here.
- In adults, the most frequent causes are motor vehicle accidents (>90% of cases), work-related trauma (industry), severe fall with stretching of the neck, assault (knife or bullet injury), and iatrogenic injury (surgery).
# Differentiating Erb's palsy from other Diseases
Erb's palsy must be differentiated from:
- Klumpke palsy. Presents with "claw hand" and negative grasp reflex, many times accompanied by Horner's syndrome.
- Clavicular fracture. Presents with visible swelling, and deformity in the clavicular region, as well as crepitation and a positive "piano key sign".
- Osteomyelitis of the humerus or clavicle. Presents with high WB cell count, and osteolysis on plain radiograph.
- Septic arthritis of the shoulder. Presents with soft tissue edema of the shoulder in an MRI.
- Spinal cord or brachial plexus tumor. Presents with a bulging mass in the shoulder, and many times, is associated with neurofibromatosis type II.
# Epidemiology and Demographics
- The prevalence of Erb's palsy is approximately 90 to 206 per 100,000 in the United States, while prevalence worldwide is approximately 50 to 500 per 100,000 individuals.
- An incidence of 36-45 per 100,000 births has been reported for Erb's palsy in the US.
- There is a greater prevalence of right arm Erb's palsy over the left side, with a rate of 1.3:1 to 7:1, with only 3% affecting both arms.
- Permanent impairment occurs at a rate of 3-25% of patients with Erb's palsy.
- In 2007, a study made by Weizsaeker et al found that African descendants had an independently higher risk for Erb's palsy.
- Mothers age greater than 34 years old, were found to be more prone to have a child with Erb´s palsy.
- Females seem to be slightly more affected by Erb's palsy in brachial plexus birth palsies than males, while this proportion greatly inverts in adulthood, with more accidents occurring in males.
# Risk Factors
Common risk factors for neonatal Erb's palsy involve maternal, fetal, and labor factors:
1. Mothers risks:
- Maternal diabetes
- Maternal obesity
- Shoulder dystocia in prior deliveries
2. Fetal risks:
- Breech presentation
- Macrosomia
3. Labor risks:
- Shoulder dystocia
- Oxytocin use
- Prolonged labor (second stage of labor > 60 minutes)
- Difficult extractions (need for forceps or other operative measures)
Studies have shown that these typical risk factors are not reliable predictors for Erb's palsy. Furthermore, the majority of Erb's palsy newborns have come from mothers with no risk factors, and even C-section does not eliminate the risk for neonatal Erb's palsy.
Interestingly, a higher rate of clavicular fractures have not shown an association with BPBP, but a notable association was found between BPBP and fracture of the middle third of the clavicle.
# Screening
As mentioned previously, the majority of Erb's palsy cases appear in children of mothers with no risk factors, for this reason, the condition is impossible to predict and becomes a challenge for the entire team to reduce this risk to the minimum. However, prenatal care can help us know when a vaginal delivery may be complicated:
- Pelvic measurements. Will inform us if the maternal pelvis is narrow and its form (gynaecoid, anthropoid, platypelloid, android), which could complicate the delivery.
- Serum glucose measurements. Will inform us of maternal diabetes, which is directly associated with macrosomic children.
- Prenatal ultrasound. Will inform us of the fetal presentation and the approximate fetal weight.
Once the child is delivered, several findings that can make us suspect an Erb's palsy:
- Negative ipsilateral Moro reflex, and positive palmar grasp reflex.
- Muscle tone and movement scale.
# Natural History, Complications, and Prognosis
Prognosis is generally good; If left untreated, <25% of neonates Erb's palsy may progress to develop permanent disability and impairment, while the rest will recover spontaneously after a month, depending on the severity of the injury (close to 100% of neuropraxias).
Denervated muscles become irreversibly injured after 18 to 24 months, and these time-sensitive changes become the basis for early management.
Several scales have been developed to predict the prognosis in Erb's palsy: Toronto test score, active movement scale, mallet scale, and Toddler Arm Use Test
Common long term complications of Erb's palsy include:
- Reduced strength and stamina
- Irregular joints function
- Muscular atrophy
- Abnormal bone growth
- Osteoarthritis
- Limb length discrepancy
- Impaired balance, and coordination
# Diagnosis
## Diagnostic Study of Choice
The diagnosis of Erb's palsy is made clinically, but several studies may help to confirm it or rule out other conditions, such as ultrasound, MRI, electromyography (EMG), x-rays, and CT.
## History
The classic history of a newborn with Erb's palsy is a macrosomic baby born from a diabetic mother with prolonged vaginal delivery, which presents with shoulder dystocia.
## Physical Examination
- Patients with Erb's palsy usually appear on physical examination with the affected arm held limply adducted, internally rotated, and pronated with an outward direction of the palm, wrist flexed and clung fingers (“waiter's tip” position). The patient is unable to abduct or externally rotate the shoulder. Sensory involvement is usually confined to the shoulder and along the distribution of the musculocutaneous nerve. Biceps, brachioradialis, and Moro reflexes are absent with hand movement and palmar grasp present (differentiating factor from Klumpke palsy). The sensation is impaired in the skin of the shoulder, anterolateral forearm, index and thumb fingers. Ocassionaly, there can be phrenic nerve palsy leading to hemidiaphragmatic paralysis.
- In prolonged Erb's palsies, atrophy of the deltoid, biceps, and brachialis muscles can be observed.
- Ultrasound is many times the initial study when there is a suspected glenohumeral dysplasia. The advantages of this study is that it doesn't produce any ionizing radiation, and can be performed without sedation.
## Electrophysiology/EMG
Electrophysiology studies are probably the single most important imaging study for Erb's palsy, and an important tool when making surgical and therapeutic decisions. EMG can detect the presence of fibrillation potentials indicate denervation. Among the applications for these kinds of studies are that they help categorize the localization, extent, and the type of lesion (preganglionic/ postganglionic), postoperative monitoring, the status of individual muscles (denervated, reinnervating, etc), and can give you a compound motor action potential (CMAP) diagnosis that will dictate the need of surgery in crucial period, before 3 months of age. EMG fails to describe the etiology and prognosis of Erb's palsy, but when used early, can distinguish between intrauterine cases of palsy from those aquiered during delivery.
## X-ray
Help to rule out shoulder dislocations, clavicular, humeral, and rib fractures, as well as accesory cervical ribs, and raised diaphragm (phrenic nerve injury).
## CT scan
- CT, in addition to evaluating bone features with greater precision than X-rays, may detect pseudomeningoceles, which could be a sign of nerve root avulsions, also evaluates the status of the nerve elements when an exploration or reconstructive surgery is planned.
- CT myelography used to be the gold standard for evaluation of nerve roots avulsion in adults but now is rarely used; It utilizes intrathecal injection of water-soluble iodinated contrast material.
## MRI
- MRI can detect the same findings as CT scans, with greater sensitivity for soft tissues.
- MR myelography is also used in the evaluation of Erb's palsy, but unlike CT myelography, it doesn't need constrast material, instead, uses the intrinsic contrast generated between the nerve roots and the surrounding CSF.
# Treatment
## Medical Therapy
There is no consensus on the appropriate treatment for Erb's palsy since this will depend on the severity of the affection, age of the patient, and prognosis. Treatment is often multidisciplinary and aimed to be as conservative as possible.
- Immobilization and splinting. It is commonly used during the first week from injury to avoid flexion contractures.
- Electrostimulation. Its use is still controversial.
- Hydrotherapy. It is a useful method of physical therapy, due to its anti-gravity properties, facilitates muscle relaxation, and range of motion; at the same time, it increases strength and muscle build-up due to water resistance.
- Physiotherapy: It can be done in combination with hydrotherapy or alone. Consist of passive and active range of motion, strengthening, and stretching exercises.
- Occupational therapy. It is usually required for adult patients with long-term damage to help them deal with daily-living activities (eating, tying shoes, playing, drawing).
## Surgery
Surgery is not the first-line treatment option for patients with Erb's palsy. Surgery is usually reserved for patients with no functional recovery from physical therapy and will depend on the time from damage, the cervical roots involved, and the patient’s age.
In infants, surgical intervention is indicated if the motor function does not improve after 3 months of age. After 20 to 24 months of denervation, exists a loss of neuro-muscular endplates, which makes the timing for surgery a crucial point.
Surgical intervention includes nerve decompression, nerve repairs, and graft implantation, with great chances of success.
One of the surgical procedures done for persistent cases is Hoffer-procedure, which has been shown to improve functional outcomes when operated before age 2.5 years.
Secondary reconstruction procedures have been realized in patients as a last resource to gain partial functionality. These include:
- Pectoralis major release to improve passive range of motion
- Tendon transfers for decreased active external rotation
- Trapezius transfer to stabilise shoulder
- Fractional release of the pronator teres and the lacertus fibrosis to improve passive supination
- Shoulder and wrist arthrodesis to improve posture
## Primary Prevention
Effective measures for the primary prevention of Erb's palsy include prenatal screening to detect fetal, or maternal risk factors, and close management of mothers with diabetes and obesity.
## Secondary Prevention
Effective measures for the secondary prevention of Erb's palsy include the application of shoulder dystocia maneuvers during labor (placement of mother in McRobert's position), and once detected a brachial plexus palsy, prompt medical or surgical management when necessary.
## Tertiary Prevention
Effective measures for the primary prevention of Erb's palsy aims to improve functionality in patients with brachial paralysis through physiotherapy and occupational therapy. | Erb's palsy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo, M.D.
# Overview
Duchenne-Erb's palsy or simply Erb's palsy, is a lesion to the C5-C6 brachial roots; it can be a form of brachial plexus birth palsy (BPBP) or can be acquired in adulthood. It occurs when there is a stretching of the superior brachial plexus (neuropraxia, neuroma, neurotmesis), leading in most of the cases to a temporal weakness and loss of sensation in certain muscles of the upper extremity.
# Historical Perspective
- Erb's palsy, was first described by William Smellie, a British obstetrician, in 1754 on his midwifery book, "Traité de la theorie et pratique des accouchemens".[1]
- In 1861, French neurologist, Guillaume Benjamin Amand Duchenne was the first to discover the association of paralysis in the same muscles (deltoid, biceps, and subscapularis) of arms and shoulders of infants delivered vaginally, naming it "obstetric palsy of the brachial plexus".[2][3]
- In 1874, German neurologist, Wilhelm Heinrich Erb concluded that paralysis was associated with a radicular lesion at the level of the superior plexus, C5-C6, and not from isolated peripheral nerve lesions.[4][5]
- In 1985, Narakas made a classification for Erb's palsy grading the severity and determining the prognosis.[6]
# Classification
- Erb's palsy may be classified according to the severity of damage produced to the brachial plexus nerves as:
- Neurapraxia: Mild, temporal disruption, or compression of the myelin sheath, with no structural damage to the axon.[7]
- Axonotmesis: Anatomic interruption of the myelin sheath and the axon of the nerve, but perineurium and epineurium remain intact.[8]
- Neurotmesis: Complete tear of the nerve, including the axon with his endoneurium, perineurium, and epineurium.[9]
- Erb's palsy, in turn, is also classified within the Narakas system, which categorizes Brachial Plexus Birth Palsy (BPBP) according to the roots involved, and its directly linked to its prognosis:[10]
Group I: Classic Erb's palsy (C5-C6 roots). Good spontaneous recovery in > 80% of cases.[11][12]
Group II: Extended Erb's palsy (C5-C7 roots). Good spontaneous recovery in > 60% of cases.[13][14]
Group III: Global palsy without Horner syndrome (C5-C8 roots). Good spontaneous recovery of shoulder/elbow in > 30–50% of cases. Functional hand frequently noted.[15][16]
Group IV: Global palsy with Horner syndrome (C5-T1). Without surgery, severe arm deficits are expected.[17][18]
- Group I: Classic Erb's palsy (C5-C6 roots). Good spontaneous recovery in > 80% of cases.[11][12]
- Group II: Extended Erb's palsy (C5-C7 roots). Good spontaneous recovery in > 60% of cases.[13][14]
- Group III: Global palsy without Horner syndrome (C5-C8 roots). Good spontaneous recovery of shoulder/elbow in > 30–50% of cases. Functional hand frequently noted.[15][16]
- Group IV: Global palsy with Horner syndrome (C5-T1). Without surgery, severe arm deficits are expected.[17][18]
# Pathophysiology
- Erb's palsy is caused by damage to the upper brachial plexus, cervical roots C5-C6,[19] and in 50% of the cases, involving C7.[20][21]
- Although, damage can occur at any time, this usually happens during a delivery complicated by shoulder dystocia.[22]
- Excessive upper traction to the baby's head in opposite direction from the shoulder produces stretching to the nerve fibers that can lead to a simple temporal disruption or compression, to a complete tear of the entire plexus.[23]
- Another way of damage to upper brachial plexus can be made by excessive pressure on the baby's raised arm during a breech delivery. [24]
- The superior trunk of the brachial plexus has a motor and sensory fibers. Palsy of C5 and C6 roots affects the movement of deltoid, biceps, brachialis, infraspinatus, supraspinatus, and serratus anterior muscles, as well as the sensation of the skin of the shoulder, anterolateral forearm, index and thumb fingers.[25]
- Consequently, the patient is unable to abduct or externally rotate the shoulder, as well as supinate the forearm because of weakness.[26]
# Causes
- The most common cause of Erb's palsy is a difficult extraction during vaginal delivery due to shoulder dystocia. To review the risk factors that aim into a difficult extraction, and ultimately promote Erb's palsy, click here.
- In adults, the most frequent causes are motor vehicle accidents (>90% of cases), work-related trauma (industry), severe fall with stretching of the neck, assault (knife or bullet injury), and iatrogenic injury (surgery).[27]
# Differentiating Erb's palsy from other Diseases
Erb's palsy must be differentiated from:
- Klumpke palsy. Presents with "claw hand" and negative grasp reflex, many times accompanied by Horner's syndrome.[28]
- Clavicular fracture.[29][30] Presents with visible swelling, and deformity in the clavicular region, as well as crepitation and a positive "piano key sign".
- Osteomyelitis of the humerus or clavicle.[31] Presents with high WB cell count, and osteolysis on plain radiograph.[32]
- Septic arthritis of the shoulder.[33][34][35] Presents with soft tissue edema of the shoulder in an MRI.[34]
- Spinal cord or brachial plexus tumor.[36] Presents with a bulging mass in the shoulder, and many times, is associated with neurofibromatosis type II.[37]
# Epidemiology and Demographics
- The prevalence of Erb's palsy is approximately 90 to 206 per 100,000 in the United States,[38] while prevalence worldwide is approximately 50 to 500 per 100,000 individuals.[39]
- An incidence of 36-45 per 100,000 births has been reported for Erb's palsy in the US.[40][41]
- There is a greater prevalence of right arm Erb's palsy over the left side, with a rate of 1.3:1 to 7:1,[42][43] with only 3% affecting both arms.[44]
- Permanent impairment occurs at a rate of 3-25% of patients with Erb's palsy.[45]
- In 2007, a study made by Weizsaeker et al found that African descendants had an independently higher risk for Erb's palsy.[46][47]
- Mothers age greater than 34 years old, were found to be more prone to have a child with Erb´s palsy.[48]
- Females seem to be slightly more affected by Erb's palsy in brachial plexus birth palsies than males,[49] while this proportion greatly inverts in adulthood, with more accidents occurring in males.
# Risk Factors
Common risk factors for neonatal Erb's palsy involve maternal, fetal, and labor factors:
1. Mothers risks:
- Maternal diabetes[50]
- Maternal obesity
- Shoulder dystocia in prior deliveries
2. Fetal risks:
- Breech presentation[51]
- Macrosomia[52]
3. Labor risks:
- Shoulder dystocia[53]
- Oxytocin use[54]
- Prolonged labor (second stage of labor > 60 minutes)[55]
- Difficult extractions (need for forceps or other operative measures)[56]
Studies have shown that these typical risk factors are not reliable predictors for Erb's palsy.[57] Furthermore, the majority of Erb's palsy newborns have come from mothers with no risk factors, and even C-section does not eliminate the risk for neonatal Erb's palsy.[58][59]
Interestingly, a higher rate of clavicular fractures have not shown an association with BPBP,[60] but a notable association was found between BPBP and fracture of the middle third of the clavicle.[61]
# Screening
As mentioned previously, the majority of Erb's palsy cases appear in children of mothers with no risk factors, for this reason, the condition is impossible to predict and becomes a challenge for the entire team to reduce this risk to the minimum. However, prenatal care can help us know when a vaginal delivery may be complicated:
- Pelvic measurements. Will inform us if the maternal pelvis is narrow and its form (gynaecoid, anthropoid, platypelloid, android), which could complicate the delivery.
- Serum glucose measurements. Will inform us of maternal diabetes, which is directly associated with macrosomic children.
- Prenatal ultrasound. Will inform us of the fetal presentation and the approximate fetal weight.
Once the child is delivered, several findings that can make us suspect an Erb's palsy:
- Negative ipsilateral Moro reflex, and positive palmar grasp reflex.
- Muscle tone and movement scale.
# Natural History, Complications, and Prognosis
Prognosis is generally good; If left untreated, <25% of neonates Erb's palsy may progress to develop permanent disability and impairment, while the rest will recover spontaneously after a month,[62] depending on the severity of the injury (close to 100% of neuropraxias).
Denervated muscles become irreversibly injured after 18 to 24 months, and these time-sensitive changes become the basis for early management.[63]
Several scales have been developed to predict the prognosis in Erb's palsy: Toronto test score, active movement scale, mallet scale, and Toddler Arm Use Test[64]
Common long term complications of Erb's palsy include:
- Reduced strength and stamina[65]
- Irregular joints function[66]
- Muscular atrophy[67]
- Abnormal bone growth[68]
- Osteoarthritis[69]
- Limb length discrepancy[70]
- Impaired balance, and coordination[71]
# Diagnosis
## Diagnostic Study of Choice
The diagnosis of Erb's palsy is made clinically, but several studies may help to confirm it or rule out other conditions, such as ultrasound, MRI, electromyography (EMG), x-rays, and CT.[72]
## History
The classic history of a newborn with Erb's palsy is a macrosomic baby born from a diabetic mother with prolonged vaginal delivery, which presents with shoulder dystocia.
## Physical Examination
- Patients with Erb's palsy usually appear on physical examination with the affected arm held limply adducted, internally rotated, and pronated with an outward direction of the palm, wrist flexed and clung fingers (“waiter's tip” position).[73] The patient is unable to abduct or externally rotate the shoulder. Sensory involvement is usually confined to the shoulder and along the distribution of the musculocutaneous nerve.[74] Biceps, brachioradialis, and Moro reflexes are absent with hand movement and palmar grasp present (differentiating factor from Klumpke palsy).[75] The sensation is impaired in the skin of the shoulder, anterolateral forearm, index and thumb fingers.[25] Ocassionaly, there can be phrenic nerve palsy leading to hemidiaphragmatic paralysis.[76][77]
- In prolonged Erb's palsies, atrophy of the deltoid, biceps, and brachialis muscles can be observed.[78]
- Ultrasound is many times the initial study when there is a suspected glenohumeral dysplasia.[79] The advantages of this study is that it doesn't produce any ionizing radiation, and can be performed without sedation.[80]
## Electrophysiology/EMG
Electrophysiology studies are probably the single most important imaging study for Erb's palsy, and an important tool when making surgical and therapeutic decisions.[81] EMG can detect the presence of fibrillation potentials indicate denervation.[82] Among the applications for these kinds of studies are that they help categorize the localization, extent, and the type of lesion (preganglionic/ postganglionic), postoperative monitoring, the status of individual muscles (denervated, reinnervating, etc), and can give you a compound motor action potential (CMAP) diagnosis that will dictate the need of surgery in crucial period, before 3 months of age.[81][83] EMG fails to describe the etiology and prognosis of Erb's palsy, but when used early, can distinguish between intrauterine cases of palsy from those aquiered during delivery.[84]
## X-ray
Help to rule out shoulder dislocations, clavicular, humeral, and rib fractures, as well as accesory cervical ribs, and raised diaphragm (phrenic nerve injury).[85][81]
## CT scan
- CT, in addition to evaluating bone features with greater precision than X-rays, may detect pseudomeningoceles, which could be a sign of nerve root avulsions,[86][82][87] also evaluates the status of the nerve elements when an exploration or reconstructive surgery is planned.[88]
- CT myelography used to be the gold standard for evaluation of nerve roots avulsion in adults but now is rarely used;[81] It utilizes intrathecal injection of water-soluble iodinated contrast material.[89]
## MRI
- MRI can detect the same findings as CT scans, with greater sensitivity for soft tissues.
- MR myelography is also used in the evaluation of Erb's palsy, but unlike CT myelography, it doesn't need constrast material, instead, uses the intrinsic contrast generated between the nerve roots and the surrounding CSF.[90]
# Treatment
## Medical Therapy
There is no consensus on the appropriate treatment for Erb's palsy since this will depend on the severity of the affection, age of the patient, and prognosis.[91] Treatment is often multidisciplinary and aimed to be as conservative as possible.[92]
- Immobilization and splinting. It is commonly used during the first week from injury to avoid flexion contractures.[93]
- Electrostimulation. Its use is still controversial.[94]
- Hydrotherapy. It is a useful method of physical therapy, due to its anti-gravity properties, facilitates muscle relaxation, and range of motion; at the same time, it increases strength and muscle build-up due to water resistance.[95]
- Physiotherapy: It can be done in combination with hydrotherapy or alone. Consist of passive and active range of motion, strengthening, and stretching exercises.[96]
- Occupational therapy. It is usually required for adult patients with long-term damage to help them deal with daily-living activities (eating, tying shoes, playing, drawing).[97]
## Surgery
Surgery is not the first-line treatment option for patients with Erb's palsy. Surgery is usually reserved for patients with no functional recovery from physical therapy and will depend on the time from damage, the cervical roots involved, and the patient’s age.[98]
In infants, surgical intervention is indicated if the motor function does not improve after 3 months of age.[99] After 20 to 24 months of denervation, exists a loss of neuro-muscular endplates, which makes the timing for surgery a crucial point.[100]
Surgical intervention includes nerve decompression, nerve repairs, and graft implantation, with great chances of success.[101]
One of the surgical procedures done for persistent cases is Hoffer-procedure, which has been shown to improve functional outcomes when operated before age 2.5 years.[102]
Secondary reconstruction procedures have been realized in patients as a last resource to gain partial functionality.[103] These include:
- Pectoralis major release to improve passive range of motion[104]
- Tendon transfers for decreased active external rotation[105]
- Trapezius transfer to stabilise shoulder[106]
- Fractional release of the pronator teres and the lacertus fibrosis to improve passive supination[107]
- Shoulder and wrist arthrodesis to improve posture[108]
## Primary Prevention
Effective measures for the primary prevention of Erb's palsy include prenatal screening to detect fetal, or maternal risk factors, and close management of mothers with diabetes and obesity.
## Secondary Prevention
Effective measures for the secondary prevention of Erb's palsy include the application of shoulder dystocia maneuvers during labor (placement of mother in McRobert's position), and once detected a brachial plexus palsy, prompt medical or surgical management when necessary.
## Tertiary Prevention
Effective measures for the primary prevention of Erb's palsy aims to improve functionality in patients with brachial paralysis through physiotherapy and occupational therapy. | https://www.wikidoc.org/index.php/Erb%27s_palsy | |
ef9204c2a6b0f366aa732ff45c102489fccf979e | wikidoc | Erich Traub | Erich Traub
Dr. Erich Traub was a Nazi germ warfare scientist allegedly smuggled into the United States in 1949 from the former Soviet Union under the auspices of the top secret United States government program Operation Paperclip.
Dr. Traub is known as the father of the Plum Island biological research lab, located 6 miles from Old Lyme, Connecticut. According to the book Lab 257, by author Michael Carroll, Dr. Traub was chief of Insel Riems, a virological research institute in the Baltic sea now known as the Friedrich Loeffler Institute.
Traub worked directly for Adolf Hitler's second in charge, Heinrich Himmler. At Insel Riems, Dr. Traub's interests included personally collecting Rinderpest virus from Anatolia, and packaging weaponized foot and mouth disease for dispersal onto cattle and reindeer in Russia. Dr. Traub also experimented with the glanders bacteria and had a particular fascination for organisms that voraciously devour the brain.
According to his National Defense Program FBI application form, he was born on June 27, 1906 in Asperglen, Germany and he died in Germany in 1988.
# Plum Island
In the book, The Belarus Secret, author John Loftus, the Justice Department employee who exposed Kurt Waldheim as a Nazi, states that Nazi germ warfare scientists had experimented with poison ticks dropped from planes to spread rare diseases. Loftus also states that he had received information that the United States had tested some of these poison ticks on the Plum Island artillery range off the coast of Connecticut during the early part of the 1950s.
Michael Carroll quotes former Plum Island lab director Jerry Callis talking about tick research on Plum Island:
"Plum Island experimented with ticks, but never outside of containment. We had a tick colony where you take them and feed them on the virus and breed ticks to see how many generations it would last, on and on, until its diluted. Recently they reinstated the tick colony."
Carroll additionally cites a 1978 US Department of Agriculture (UDSA) document titled "African Swine Fever," which further confirms the use of ticks as biowar vectors on Plum Island, noting that the report stated:
"In 1975 and 1976 the adult and nyphal stages of Ablyomma americanum (the Lone Star tick) and Ablyomma cajunense (the Cayenne tick) were found to be incapable of harboring and transmitting African Swine fever virus."
Coincidentally, the Lyme disease outbreak was identified about the time of the Swine Fever tick study conducted on Plum Island. Also at the time of the Plum Island Swine Fever experiments, the Lone Star tick's range was limited to Texas. Today it is endemic in New Jersey, New York State and Connecticut, and as Carroll states in Lab 257, no one can answer how the Lone Star tick migrated from Texas to New York and Connecticut.
Erich Traub's legacy of experimentation using insects as disease vectors continued during the 1980s at Plum Island under the jurisdiction of Entomologist Dr. Richard Endris, who is reported to have nurtured over 200,000 soft and hard ticks of varying species in tick nurseries on Plum Island, personally collected from locations as far away as Cameroon, Africa. In a footnote in Lab 257, Carroll notes that Endris, while under contract with the US Army lab at Fort Detrick had also conducted experiments in 1987 on Plum Island, using sand flies as vectors of the fatal illness Leishmaniasis. The work is alleged by Carroll to have been done in secrecy, with few safety precautions.
Carroll cites Dr. Traub as having worked with the U.S. Army, the Navy, the Central Intelligence Agency (CIA) and the UDSA before he returned to Germany in 1953. Dr. Traub is known to have visited Plum Island on at least three different occasions, and was offered the directorship there several times. | Erich Traub
Dr. Erich Traub was a Nazi germ warfare scientist allegedly smuggled into the United States in 1949 from the former Soviet Union under the auspices of the top secret United States government program Operation Paperclip.[1]
Dr. Traub is known as the father of the Plum Island biological research lab, located 6 miles from Old Lyme, Connecticut. According to the book Lab 257, by author Michael Carroll, Dr. Traub was chief of Insel Riems, a virological research institute in the Baltic sea now known as the Friedrich Loeffler Institute.[2]
Traub worked directly for Adolf Hitler's second in charge, Heinrich Himmler.[3] At Insel Riems, Dr. Traub's interests included personally collecting Rinderpest virus from Anatolia, and packaging weaponized foot and mouth disease for dispersal onto cattle and reindeer in Russia.[3] Dr. Traub also experimented with the glanders bacteria and had a particular fascination for organisms that voraciously devour the brain.[3]
According to his National Defense Program FBI application form, he was born on June 27, 1906 in Asperglen, Germany and he died in Germany in 1988.[3]
# Plum Island
In the book, The Belarus Secret, author John Loftus, the Justice Department employee who exposed Kurt Waldheim as a Nazi, states that Nazi germ warfare scientists had experimented with poison ticks dropped from planes to spread rare diseases. Loftus also states that he had received information that the United States had tested some of these poison ticks on the Plum Island artillery range off the coast of Connecticut during the early part of the 1950s. [4]
Michael Carroll quotes former Plum Island lab director Jerry Callis talking about tick research on Plum Island:
"Plum Island experimented with ticks, but never outside of containment. We had a tick colony where you take them and feed them on the virus and breed ticks to see how many generations it would last, on and on, until its diluted. Recently they reinstated the tick colony."
Carroll additionally cites a 1978 US Department of Agriculture (UDSA) document titled "African Swine Fever," which further confirms the use of ticks as biowar vectors on Plum Island, noting that the report stated:
"In 1975 and 1976 the adult and nyphal stages of Ablyomma americanum (the Lone Star tick) and Ablyomma cajunense (the Cayenne tick) were found to be incapable of harboring and transmitting African Swine fever virus."
Coincidentally, the Lyme disease outbreak was identified about the time of the Swine Fever tick study conducted on Plum Island. Also at the time of the Plum Island Swine Fever experiments, the Lone Star tick's range was limited to Texas. Today it is endemic in New Jersey, New York State and Connecticut, and as Carroll states in Lab 257, no one can answer how the Lone Star tick migrated from Texas to New York and Connecticut.
Erich Traub's legacy of experimentation using insects as disease vectors continued during the 1980s at Plum Island under the jurisdiction of Entomologist Dr. Richard Endris, who is reported to have nurtured over 200,000 soft and hard ticks of varying species in tick nurseries on Plum Island, personally collected from locations as far away as Cameroon, Africa.[3] In a footnote in Lab 257, Carroll notes that Endris, while under contract with the US Army lab at Fort Detrick had also conducted experiments in 1987 on Plum Island, using sand flies as vectors of the fatal illness Leishmaniasis.[3] The work is alleged by Carroll to have been done in secrecy, with few safety precautions.
Carroll cites Dr. Traub as having worked with the U.S. Army, the Navy, the Central Intelligence Agency (CIA) and the UDSA before he returned to Germany in 1953. Dr. Traub is known to have visited Plum Island on at least three different occasions, and was offered the directorship there several times. | https://www.wikidoc.org/index.php/Erich_Traub | |
994524d3485a74647aa3022e417b9476bb434cfc | wikidoc | Erinaceidae | Erinaceidae
Erinaceidae is the only living family in the order of the Erinaceomorpha. It contains the well-known hedgehogs (subfamily Erinaceinae) of Eurasia and Africa and the gymnures or moonrats (subfamily Galericinae) of South-east Asia. This family was once considered part of the order Insectivora, but that polyphyletic order is now considered defunct.
# Characteristics
Erinaceids are generally shrew-like in form, with long snouts and short tails. They are, however, much larger than shrews, ranging from 10-15 cm in body length and 40-60 grams in weight, in the case of the Short-tailed Gymnure, up to 26-45 cm and 1-1.4 kilograms in the Greater Moonrat. All but one species have five toes in each foot, in some cases with strong claws for digging, and they have large eyes and ears. Hedgehogs possess hair modified into sharp spines to form a protective covering over the upper body and flanks, while gymnures have only normal hair. All species have anal scent glands, but these are far better developed in gymnures, which can have a powerful odor.
Erinaceids are omnivorous, with the major part of their diet consisting of insects, earthworms, and other small invertebrates. They also eat seeds and fruit, and occasionally bird's eggs, along with any carrion they come across. Their teeth are sharp and suited for impaling invertebrate prey. The dental formula for erinaceids is:Template:Dentition2
Hedgehogs are nocturnal, but gymnures are less so, and may be active during the day. Many species live in simple burrows, while others construct temporary nests on the surface from leaves and grass, or shelter in hollow logs or similar hiding places. Erinaceids are solitary animals outside the breeding season, and the father plays no role in raising the young.
Female erinaceids give birth a gestation period of around six to seven weeks. The young are born blind and hairless, although hedgehogs begin to sprout their spines within 36 hours of birth.
# Evolution
Erinaceids are a relatively primitive group of placental mammals, having changed little since their origin in the Eocene. The so-called 'giant hedgehog' (actually a gymnure) Deinogalerix, from the Miocene of Italy, was the size of a large rabbit, and may have eaten vertebrate prey or carrion, rather than insects.
# Classification
There are 10 genera and 24 species of erinaceid.
- ORDER ERINACEOMORPHA
Family Erinaceidae
Subfamily Erinaceinae (Hedgehogs)
Genus Atelerix
Four-toed Hedgehog, Atelerix albiventris
North African Hedgehog, Atelerix algirus
Southern African Hedgehog, Atelerix frontalis
Somali Hedgehog, Atelerix sclateri
Genus Erinaceus
Amur Hedgehog, Erinaceus amurensis
Southern White-breasted Hedgehog, Erinaceus concolor
West European Hedgehog, Erinaceus europaeus
Northern White-breasted Hedgehog, Erinaceus roumanicus
Genus Hemiechinus
Long-eared Hedgehog, Hemiechinus auritus
Indian Long-eared Hedgehog, Hemiechinus collaris
Genus Mesechinus
Daurian Hedgehog, Mesechinus dauuricus
Hugh's Hedgehog, Mesechinus hughi
Genus Paraechinus
Desert Hedgehog, Paraechinus aethiopicus
Brandt's Hedgehog, Paraechinus hypomelas
Indian Hedgehog, Paraechinus micropus
Bare-bellied Hedgehog, Paraechinus nudiventris
Subfamily Galericinae (Gymnures, or Moonrats)
Genus Echinosorex
Greater Moonrat, Echinosorex gymnura
Genus Hylomys
Long-eared Gymnure, Hylomys megalotis
Dwarf Gymnure, Hylomys parvus
Short-tailed Gymnure or Lesser Moonrat, Hylomys suillus
Genus Neohylomys
Hainan Gymnure, Neonylomys hainanensis
Genus Neotetracus
Shrew Gymnure, Neotetracus sinensis
Genus Podogymnura
Dinagat Gymnure, Podogymnura aureospinula
Mindanao Gymnure, Podogymnura truei
- Family Erinaceidae
Subfamily Erinaceinae (Hedgehogs)
Genus Atelerix
Four-toed Hedgehog, Atelerix albiventris
North African Hedgehog, Atelerix algirus
Southern African Hedgehog, Atelerix frontalis
Somali Hedgehog, Atelerix sclateri
Genus Erinaceus
Amur Hedgehog, Erinaceus amurensis
Southern White-breasted Hedgehog, Erinaceus concolor
West European Hedgehog, Erinaceus europaeus
Northern White-breasted Hedgehog, Erinaceus roumanicus
Genus Hemiechinus
Long-eared Hedgehog, Hemiechinus auritus
Indian Long-eared Hedgehog, Hemiechinus collaris
Genus Mesechinus
Daurian Hedgehog, Mesechinus dauuricus
Hugh's Hedgehog, Mesechinus hughi
Genus Paraechinus
Desert Hedgehog, Paraechinus aethiopicus
Brandt's Hedgehog, Paraechinus hypomelas
Indian Hedgehog, Paraechinus micropus
Bare-bellied Hedgehog, Paraechinus nudiventris
Subfamily Galericinae (Gymnures, or Moonrats)
Genus Echinosorex
Greater Moonrat, Echinosorex gymnura
Genus Hylomys
Long-eared Gymnure, Hylomys megalotis
Dwarf Gymnure, Hylomys parvus
Short-tailed Gymnure or Lesser Moonrat, Hylomys suillus
Genus Neohylomys
Hainan Gymnure, Neonylomys hainanensis
Genus Neotetracus
Shrew Gymnure, Neotetracus sinensis
Genus Podogymnura
Dinagat Gymnure, Podogymnura aureospinula
Mindanao Gymnure, Podogymnura truei
- Subfamily Erinaceinae (Hedgehogs)
Genus Atelerix
Four-toed Hedgehog, Atelerix albiventris
North African Hedgehog, Atelerix algirus
Southern African Hedgehog, Atelerix frontalis
Somali Hedgehog, Atelerix sclateri
Genus Erinaceus
Amur Hedgehog, Erinaceus amurensis
Southern White-breasted Hedgehog, Erinaceus concolor
West European Hedgehog, Erinaceus europaeus
Northern White-breasted Hedgehog, Erinaceus roumanicus
Genus Hemiechinus
Long-eared Hedgehog, Hemiechinus auritus
Indian Long-eared Hedgehog, Hemiechinus collaris
Genus Mesechinus
Daurian Hedgehog, Mesechinus dauuricus
Hugh's Hedgehog, Mesechinus hughi
Genus Paraechinus
Desert Hedgehog, Paraechinus aethiopicus
Brandt's Hedgehog, Paraechinus hypomelas
Indian Hedgehog, Paraechinus micropus
Bare-bellied Hedgehog, Paraechinus nudiventris
- Genus Atelerix
Four-toed Hedgehog, Atelerix albiventris
North African Hedgehog, Atelerix algirus
Southern African Hedgehog, Atelerix frontalis
Somali Hedgehog, Atelerix sclateri
- Four-toed Hedgehog, Atelerix albiventris
- North African Hedgehog, Atelerix algirus
- Southern African Hedgehog, Atelerix frontalis
- Somali Hedgehog, Atelerix sclateri
- Genus Erinaceus
Amur Hedgehog, Erinaceus amurensis
Southern White-breasted Hedgehog, Erinaceus concolor
West European Hedgehog, Erinaceus europaeus
Northern White-breasted Hedgehog, Erinaceus roumanicus
- Amur Hedgehog, Erinaceus amurensis
- Southern White-breasted Hedgehog, Erinaceus concolor
- West European Hedgehog, Erinaceus europaeus
- Northern White-breasted Hedgehog, Erinaceus roumanicus
- Genus Hemiechinus
Long-eared Hedgehog, Hemiechinus auritus
Indian Long-eared Hedgehog, Hemiechinus collaris
- Long-eared Hedgehog, Hemiechinus auritus
- Indian Long-eared Hedgehog, Hemiechinus collaris
- Genus Mesechinus
Daurian Hedgehog, Mesechinus dauuricus
Hugh's Hedgehog, Mesechinus hughi
- Daurian Hedgehog, Mesechinus dauuricus
- Hugh's Hedgehog, Mesechinus hughi
- Genus Paraechinus
Desert Hedgehog, Paraechinus aethiopicus
Brandt's Hedgehog, Paraechinus hypomelas
Indian Hedgehog, Paraechinus micropus
Bare-bellied Hedgehog, Paraechinus nudiventris
- Desert Hedgehog, Paraechinus aethiopicus
- Brandt's Hedgehog, Paraechinus hypomelas
- Indian Hedgehog, Paraechinus micropus
- Bare-bellied Hedgehog, Paraechinus nudiventris
- Subfamily Galericinae (Gymnures, or Moonrats)
Genus Echinosorex
Greater Moonrat, Echinosorex gymnura
Genus Hylomys
Long-eared Gymnure, Hylomys megalotis
Dwarf Gymnure, Hylomys parvus
Short-tailed Gymnure or Lesser Moonrat, Hylomys suillus
Genus Neohylomys
Hainan Gymnure, Neonylomys hainanensis
Genus Neotetracus
Shrew Gymnure, Neotetracus sinensis
Genus Podogymnura
Dinagat Gymnure, Podogymnura aureospinula
Mindanao Gymnure, Podogymnura truei
- Genus Echinosorex
Greater Moonrat, Echinosorex gymnura
- Greater Moonrat, Echinosorex gymnura
- Genus Hylomys
Long-eared Gymnure, Hylomys megalotis
Dwarf Gymnure, Hylomys parvus
Short-tailed Gymnure or Lesser Moonrat, Hylomys suillus
- Long-eared Gymnure, Hylomys megalotis
- Dwarf Gymnure, Hylomys parvus
- Short-tailed Gymnure or Lesser Moonrat, Hylomys suillus
- Genus Neohylomys
Hainan Gymnure, Neonylomys hainanensis
- Hainan Gymnure, Neonylomys hainanensis
- Genus Neotetracus
Shrew Gymnure, Neotetracus sinensis
- Shrew Gymnure, Neotetracus sinensis
- Genus Podogymnura
Dinagat Gymnure, Podogymnura aureospinula
Mindanao Gymnure, Podogymnura truei
- Dinagat Gymnure, Podogymnura aureospinula
- Mindanao Gymnure, Podogymnura truei | Erinaceidae
Erinaceidae is the only living family in the order of the Erinaceomorpha. It contains the well-known hedgehogs (subfamily Erinaceinae) of Eurasia and Africa and the gymnures or moonrats (subfamily Galericinae) of South-east Asia. This family was once considered part of the order Insectivora, but that polyphyletic order is now considered defunct.[1]
# Characteristics
Erinaceids are generally shrew-like in form, with long snouts and short tails. They are, however, much larger than shrews, ranging from 10-15 cm in body length and 40-60 grams in weight, in the case of the Short-tailed Gymnure, up to 26-45 cm and 1-1.4 kilograms in the Greater Moonrat. All but one species have five toes in each foot, in some cases with strong claws for digging, and they have large eyes and ears. Hedgehogs possess hair modified into sharp spines to form a protective covering over the upper body and flanks, while gymnures have only normal hair. All species have anal scent glands, but these are far better developed in gymnures, which can have a powerful odor[2].
Erinaceids are omnivorous, with the major part of their diet consisting of insects, earthworms, and other small invertebrates. They also eat seeds and fruit, and occasionally bird's eggs, along with any carrion they come across. Their teeth are sharp and suited for impaling invertebrate prey. The dental formula for erinaceids is:Template:Dentition2
Hedgehogs are nocturnal, but gymnures are less so, and may be active during the day. Many species live in simple burrows, while others construct temporary nests on the surface from leaves and grass, or shelter in hollow logs or similar hiding places. Erinaceids are solitary animals outside the breeding season, and the father plays no role in raising the young[2].
Female erinaceids give birth a gestation period of around six to seven weeks. The young are born blind and hairless, although hedgehogs begin to sprout their spines within 36 hours of birth.
# Evolution
Erinaceids are a relatively primitive group of placental mammals, having changed little since their origin in the Eocene. The so-called 'giant hedgehog' (actually a gymnure) Deinogalerix, from the Miocene of Italy, was the size of a large rabbit, and may have eaten vertebrate prey or carrion, rather than insects[3].
# Classification
There are 10 genera and 24 species of erinaceid.
- ORDER ERINACEOMORPHA
Family Erinaceidae
Subfamily Erinaceinae (Hedgehogs)
Genus Atelerix
Four-toed Hedgehog, Atelerix albiventris
North African Hedgehog, Atelerix algirus
Southern African Hedgehog, Atelerix frontalis
Somali Hedgehog, Atelerix sclateri
Genus Erinaceus
Amur Hedgehog, Erinaceus amurensis
Southern White-breasted Hedgehog, Erinaceus concolor
West European Hedgehog, Erinaceus europaeus
Northern White-breasted Hedgehog, Erinaceus roumanicus
Genus Hemiechinus
Long-eared Hedgehog, Hemiechinus auritus
Indian Long-eared Hedgehog, Hemiechinus collaris
Genus Mesechinus
Daurian Hedgehog, Mesechinus dauuricus
Hugh's Hedgehog, Mesechinus hughi
Genus Paraechinus
Desert Hedgehog, Paraechinus aethiopicus
Brandt's Hedgehog, Paraechinus hypomelas
Indian Hedgehog, Paraechinus micropus
Bare-bellied Hedgehog, Paraechinus nudiventris
Subfamily Galericinae (Gymnures, or Moonrats)
Genus Echinosorex
Greater Moonrat, Echinosorex gymnura
Genus Hylomys
Long-eared Gymnure, Hylomys megalotis
Dwarf Gymnure, Hylomys parvus
Short-tailed Gymnure or Lesser Moonrat, Hylomys suillus
Genus Neohylomys
Hainan Gymnure, Neonylomys hainanensis
Genus Neotetracus
Shrew Gymnure, Neotetracus sinensis
Genus Podogymnura
Dinagat Gymnure, Podogymnura aureospinula
Mindanao Gymnure, Podogymnura truei
- Family Erinaceidae
Subfamily Erinaceinae (Hedgehogs)
Genus Atelerix
Four-toed Hedgehog, Atelerix albiventris
North African Hedgehog, Atelerix algirus
Southern African Hedgehog, Atelerix frontalis
Somali Hedgehog, Atelerix sclateri
Genus Erinaceus
Amur Hedgehog, Erinaceus amurensis
Southern White-breasted Hedgehog, Erinaceus concolor
West European Hedgehog, Erinaceus europaeus
Northern White-breasted Hedgehog, Erinaceus roumanicus
Genus Hemiechinus
Long-eared Hedgehog, Hemiechinus auritus
Indian Long-eared Hedgehog, Hemiechinus collaris
Genus Mesechinus
Daurian Hedgehog, Mesechinus dauuricus
Hugh's Hedgehog, Mesechinus hughi
Genus Paraechinus
Desert Hedgehog, Paraechinus aethiopicus
Brandt's Hedgehog, Paraechinus hypomelas
Indian Hedgehog, Paraechinus micropus
Bare-bellied Hedgehog, Paraechinus nudiventris
Subfamily Galericinae (Gymnures, or Moonrats)
Genus Echinosorex
Greater Moonrat, Echinosorex gymnura
Genus Hylomys
Long-eared Gymnure, Hylomys megalotis
Dwarf Gymnure, Hylomys parvus
Short-tailed Gymnure or Lesser Moonrat, Hylomys suillus
Genus Neohylomys
Hainan Gymnure, Neonylomys hainanensis
Genus Neotetracus
Shrew Gymnure, Neotetracus sinensis
Genus Podogymnura
Dinagat Gymnure, Podogymnura aureospinula
Mindanao Gymnure, Podogymnura truei
- Subfamily Erinaceinae (Hedgehogs)
Genus Atelerix
Four-toed Hedgehog, Atelerix albiventris
North African Hedgehog, Atelerix algirus
Southern African Hedgehog, Atelerix frontalis
Somali Hedgehog, Atelerix sclateri
Genus Erinaceus
Amur Hedgehog, Erinaceus amurensis
Southern White-breasted Hedgehog, Erinaceus concolor
West European Hedgehog, Erinaceus europaeus
Northern White-breasted Hedgehog, Erinaceus roumanicus
Genus Hemiechinus
Long-eared Hedgehog, Hemiechinus auritus
Indian Long-eared Hedgehog, Hemiechinus collaris
Genus Mesechinus
Daurian Hedgehog, Mesechinus dauuricus
Hugh's Hedgehog, Mesechinus hughi
Genus Paraechinus
Desert Hedgehog, Paraechinus aethiopicus
Brandt's Hedgehog, Paraechinus hypomelas
Indian Hedgehog, Paraechinus micropus
Bare-bellied Hedgehog, Paraechinus nudiventris
- Genus Atelerix
Four-toed Hedgehog, Atelerix albiventris
North African Hedgehog, Atelerix algirus
Southern African Hedgehog, Atelerix frontalis
Somali Hedgehog, Atelerix sclateri
- Four-toed Hedgehog, Atelerix albiventris
- North African Hedgehog, Atelerix algirus
- Southern African Hedgehog, Atelerix frontalis
- Somali Hedgehog, Atelerix sclateri
- Genus Erinaceus
Amur Hedgehog, Erinaceus amurensis
Southern White-breasted Hedgehog, Erinaceus concolor
West European Hedgehog, Erinaceus europaeus
Northern White-breasted Hedgehog, Erinaceus roumanicus
- Amur Hedgehog, Erinaceus amurensis
- Southern White-breasted Hedgehog, Erinaceus concolor
- West European Hedgehog, Erinaceus europaeus
- Northern White-breasted Hedgehog, Erinaceus roumanicus
- Genus Hemiechinus
Long-eared Hedgehog, Hemiechinus auritus
Indian Long-eared Hedgehog, Hemiechinus collaris
- Long-eared Hedgehog, Hemiechinus auritus
- Indian Long-eared Hedgehog, Hemiechinus collaris
- Genus Mesechinus
Daurian Hedgehog, Mesechinus dauuricus
Hugh's Hedgehog, Mesechinus hughi
- Daurian Hedgehog, Mesechinus dauuricus
- Hugh's Hedgehog, Mesechinus hughi
- Genus Paraechinus
Desert Hedgehog, Paraechinus aethiopicus
Brandt's Hedgehog, Paraechinus hypomelas
Indian Hedgehog, Paraechinus micropus
Bare-bellied Hedgehog, Paraechinus nudiventris
- Desert Hedgehog, Paraechinus aethiopicus
- Brandt's Hedgehog, Paraechinus hypomelas
- Indian Hedgehog, Paraechinus micropus
- Bare-bellied Hedgehog, Paraechinus nudiventris
- Subfamily Galericinae (Gymnures, or Moonrats)
Genus Echinosorex
Greater Moonrat, Echinosorex gymnura
Genus Hylomys
Long-eared Gymnure, Hylomys megalotis
Dwarf Gymnure, Hylomys parvus
Short-tailed Gymnure or Lesser Moonrat, Hylomys suillus
Genus Neohylomys
Hainan Gymnure, Neonylomys hainanensis
Genus Neotetracus
Shrew Gymnure, Neotetracus sinensis
Genus Podogymnura
Dinagat Gymnure, Podogymnura aureospinula
Mindanao Gymnure, Podogymnura truei
- Genus Echinosorex
Greater Moonrat, Echinosorex gymnura
- Greater Moonrat, Echinosorex gymnura
- Genus Hylomys
Long-eared Gymnure, Hylomys megalotis
Dwarf Gymnure, Hylomys parvus
Short-tailed Gymnure or Lesser Moonrat, Hylomys suillus
- Long-eared Gymnure, Hylomys megalotis
- Dwarf Gymnure, Hylomys parvus
- Short-tailed Gymnure or Lesser Moonrat, Hylomys suillus
- Genus Neohylomys
Hainan Gymnure, Neonylomys hainanensis
- Hainan Gymnure, Neonylomys hainanensis
- Genus Neotetracus
Shrew Gymnure, Neotetracus sinensis
- Shrew Gymnure, Neotetracus sinensis
- Genus Podogymnura
Dinagat Gymnure, Podogymnura aureospinula
Mindanao Gymnure, Podogymnura truei
- Dinagat Gymnure, Podogymnura aureospinula
- Mindanao Gymnure, Podogymnura truei | https://www.wikidoc.org/index.php/Erinaceidae | |
5754a031db9da849010281a511c58325a266bd9d | wikidoc | Erlang unit | Erlang unit
The erlang (symbol E) as a dimensionless unit is used in telephony as a statistical measure of the volume of telecommunications traffic. It is named after the Danish telephone engineer A. K. Erlang, the originator of traffic engineering and queueing theory.
Traffic of one Erlang refers to a single resource being in continuous use, or two channels being at fifty percent use, and so on, pro rata. For example, if an office had two telephone operators who are both busy all the time, that would represent two erlangs (2 E) of traffic, or a radio channel that is occupied for thirty minutes during an hour is said to carry 0.5 E of traffic.
Alternatively, an erlang may be regarded as a "use multiplier" per
unit time, so 100% use is 1 E, 200% use is 2 E, and so on. For example, if total cell phone use in a given
area per hour is 180 minutes, this represents 180/60 = 3 E. In general, if the mean arrival rate of new calls is λ per unit time and the mean call holding time is h, then the traffic in erlangs A is:
This may be used to determine if a system is over-provisioned or under-provisioned (has too many or too few resources allocated).
For example, the traffic measured over many busy hours might be used for a T1 or E1 circuit group to determine how many voice lines are likely to be used during the busiest hours. If no more than 12 out of 24 channels are likely to be used at any given time, the other 12 might be made available as data channels.
Traffic measured in erlangs is used to calculate grade of service (GOS) or quality of service (QoS). There are a range of different Erlang formulae to calculate these, including Erlang B, Erlang C and the related Engset formula. These are discussed below, and may each be derived by means of a special case of continuous-time Markov processes known as a birth-death process.
# Erlang B formula
The Erlang B formula assumes an infinite population of sources (such as telephone subscribers), which jointly offer traffic to N servers (such as links in a trunk group). The rate of arrival of new calls (birth rate) is equal to λ and is constant, not depending on the number of active sources, because the total number of sources is assumed to be infinite. The rate of call departure (death rate) is equal to the number of calls in progress divided by h, the mean call holding time. The formula calculates blocking probability in a loss system, where if a request is not served immediately when it tries to use a resource, it is aborted. Requests are therefore not queued. Blocking occurs when there is a new request from a source, but all the servers are already busy. The formula assumes that blocked traffic is immediately cleared.
This may be expressed recursively as follows, in a form that is used to calculate tables of the Erlang B formula:
where:
- B is the probability of blocking
- N is the number of resources such as servers or circuits in a group
- A = λh is the total amount of traffic offered in erlangs
The Erlang B formula applies to loss systems, such as telephone systems on both fixed and mobile networks, which do not provide traffic buffering, and are not intended to do so. It assumes that the call arrivals may be modeled by a Poisson process, but is valid for any statistical distribution of call holding times.
Erlang B is a trunk sizing tool for voice switch to voice switch traffic.
# Erlang C formula
The Erlang C formula also assumes an infinite population of sources, which jointly offer traffic of A erlangs to N servers. However, if all the servers are busy when a request arrives from a source, the request is queued. An unlimited number of requests may be held in the queue in this way simultaneously. This formula calculates the probability of queuing offered traffic, assuming that blocked calls stay in the system until they can be handled. This formula is used to determine the number of agents or customer service representatives needed to staff a call centre, for a specified desired probability of queuing.
where:
- A is the total traffic offered in units of erlangs
- N is the number of servers
- PW is the probability that a customer has to wait for service
It is assumed that the call arrivals can be modeled by a Poisson process and that call holding times are described by a negative exponential distribution.
# Engset formula
The Engset formula, named after T. O. Engset, is related but deals with a finite population of S sources rather than the infinite population of sources that Erlang assumes:
{\left( \begin{array}{c} S \\ N \end{array} \right)}}
{\sum_{i=0}^NA^i
{\left( \begin{array}{c} S \\ i \end{array} \right)}}
This may be expressed recursively as follows, in a form that is used to calculate tables of the Engset formula:
where:
- E is the probability of blocking
- A is the traffic in erlangs generated by each source when idle
- S is the number of sources
- N is the number of servers
Again, it is assumed that the call arrivals can be modeled by a Poisson process and that call holding times are described by a negative exponential distribution. However, because there are a finite number of sources, the arrival rate of new calls decreases as more sources (such as telephone subscribers) become busy and hence cannot originate new calls. When N = S, the formula reduces to a binomial distribution. | Erlang unit
The erlang (symbol E[1]) as a dimensionless unit is used in telephony as a statistical measure of the volume of telecommunications traffic. It is named after the Danish telephone engineer A. K. Erlang, the originator of traffic engineering and queueing theory.
Traffic of one Erlang refers to a single resource being in continuous use, or two channels being at fifty percent use, and so on, pro rata. For example, if an office had two telephone operators who are both busy all the time, that would represent two erlangs (2 E) of traffic, or a radio channel that is occupied for thirty minutes during an hour is said to carry 0.5 E of traffic.
Alternatively, an erlang may be regarded as a "use multiplier" per
unit time, so 100% use is 1 E, 200% use is 2 E, and so on. For example, if total cell phone use in a given
area per hour is 180 minutes, this represents 180/60 = 3 E. In general, if the mean arrival rate of new calls is λ per unit time and the mean call holding time is h, then the traffic in erlangs A is:
This may be used to determine if a system is over-provisioned or under-provisioned (has too many or too few resources allocated).
For example, the traffic measured over many busy hours might be used for a T1 or E1 circuit group to determine how many voice lines are likely to be used during the busiest hours. If no more than 12 out of 24 channels are likely to be used at any given time, the other 12 might be made available as data channels.
Traffic measured in erlangs is used to calculate grade of service (GOS) or quality of service (QoS). There are a range of different Erlang formulae to calculate these, including Erlang B, Erlang C and the related Engset formula. These are discussed below, and may each be derived by means of a special case of continuous-time Markov processes known as a birth-death process.
# Erlang B formula
The Erlang B formula assumes an infinite population of sources (such as telephone subscribers), which jointly offer traffic to N servers (such as links in a trunk group). The rate of arrival of new calls (birth rate) is equal to λ and is constant, not depending on the number of active sources, because the total number of sources is assumed to be infinite. The rate of call departure (death rate) is equal to the number of calls in progress divided by h, the mean call holding time. The formula calculates blocking probability in a loss system, where if a request is not served immediately when it tries to use a resource, it is aborted. Requests are therefore not queued. Blocking occurs when there is a new request from a source, but all the servers are already busy. The formula assumes that blocked traffic is immediately cleared.
This may be expressed recursively as follows, in a form that is used to calculate tables of the Erlang B formula:
where:
- B is the probability of blocking
- N is the number of resources such as servers or circuits in a group
- A = λh is the total amount of traffic offered in erlangs
The Erlang B formula applies to loss systems, such as telephone systems on both fixed and mobile networks, which do not provide traffic buffering, and are not intended to do so. It assumes that the call arrivals may be modeled by a Poisson process, but is valid for any statistical distribution of call holding times.
Erlang B is a trunk sizing tool for voice switch to voice switch traffic.
# Erlang C formula
The Erlang C formula also assumes an infinite population of sources, which jointly offer traffic of A erlangs to N servers. However, if all the servers are busy when a request arrives from a source, the request is queued. An unlimited number of requests may be held in the queue in this way simultaneously. This formula calculates the probability of queuing offered traffic, assuming that blocked calls stay in the system until they can be handled. This formula is used to determine the number of agents or customer service representatives needed to staff a call centre, for a specified desired probability of queuing.
where:
- A is the total traffic offered in units of erlangs
- N is the number of servers
- PW is the probability that a customer has to wait for service
It is assumed that the call arrivals can be modeled by a Poisson process and that call holding times are described by a negative exponential distribution.
# Engset formula
The Engset formula, named after T. O. Engset, is related but deals with a finite population of S sources rather than the infinite population of sources that Erlang assumes:
{\left( \begin{array}{c} S \\ N \end{array} \right)}}
{\sum_{i=0}^NA^i
{\left( \begin{array}{c} S \\ i \end{array} \right)}} </math>
This may be expressed recursively as follows, in a form that is used to calculate tables of the Engset formula:
where:
- E is the probability of blocking
- A is the traffic in erlangs generated by each source when idle
- S is the number of sources
- N is the number of servers
Again, it is assumed that the call arrivals can be modeled by a Poisson process and that call holding times are described by a negative exponential distribution. However, because there are a finite number of sources, the arrival rate of new calls decreases as more sources (such as telephone subscribers) become busy and hence cannot originate new calls. When N = S, the formula reduces to a binomial distribution. | https://www.wikidoc.org/index.php/Erlang_unit | |
002951957f2522d21879bc2169dbc9294f96d374 | wikidoc | Erysipeloid | Erysipeloid
Synonyms and Keywords: Erysipelotrichosis, Rose fish-handlers disease, Rosenbach's disease, Rosenbach's Erysipeloid or Erysipeloid of Rosenbach
# Overview
Erysipeloid is an occupational infection resulting from introduction of Erysipelothrix rhusiopathiae (formerly E. insidiosa) into a traumatized patch of skin. Clinically, the disease is observed as erythematous edema, with well-defined and raised borders. Lesions are mostly localized to the back of the hand. Vesicular, bullous, and erosive lesions may also be present. The lesions are usually asymptomatic and occasionally associated with pain, fever, and mild pruritus. In addition to cutaneous infection, E. rhusiopathiae may be complicated by acute or subacute endocarditis. Endocarditis is rare and has a male predilection. It usually occurs in previously damaged valves, predominantly the aortic valve. Endocarditis does not occur in patients with valvular prostheses and is not associated with intravenous drug misuse. Eysipeloid is a clinical diagnosis. Affected patients usually present with a history of occupational exposure to unprocessed fish or meat with characteristic cutaneous lesions. It typically gains entry through abrasions in the hand. Bacteremia and endocarditis are uncommon but serious complications. Erysipeloid is frequently misidentified due to the rarity of reported cases.
# Historical Perspective
- In 1884, Friedrich Julius Rosenbach (also called Anton Julius Friedrich Rosenbach), a German physician and microbiologist, was the first to accurately describe the association between Erysipelothrix rhusiopathiae and the development of erysipeloid.
- Erysipelothrix rhusiopathiae was first isolated from mice in 1880 by Robert Koch.
# Classification
Erysipeloid may be classified into the following categories according to the severity of the condition:
## Localized cutaneous erysipeloid
- Usually a mild, localized infection
- Patients present with localized swelling and redness of the skin
- Commonly referred to as "erysipeloid of Rosenbach"
## Diffuse cutaneous erysipeloid
- Patients may present with fever
## Generalized or systemic erysipeloid
- Manifests as bacteremia with associated complications (e.g., endocarditis, arthritis)
# Pathophysiology
## Pathogenesis
Erysipeloid results from an infection with Erysipelothrix rhusiopathiae after an area of skin containing an abrasion comes into contact with contaminated fish, poultry, or raw meat.
The organism is known for its high environmental resistance. Various virulence factors have been implicated in the pathogenicity of erysipeloid. Following infection in the skin, the organism produces certain enzymes that help it dissect its way through the tissues. Significant among them are hyaluronidase and neuraminidase. Neuraminidase has been shown to play vital role in the attachment of Erysipelothrix rhusiopathiae. This subsequently aids in the invasion of host cells. The role of hyaluronidase in the disease process is not well understood. The presence of a heat labile capsule has been reported as being important in virulence.. At the same time, the patient's immune response is activated to fight against the organism. Failure of the immune surveillance leads to systemic dissemination of the bacteria to the heart, brain, kidney, vascular system, joints, central nervous system, and lungs. The heart is the most commonly affected systemic organ.
## Associated conditions
The following conditions are associated with erysipeloid:
- Endocarditis
- Hodgkins lymphoma
- Use of gemcitabine
- Sweet's syndrome
- Renal failure
- Septic arthritis
- Polyarthralgia
# Causes
Erysipeloid is caused by an infection with Erysipelothrix rhusiopathiae, a Gram-positive rod bacteria. Infection with Erysipelothrix rhusiopathiae commonly results from contact between skin containing abrasions or lesions and contaminated fish, poultry, or raw meat.
# Differentiating Erysipeloid from Other Diseases
Erysipeloid must be differentiated from the following conditions:
- Abscess
- Cellulitis
- Contact dermatitis
- Erysipelas
- Furuncle
- Insect or animal bites
- Ulcer
# Epidemiology and Demographics
Infection with E. rhusiopathiae occurs worldwide in a variety of animals, including sheep, rabbits, turkeys, birds, cattle, rats, and fish.
## Race
No racial predilection is recognized for erysipeloid.
## Sex
Males are more commonly affected with erysipeloid than females because of the relative frequency of occupational exposure.
## Age
Erysipeloid can affect any age group.
# Risk Factors
Erysipeloid is most common among individuals who have direct contact with infected animals.
People in the following occupations are at the highest risk for contracting the condition:
- Fishermen
- Farmers
- Slaughterhouse workers
- Butchers
- Meat handlers
- Agricultural workers
Erysipeloid is observed most frequently during the summer and early fall.
# Screening
There is no established screening modality for erysipeloid.
# Natural History, Complications, and Prognosis
Cutaneous forms of the disease usually resolve spontaneously. The prognosis is excellent with appropriate antibiotics. Inadequate treatment can lead to complications such as endocarditis or arthritis.
Antibiotic-resistant strains will complicate therapy. Repeated infection may result in the development of allergies. Reduced immunity may complicate the infection. Individuals with the severe, systemic form of erysipeloid may suffer irreversible neurological damage. Endocarditis may result in long-term valvular heart disease. Septic arthritis may result in long-term joint disease.
# Diagnosis
## History and Symptoms
Patients with erysipeloid usually present with a history of occupational exposure to unprocessed fish or meat.
Symptoms may include:
- skin irritation
- localized burning sensation
- itching
- pain
Patients with systemic infections may present with:
- fever
- chills
- fatigue
- malaise
## Physical Examination
Physical examination of patients with erysipeloid is usually remarkable for lesions with the following features:
- purplish-red rash with associated burning and itching
- crusted formation
- erythematous edema or infiltrative plaque with raised borders
- localized tenderness
- joint lesions may manifest as tenosynovitis
- individuals with endocarditis may have a heart murmur noted on examination
## Laboratory Findings
Laboratory investigations are usually not needed to diagnose erysipeloid since the diagnosis is mostly clinical.
## Imaging Findings
CT scans may be helpful in the diagnosis of erysipeloid endocarditis. A CT scan may show vegetations, paravalvular abscesses, and/or pseudoaneurysms.
# Treatment
## Medical Therapy
The treatment of choice is intramuscular benzathine benzylpenicillin, oral penicillin, or intramuscular procaine benzylpenicillin.
Patients who are allergic to penicillin may be treated with erythromycin or doxycycline.
## Antimicrobial Regimen
- Preferred regimen (1): Penicillin 500 mg qid for 7–10 days
- Preferred regimen (2): Amoxicillin 500 mg tid for 7–10 days
- Erysipelothrix rhusiopathiae
- 1. Erysipeloid of Rosenbach (localized cutaneous infection)
- Preferred regimen (1): Penicillin G benzathine 1.2 MU IV single dose
- Preferred regimen (2): Penicillin VK 250 mg PO qid for 5-7 days
- Preferred regimen (3): Procaine penicillin 0.6-1.2 MU IM qd for 5-7 days
- Alternative regimen (1): Erythromycin 250 mg PO qid for 5-7 days
- Alternative regimen (2): Doxycycline 100 mg PO bid for 5-7 days
- 2. Diffuse cutaneous infection
- Preferred regimen: See localized infection
- 3. Bacteremia or endocarditis
- Preferred regimen: Penicillin G benzathine 2-4 MU IV q4h for 4-6 weeks
- Alternative regimen (1): Ceftriaxone 2 g IV q24h for 4-6 weeks
- Alternative regimen (2): Imipenem 500 mg IV q6h for 4-6 weeks
- Alternative regimen (3): Ciprofloxacin 400 mg IV q12h for 4-6 weeks
- Alternative regimen (4): Daptomycin 6 mg/kg IV q24h for 4-6 weeks
- Note: Recommended duration of therapy for endocarditis is 4 to 6 weeks, although shorter courses consisting of 2 weeks of intravenous therapy followed by 2 to 4 weeks of oral therapy have been successful.
## Surgery
Surgery is usually not necessary for the management of erysipeloid. However, in rare cases with massive valvular destruction complicating endocarditis, surgical valvular replacement may be needed.
# Prevention
## Primary prevention
Effective measures for the primary prevention of erysipeloid include:
- Individuals whose work involves handling raw meat, fishing, and/or agricultural jobs should wear protective gloves when possible to avoid infection with contaminated food.
- Restriction of food-handling in people diagnosed with erysipeloid.
## Secondary Prevention
There are no established methods of secondary prevention for erysipeloid. | Erysipeloid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2], Faizan Sheraz, M.D. [3]
Synonyms and Keywords: Erysipelotrichosis, Rose fish-handlers disease, Rosenbach's disease, Rosenbach's Erysipeloid or Erysipeloid of Rosenbach
# Overview
Erysipeloid is an occupational infection resulting from introduction of Erysipelothrix rhusiopathiae (formerly E. insidiosa) into a traumatized patch of skin. Clinically, the disease is observed as erythematous edema, with well-defined and raised borders. Lesions are mostly localized to the back of the hand. Vesicular, bullous, and erosive lesions may also be present. The lesions are usually asymptomatic and occasionally associated with pain, fever, and mild pruritus. In addition to cutaneous infection, E. rhusiopathiae may be complicated by acute or subacute endocarditis. Endocarditis is rare and has a male predilection. It usually occurs in previously damaged valves, predominantly the aortic valve. Endocarditis does not occur in patients with valvular prostheses and is not associated with intravenous drug misuse. Eysipeloid is a clinical diagnosis. Affected patients usually present with a history of occupational exposure to unprocessed fish[1] or meat with characteristic cutaneous lesions.[2][3] It typically gains entry through abrasions in the hand. Bacteremia and endocarditis are uncommon but serious complications.[4][5] Erysipeloid is frequently misidentified due to the rarity of reported cases.[2]
# Historical Perspective
- In 1884, Friedrich Julius Rosenbach (also called Anton Julius Friedrich Rosenbach), a German physician and microbiologist, was the first to accurately describe the association between Erysipelothrix rhusiopathiae and the development of erysipeloid.
- Erysipelothrix rhusiopathiae was first isolated from mice in 1880 by Robert Koch. [6][7]
# Classification
Erysipeloid may be classified into the following categories according to the severity of the condition:[7]
## Localized cutaneous erysipeloid
- Usually a mild, localized infection
- Patients present with localized swelling and redness of the skin
- Commonly referred to as "erysipeloid of Rosenbach"
## Diffuse cutaneous erysipeloid
- Patients may present with fever
## Generalized or systemic erysipeloid
- Manifests as bacteremia with associated complications (e.g., endocarditis, arthritis)
# Pathophysiology
## Pathogenesis
Erysipeloid results from an infection with Erysipelothrix rhusiopathiae after an area of skin containing an abrasion comes into contact with contaminated fish, poultry, or raw meat.[8]
The organism is known for its high environmental resistance.[7] Various virulence factors have been implicated in the pathogenicity of erysipeloid. Following infection in the skin, the organism produces certain enzymes that help it dissect its way through the tissues. Significant among them are hyaluronidase and neuraminidase.[8] Neuraminidase has been shown to play vital role in the attachment of Erysipelothrix rhusiopathiae. This subsequently aids in the invasion of host cells. The role of hyaluronidase in the disease process is not well understood. The presence of a heat labile capsule has been reported as being important in virulence.[8]. At the same time, the patient's immune response is activated to fight against the organism. Failure of the immune surveillance leads to systemic dissemination of the bacteria to the heart, brain, kidney, vascular system, joints, central nervous system, and lungs. The heart is the most commonly affected systemic organ.
## Associated conditions
The following conditions are associated with erysipeloid:[8][9][10][11][12][13]
- Endocarditis
- Hodgkins lymphoma
- Use of gemcitabine
- Sweet's syndrome
- Renal failure
- Septic arthritis
- Polyarthralgia
# Causes
Erysipeloid is caused by an infection with Erysipelothrix rhusiopathiae, a Gram-positive rod bacteria. Infection with Erysipelothrix rhusiopathiae commonly results from contact between skin containing abrasions or lesions and contaminated fish, poultry, or raw meat. [7][8][10][11]
# Differentiating Erysipeloid from Other Diseases
Erysipeloid must be differentiated from the following conditions:
- Abscess
- Cellulitis
- Contact dermatitis
- Erysipelas
- Furuncle
- Insect or animal bites
- Ulcer
# Epidemiology and Demographics
Infection with E. rhusiopathiae occurs worldwide in a variety of animals, including sheep, rabbits, turkeys, birds, cattle, rats, and fish.[6]
## Race
No racial predilection is recognized for erysipeloid.
## Sex
Males are more commonly affected with erysipeloid than females because of the relative frequency of occupational exposure.
## Age
Erysipeloid can affect any age group.
# Risk Factors
Erysipeloid is most common among individuals who have direct contact with infected animals.
People in the following occupations are at the highest risk for contracting the condition:[6]
- Fishermen
- Farmers
- Slaughterhouse workers
- Butchers
- Meat handlers
- Agricultural workers
Erysipeloid is observed most frequently during the summer and early fall.[7]
# Screening
There is no established screening modality for erysipeloid.[6]
# Natural History, Complications, and Prognosis
Cutaneous forms of the disease usually resolve spontaneously.[11] The prognosis is excellent with appropriate antibiotics. Inadequate treatment can lead to complications such as endocarditis or arthritis.
Antibiotic-resistant strains will complicate therapy. Repeated infection may result in the development of allergies. Reduced immunity may complicate the infection. Individuals with the severe, systemic form of erysipeloid may suffer irreversible neurological damage. Endocarditis may result in long-term valvular heart disease. Septic arthritis may result in long-term joint disease.
# Diagnosis
## History and Symptoms
Patients with erysipeloid usually present with a history of occupational exposure to unprocessed fish or meat.
Symptoms may include:[14]
- skin irritation
- localized burning sensation
- itching
- pain
Patients with systemic infections may present with:[15]
- fever
- chills
- fatigue
- malaise
## Physical Examination
Physical examination of patients with erysipeloid is usually remarkable for lesions with the following features:[6][16][14][15][17]
- purplish-red rash with associated burning and itching
- crusted formation
- erythematous edema or infiltrative plaque with raised borders
- localized tenderness
- joint lesions may manifest as tenosynovitis
- individuals with endocarditis may have a heart murmur noted on examination
## Laboratory Findings
Laboratory investigations are usually not needed to diagnose erysipeloid since the diagnosis is mostly clinical.[14]
## Imaging Findings
CT scans may be helpful in the diagnosis of erysipeloid endocarditis. A CT scan may show vegetations, paravalvular abscesses, and/or pseudoaneurysms.
# Treatment
## Medical Therapy
The treatment of choice is intramuscular benzathine benzylpenicillin, oral penicillin, or intramuscular procaine benzylpenicillin.[11][7][18]
Patients who are allergic to penicillin may be treated with erythromycin or doxycycline.[18]
## Antimicrobial Regimen
- Preferred regimen (1): Penicillin 500 mg qid for 7–10 days
- Preferred regimen (2): Amoxicillin 500 mg tid for 7–10 days
- Erysipelothrix rhusiopathiae [19]
- 1. Erysipeloid of Rosenbach (localized cutaneous infection)
- Preferred regimen (1): Penicillin G benzathine 1.2 MU IV single dose
- Preferred regimen (2): Penicillin VK 250 mg PO qid for 5-7 days
- Preferred regimen (3): Procaine penicillin 0.6-1.2 MU IM qd for 5-7 days
- Alternative regimen (1): Erythromycin 250 mg PO qid for 5-7 days
- Alternative regimen (2): Doxycycline 100 mg PO bid for 5-7 days
- 2. Diffuse cutaneous infection
- Preferred regimen: See localized infection
- 3. Bacteremia or endocarditis
- Preferred regimen: Penicillin G benzathine 2-4 MU IV q4h for 4-6 weeks
- Alternative regimen (1): Ceftriaxone 2 g IV q24h for 4-6 weeks
- Alternative regimen (2): Imipenem 500 mg IV q6h for 4-6 weeks
- Alternative regimen (3): Ciprofloxacin 400 mg IV q12h for 4-6 weeks
- Alternative regimen (4): Daptomycin 6 mg/kg IV q24h for 4-6 weeks
- Note: Recommended duration of therapy for endocarditis is 4 to 6 weeks, although shorter courses consisting of 2 weeks of intravenous therapy followed by 2 to 4 weeks of oral therapy have been successful.
## Surgery
Surgery is usually not necessary for the management of erysipeloid. However, in rare cases with massive valvular destruction complicating endocarditis, surgical valvular replacement may be needed.[20]
# Prevention
## Primary prevention
Effective measures for the primary prevention of erysipeloid include:[6]
- Individuals whose work involves handling raw meat, fishing, and/or agricultural jobs should wear protective gloves when possible to avoid infection with contaminated food.
- Restriction of food-handling in people diagnosed with erysipeloid.
## Secondary Prevention
There are no established methods of secondary prevention for erysipeloid. | https://www.wikidoc.org/index.php/Erysipeloid | |
58e86c3bde70fdc3b4e77715f36fb44966bf6298 | wikidoc | Erythrulose | Erythrulose
D-Erythrulose (also known as erythrulose) is a tetrose carbohydrate with the chemical formula C4H8O4. It has one ketone group and so is part of the ketose family. It is used in some self-tanning cosmetics, generally combined with dihydroxyacetone (DHA).
Erythrulose is a natural based keto-sugar which reacts with the amino acids in the keratin protein on the outer or dead surface layer of the skin. (the stratum corneum layer of the epidermis) This non-toxic reaction produces a temporary browning effect similar to the Maillard reaction. This is not a stain or dye, but rather a chemical reaction that produces a color change on all treated skin. The reaction is similar to the browning effect seen when a cut apple slice is exposed to oxygen.
The brown color is comparable to the appearance of a UV based suntan. Because the skin continually exfoliates itself, losing thousands of dead surface skin cells each day, the tan hue is temporary. The tan appearance typically lasts from 2 to 10 days depending on application type, and skin condition.
Erythrulose is a clear to pale yellowish liquid, which naturally occurs in red raspberries. According to the manufacturing company Centerchem, inc. Erythrulose is manufactured from the aerobic fermentation of the bacterium Gluconobacter followed by extensive multi-step purification.
Erythrulose and dihydroxyacetone (DHA) are very similar in composition, and both react much the same way on the skin surface. Erythrulose produces a lighter and slower developing tan, taking 24 to 48 hours to complete development. When used alone, it fades faster than a DHA based sunless tan. Some people feel the final tone of erythrulose is slightly redder, and less bronze, than the DHA based tan. It may be less drying to the skin surface, helping provide a smoother fading tint. When combined with DHA, the resulting sunless tan is said to last longer, fade better, and provide a more cosmetically pleasing color tone. In sunless tanning products, it is incorporated at 1% to 3% levels.
Not all users develop a tan coloration from erythrulose, some may find that their fading is more uneven and blotchy, when this ingredient is used. Because of the added cost associated with this ingredient, some manufacturers feel it is an inefficient additive to the sunless tanning product line.
Individuals, who are sensitive to DHA, may be able to use erythrulose as a skin safe self-tanning replacement. Erythrulose is more expensive, and difficult to obtain. Because DHA and erythrulose are very similar in composition, it is not unusual for someone to be reactive to both DHA and erythrulose.
Erythrulose reacts on the skin's surface and does not seem to penetrate beyond the dead surface skin layers. Side effects are limited to occasional contact dermatitis in sensitive individuals. In many suspected cases of sensitivity, the reaction is related to other ingredients in the self-tanning product such as preservatives, dyes, fragrances or plant based additives and extracts.
Though erythrulose appears safe for use by all indications, it is not currently approved by the Food and Drug Administration (FDA) as a self tanning agent. | Erythrulose
Template:Chembox new
D-Erythrulose (also known as erythrulose) is a tetrose carbohydrate with the chemical formula C4H8O4. It has one ketone group and so is part of the ketose family. It is used in some self-tanning cosmetics, generally combined with dihydroxyacetone (DHA).
Erythrulose is a natural based keto-sugar which reacts with the amino acids in the keratin protein on the outer or dead surface layer of the skin. (the stratum corneum layer of the epidermis) This non-toxic reaction produces a temporary browning effect similar to the Maillard reaction. This is not a stain or dye, but rather a chemical reaction that produces a color change on all treated skin. The reaction is similar to the browning effect seen when a cut apple slice is exposed to oxygen.
The brown color is comparable to the appearance of a UV based suntan. Because the skin continually exfoliates itself, losing thousands of dead surface skin cells each day, the tan hue is temporary. The tan appearance typically lasts from 2 to 10 days depending on application type, and skin condition.
Erythrulose is a clear to pale yellowish liquid, which naturally occurs in red raspberries. According to the manufacturing company Centerchem, inc. [1] Erythrulose is manufactured from the aerobic fermentation of the bacterium Gluconobacter followed by extensive multi-step purification.
Erythrulose and dihydroxyacetone (DHA) are very similar in composition, and both react much the same way on the skin surface. Erythrulose produces a lighter and slower developing tan, taking 24 to 48 hours to complete development. When used alone, it fades faster than a DHA based sunless tan. Some people feel the final tone of erythrulose is slightly redder, and less bronze, than the DHA based tan. It may be less drying to the skin surface, helping provide a smoother fading tint. When combined with DHA, the resulting sunless tan is said to last longer, fade better, and provide a more cosmetically pleasing color tone. In sunless tanning products, it is incorporated at 1% to 3% levels.
Not all users develop a tan coloration from erythrulose, some may find that their fading is more uneven and blotchy, when this ingredient is used. Because of the added cost associated with this ingredient, some manufacturers feel it is an inefficient additive to the sunless tanning product line.
Individuals, who are sensitive to DHA, may be able to use erythrulose as a skin safe self-tanning replacement. Erythrulose is more expensive, and difficult to obtain. Because DHA and erythrulose are very similar in composition, it is not unusual for someone to be reactive to both DHA and erythrulose.
Erythrulose reacts on the skin's surface and does not seem to penetrate beyond the dead surface skin layers. Side effects are limited to occasional contact dermatitis in sensitive individuals. In many suspected cases of sensitivity, the reaction is related to other ingredients in the self-tanning product such as preservatives, dyes, fragrances or plant based additives and extracts.
Though erythrulose appears safe for use by all indications, it is not currently approved by the Food and Drug Administration (FDA) as a self tanning agent. | https://www.wikidoc.org/index.php/Erythrulose | |
67f842750083b1a355bc7153351e5f0a1652e317 | wikidoc | Pirfenidone | Pirfenidone
# Disclaimer
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# Overview
Pirfenidone is a respiratory agent that is FDA approved for the treatment of idiopathic pulmonary fibrosis (IPF). Common adverse reactions include nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, gastroesophageal reflux disease, sinusitis, insomnia, weight decreased, and arthralgia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Pirfenidone is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
- Dosage:
- 267 mg (1 capsule) ORALLY 3 times daily for 7 days
- Then 534 mg (2 capsules) ORALLY 3 times daily on days 8 through 14
- Then 801 mg (3 capsules) ORALLY 3 times daily thereafter
- All doses should be taken with food
- Doses greater than 2403 mg/day not recommended
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pirfenidone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pirfenidone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pirfenidone FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pirfenidone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pirfenidone in pediatric patients.
# Contraindications
None
# Warnings
### Elevated Liver Enzymes
Increases in ALT and AST >3 × ULN have been reported in patients treated with pirfenidone. Rarely these have been associated with concomitant elevations in bilirubin. Patients treated with pirfenidone 2403 mg/day in the three Phase 3 trials had a higher incidence of elevations in ALT or AST ≥3 × ULN than placebo patients (3.7% vs. 0.8%, respectively). Elevations ≥10 × ULN in ALT or AST occurred in 0.3% of patients in the pirfenidone 2403 mg/day group and in 0.2% of patients in the placebo group. Increases in ALT and AST ≥3 × ULN were reversible with dose modification or treatment discontinuation. No cases of liver transplant or death due to liver failure that were related to pirfenidone have been reported. However, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury, that could lead to death or the need for liver transplants in some patients. Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with pirfenidone in all patients, then monthly for the first 6 months and every 3 months thereafter. Dosage modifications or interruption may be necessary for liver enzyme elevations.
### Photosensitivity Reaction or Rash
Patients treated with pirfenidone 2403 mg/day in the three Phase 3 studies had a higher incidence of photosensitivity reactions (9%) compared with patients treated with placebo (1%). The majority of the photosensitivity reactions occurred during the initial 6 months. Instruct patients to avoid or minimize exposure to sunlight (including sunlamps), to use a sunblock (SPF 50 or higher), and to wear clothing that protects against sun exposure. Additionally, instruct patients to avoid concomitant medications known to cause photosensitivity. Dosage reduction or discontinuation may be necessary in some cases of photosensitivity reaction or rash.
### Gastrointestinal Disorders
In the clinical studies, gastrointestinal events of nausea, diarrhea, dyspepsia, vomiting, gastroesophageal reflux disease, and abdominal pain were more frequently reported by patients in the pirfenidone treatment groups than in those taking placebo. Dosage reduction or interruption for gastrointestinal events was required in 18.5% of patients in the 2403 mg/day group, as compared to 5.8% of patients in the placebo group; 2.2% of patients in the pirfenidone 2403 mg/day group discontinued treatment due to a gastrointestinal event, as compared to 1.0% in the placebo group. The most common (>2%) gastrointestinal events that led to dosage reduction or interruption were nausea, diarrhea, vomiting, and dyspepsia. The incidence of gastrointestinal events was highest early in the course of treatment (with highest incidence occurring during the initial 3 months) and decreased over time. Dosage modifications may be necessary in some cases of gastrointestinal adverse reactions.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of pirfenidone has been evaluated in more than 1400 subjects with over 170 subjects exposed to pirfenidone for more than 5 years in clinical trials.
pirfenidone was studied in 3 randomized, double-blind, placebo-controlled trials (Studies 1, 2, and 3) in which a total of 623 patients received 2403 mg/day of pirfenidone and 624 patients received placebo. Subjects ages ranged from 40 to 80 years (mean age of 67 years). Most patients were male (74%) and Caucasian (95%). The mean duration of exposure to pirfenidone was 62 weeks (range: 2 to 118 weeks) in these 3 trials.
At the recommended dosage of 2403 mg/day, 14.6% of patients on pirfenidone compared to 9.6% on placebo permanently discontinued treatment because of an adverse event. The most common (>1%) adverse reactions leading to discontinuation were rash and nausea. The most common (>3%) adverse reactions leading to dosage reduction or interruption were rash, nausea, diarrhea, and photosensitivity reaction.
The most common adverse reactions with an incidence of ≥10% and more frequent in the pirfenidone than placebo treatment group are listed in TABLE 2.
Adverse reactions occurring in ≥5 to <10% of pirfenidone-treated patients and more commonly than placebo are photosensitivity reaction (9% vs. 1%), decreased appetite (8% vs. 3%), pruritus (8% vs. 5%), asthenia (6% vs. 4%), dysgeusia (6% vs. 2%), and non-cardiac chest pain (5% vs. 4%).
## Postmarketing Experience
In addition to adverse reactions identified from clinical trials the following adverse reactions have been identified during postapproval use of pirfenidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
- Blood and Lymphatic System Disorders
- Agranulocytosis
- Immune System Disorders
- Angioedema
- Hepatobiliary Disorders
- Bilirubin increased in combination with increases of ALT and AST
# Drug Interactions
### CYP1A2 Inhibitors
Pirfenidone is metabolized primarily (70 to 80%) via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1.
The concomitant administration of pirfenidone and fluvoxamine or other strong CYP1A2 inhibitors (e.g., enoxacin) is not recommended because it significantly increases exposure to pirfenidone. Use of fluvoxamine or other strong CYP1A2 inhibitors should be discontinued prior to administration of pirfenidone and avoided during pirfenidone treatment. In the event that fluvoxamine or other strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended. Monitor for adverse reactions and consider discontinuation of pirfenidone as needed.
Concomitant administration of pirfenidone and ciprofloxacin (a moderate inhibitor of CYP1A2) moderately increases exposure to pirfenidone. If ciprofloxacin at the dosage of 750 mg twice daily cannot be avoided, dosage reductions are recommended. Monitor patients closely when ciprofloxacin is used at a dosage of 250 mg or 500 mg once daily.
Agents or combinations of agents that are moderate or strong inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (i.e., CYP2C9, 2C19, 2D6, and 2E1) should be discontinued prior to and avoided during pirfenidone treatment.
### CYP1A2 Inducers
The concomitant use of pirfenidone and a CYP1A2 inducer may decrease the exposure of pirfenidone and this may lead to loss of efficacy. Therefore, discontinue use of strong CYP1A2 inducers prior to pirfenidone treatment and avoid the concomitant use of pirfenidone and a strong CYP1A2 inducer.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies of pirfenidone in pregnant women. Pirfenidone was not teratogenic in rats and rabbits. Because animal reproduction studies are not always predictive of human response, pirfenidone should be used during pregnancy only if the benefit outweighs the risk to the patient.
A fertility and embryo-fetal development study with rats and an embryo-fetal development study with rabbits that received oral doses up to 3 and 2 times, respectively, the maximum recommended daily dose (MRDD) in adults (on mg/m2 basis at maternal doses up to 1000 and 300 mg/kg/day, respectively) revealed no evidence of impaired fertility or harm to the fetus due to pirfenidone. In the presence of maternal toxicity, acyclic/irregular cycles (e.g., prolonged estrous cycle) were seen in rats at doses approximately equal to and higher than the MRDD in adults (on a mg/m2 basis at maternal doses of 450 mg/kg/day and higher). In a pre- and post-natal development study, prolongation of the gestation period, decreased numbers of live newborn, and reduced pup viability and body weights were seen in rats at an oral dosage approximately 3 times the MRDD in adults (on a mg/m2 basis at a maternal dose of 1000 mg/kg/day).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pirfenidone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pirfenidone during labor and delivery.
### Nursing Mothers
A study with radio-labeled pirfenidone in rats has shown that pirfenidone or its metabolites are excreted in milk. It is not known whether pirfenidone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue pirfenidone, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness of pirfenidone in pediatric patients have not been established.
### Geriatic Use
Of the total number of subjects in the clinical studies receiving pirfenidone, 714 (67%) were 65 years old and over, while 231 (22%) were 75 years old and over. No overall differences in safety or effectiveness were observed between older and younger patients. No dosage adjustment is required based upon age.
### Gender
Results of population pharmacokinetic analysis of pirfenidone showed no significant differences in pharmacokinetics between males and females.
### Race
Population pharmacokinetic analysis showed that race has no significant effect on the pharmacokinetics of pirfenidone.
### Renal Impairment
Pirfenidone should be used with caution in patients with mild (CLcr 50–80 mL/min), moderate (CLcr 30–50 mL/min), or severe (CLcr less than 30 mL/min) renal impairment. Monitor for adverse reactions and consider dosage modification or discontinuation of pirfenidone as needed. The safety, efficacy, and pharmacokinetics of pirfenidone have not been studied in patients with end-stage renal disease requiring dialysis. Use of pirfenidone in patients with end-stage renal diseases requiring dialysis is not recommended.
### Hepatic Impairment
Pirfenidone should be used with caution in patients with mild (Child Pugh Class A) to moderate (Child Pugh Class B) hepatic impairment. Monitor for adverse reactions and consider dosage modification or discontinuation of pirfenidone as needed.
The safety, efficacy, and pharmacokinetics of pirfenidone have not been studied in patients with severe hepatic impairment. Pirfenidone is not recommended for use in patients with severe (Child Pugh Class C) hepatic impairment.
### Females of Reproductive Potential and Males
Pirfenidone had no effects on fertility and reproductive performance in rats at dosages up to 1000 mg/kg/day (approximately 3 times the MRDD in adults on a mg/m2 basis).
### Immunocompromised Patients
There is no FDA guidance one the use of Pirfenidone in patients who are immunocompromised.
### Smokers
Smoking causes decreased exposure to pirfenidone, which may alter the efficacy profile of pirfenidone. Instruct patients to stop smoking prior to treatment with pirfenidone and to avoid smoking when using pirfenidone.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Pirfenidone Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Pirfenidone and IV administrations.
# Overdosage
There is limited clinical experience with overdosage. Multiple dosages of pirfenidone up to a maximum tolerated dose of 4005 mg per day were administered as five 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation.
In the event of a suspected overdosage, appropriate supportive medical care should be provided, including monitoring of vital signs and observation of the clinical status of the patient.
# Pharmacology
## Mechanism of Action
The mechanism of action of pirfenidone in the treatment of IPF has not been established.
## Structure
The chemical name of pirfenidone is 5-methyl-1-phenyl-2-1(H)-pyridone. It has a molecular formula of C12H11NO and a molecular weight of 185.23. The structural formula of pirfenidone is:
## Pharmacodynamics
### Cardiac Electrophysiology
The effect of pirfenidone on QT interval was evaluated in a randomized, placebo, and positive controlled parallel study in 160 healthy adult volunteers. Volunteers received pirfenidone 2403 mg/day (recommended dose) and 4005 mg/day (1.6 times recommended dose) or placebo for 10 days or a single dose of 400 mg moxifloxacin (active control).
Relative to placebo, the maximum mean change from baseline in study-specific QT interval was 3.2 milliseconds (ms) and 2.2 ms for pirfenidone 2403 mg/day and 4005 mg/day, respectively. No volunteer had a QTc interval greater than 480 ms or change from baseline greater than 60 ms. Although there was no evidence that pirfenidone prolonged the QTc interval in this study, a definitive conclusion may not be drawn as the positive control (moxifloxacin) did not perform as expected in this study, and pirfenidone at 4005 mg/day (1.7 times the maximum recommended dose) did not cover the maximum pirfenidone exposure increase with co-administration of fluvoxamine, a strong CYP1A2 inhibitor.
## Pharmacokinetics
### Absorption
After single oral-dose administration of 801 mg pirfenidone, the maximum observed plasma concentration (Cmax) was achieved between 30 minutes and 4 hours (median time of 0.5 hours). Food decreased the rate and extent of absorption. Median Tmax increased from 0.5 hours to 3 hours with food. Maximum plasma concentrations and AUC0-inf decreased by approximately 49% and 16% with food, respectively. A reduced incidence of adverse reactions was observed in the fed group when compared to the fasted group. In controlled studies with IPF patients, pirfenidone was taken with food.
The absolute bioavailability of pirfenidone has not been determined in humans.
### Distribution
pirfenidone binds to human plasma proteins, primarily to serum albumin, in a concentration-independent manner over the range of concentrations observed in clinical trials. The overall mean binding was 58% at concentrations observed in clinical studies (1 to 10 µg/mL). Mean apparent oral volume of distribution is approximately 59 to 71 liters.
### Metabolism
In vitro profiling studies in hepatocytes and liver microsomes have shown that pirfenidone is primarily metabolized in the liver by CYP1A2 and multiple other CYPs (CYP2C9, 2C19, 2D6, and 2E1). Oral administration of pirfenidone results in the formation of four metabolites. In humans, only pirfenidone and 5-carboxy-pirfenidone are present in plasma in significant quantities. The mean metabolite-to-parent ratio ranged from approximately 0.6 to 0.7.
No formal radiolabeled studies have assessed the metabolism of pirfenidone in humans. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
### Elimination
The mean terminal half-life is approximately 3 hours in healthy subjects. Pirfenidone is excreted predominantly as metabolite 5-carboxy-pirfenidone, mainly in the urine (approximately 80% of the dose). The majority of pirfenidone was excreted as the 5-carboxy metabolite (approximately 99.6% of that recovered).
## Nonclinical Toxicology
### Carcinogenesis
Long-term studies were conducted in mice and rats with admixture of pirfenidone to the diet to evaluate its carcinogenic potential.
In a 24-month carcinogenicity study in B6C3F1 mice, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma and hepatoblastoma in male mice at doses of 800 mg/kg and above (AUC exposure approximately 0.4 times adult exposure at the MRDD). There were statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in female mice at doses of 2000 mg/kg and above (AUC exposure approximately 0.7 times adult exposure at the MRDD).
In a 24-month carcinogenicity study in Fischer rats, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in male rats at doses of 750 mg/kg and above (AUC exposure approximately 1.9 times adult exposure at the MRDD). There were statistically significant increases of the combination of hepatocellular adenoma and carcinoma and the combination of uterine adenocarcinoma and adenoma at a dose of 1500 mg/kg/day (AUC exposure approximately 3.0 times adult exposure at the MRDD).
The relevance of these tumor findings in rodents to humans is unknown.
### Mutagenesis
Pirfenidone was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, a chromosomal aberration test in Chinese hamster lung cells, and a micronucleus test in mice.
# Clinical Studies
The efficacy of pirfenidone was evaluated in patients with IPF in three phase 3, randomized, double-blind, placebo-controlled, multicenter trials (Studies 1, 2, and 3).
Study 1 was a 52-week trial comparing pirfenidone 2403 mg/day (n=278) versus placebo (n=277) in patients with IPF. Study 2 and Study 3 were nearly identical to each other in design, with few exceptions, including an intermediate dose treatment arm in Study 2. Study 2 compared treatment with either pirfenidone 2403 mg/day (n=174) or pirfenidone 1197 mg/day (n=87) to placebo (n=174), while Study 3 compared pirfenidone 2403 mg/day (n=171) to placebo (n=173). Study drug was administered three times daily with food for a minimum of 72 weeks. Patients continued on treatment until the last patient completed 72 weeks of treatment, which included observations to approximately 120 weeks of study treatment. The primary endpoint was the change in percent predicted forced vital capacity (%FVC) from baseline to study end, measured at 52 weeks in Study 1, and at 72 weeks in Studies 2 and 3.
Studies 1, 2 and 3 enrolled adult patients who had a clinical and radiographic diagnosis of IPF (with or without accompanying surgical lung biopsy), without evidence or suspicion of an alternative diagnosis for interstitial lung disease. Eligible patients were to have %FVC greater than or equal to 50% at baseline and a percent predicted diffusing capacity of the lungs for carbon monoxide (%DLCO) greater than or equal to 30% (Study 1) or 35% (Studies 2 and 3) at baseline. In all three trials, over 80% of patients completed study treatment.
A total of 1247 patients with IPF were randomized to receive pirfenidone 2403 mg/day (n=623) or placebo (n=624) in these three trials. Baseline characteristics were generally balanced across treatment groups. The study population ranged from 40 to 80 years of age (mean age 67 years). Most patients were male (74%), white (95%), and current or former smokers (65%). Approximately 93% of patients met criteria for definite IPF on high resolution computed tomography (HRCT). Baseline mean %FVC and %DLCO were 72% and 46%, respectively. Approximately 15% subjects discontinued from each treatment group.
### Change from Baseline in Percent Predicted Forced Vital Capacity
In Study 1, the primary efficacy analysis for the change in %FVC from baseline to Week 52 demonstrated a statistically significant treatment effect of pirfenidone 2403 mg/day (n=278) compared with placebo (n=277) using a rank ANCOVA with the lowest rank imputation for missing data due to death. In Study 2, there was a statistically significant difference at Week 72 for the change in %FVC from baseline. In Study 3, there was no statistically significant difference at Week 72 for the change in %FVC from baseline.
FIGURE 1 presents the cumulative distribution for all cut-offs for the change from baseline in %FVC at Week 52 for Study 1. For all categorical declines in lung function, the proportion of patients declining was lower on pirfenidone than on placebo. Study 2 showed similar results.
### Mean Change from Baseline in FVC (mL)
In Study 1, a reduction in the mean decline in FVC (in mL) was observed in patients receiving pirfenidone 2403 mg/day (-235 mL) compared to placebo (-428 mL) (mean treatment difference 193 mL) at Week 52 (see FIGURE 2). In Study 2, a reduction in the decline in FVC volume was also observed in patients receiving pirfenidone 2403 mg/day compared with placebo (mean treatment difference 157 mL) at Week 72. There was no statistically significant difference in decline in FVC volume seen in Study 3.
### Survival
Survival was evaluated for pirfenidone compared to placebo in Studies 1, 2, and 3 as an exploratory analysis to support the primary endpoint (FVC). All-cause mortality was assessed over the study duration and available follow-up period, irrespective of cause of death and whether patients continued treatment. All-cause mortality did not show a statistically significant difference (see FIGURE 3).
# How Supplied
Bottle for a 30-day supply
- Bottle containing 270 capsules and closed with a child-resistant closure
- NDC 64116-121-01
14-day Titration Blister Pack
- Carton containing a total of 63 capsules in two blister cards
- NDC 64116-121-02
4-Week Maintenance Blister Pack
- Carton containing a total of 252 capsules in four blister cards
- NDC 64116-121-03
## Storage
Store at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Liver Enzyme Elevations
Advise patients that they may be required to undergo liver function testing periodically. Instruct patients to immediately report any symptoms of a liver problem (e.g., skin or the white of eyes turn yellow, urine turns dark or brown , pain on the right side of stomach, bleed or bruise more easily than normal, lethargy).
### Photosensitivity Reaction or Rash
Advise patients to avoid or minimize exposure to sunlight (including sunlamps) during use of pirfenidone because of concern for photosensitivity reactions or rash. Instruct patients to use a sunblock and to wear clothing that protects against sun exposure. Instruct patients to report symptoms of photosensitivity reaction or rash to their physician. Temporary dosage reductions or discontinuations may be required.
### Gastrointestinal Events
Instruct patients to report symptoms of persistent gastrointestinal effects including nausea, diarrhea, dyspepsia, vomiting, gastroesophageal reflux disease, and abdominal pain. Temporary dosage reductions or discontinuations may be required.
### Smokers
Encourage patients to stop smoking prior to treatment with pirfenidone and to avoid smoking when using pirfenidone.
### Take with Food
Instruct patients to take pirfenidone with food to help decrease nausea and dizziness.
# Precautions with Alcohol
Alcohol-Pirfenidone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Esbriet
# Look-Alike Drug Names
There is limited information regarding Pirfenidone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Pirfenidone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
# Disclaimer
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# Overview
Pirfenidone is a respiratory agent that is FDA approved for the treatment of idiopathic pulmonary fibrosis (IPF). Common adverse reactions include nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, gastroesophageal reflux disease, sinusitis, insomnia, weight decreased, and arthralgia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Pirfenidone is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
- Dosage:
- 267 mg (1 capsule) ORALLY 3 times daily for 7 days
- Then 534 mg (2 capsules) ORALLY 3 times daily on days 8 through 14
- Then 801 mg (3 capsules) ORALLY 3 times daily thereafter
- All doses should be taken with food
- Doses greater than 2403 mg/day not recommended
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pirfenidone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pirfenidone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pirfenidone FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pirfenidone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pirfenidone in pediatric patients.
# Contraindications
None
# Warnings
### Elevated Liver Enzymes
Increases in ALT and AST >3 × ULN have been reported in patients treated with pirfenidone. Rarely these have been associated with concomitant elevations in bilirubin. Patients treated with pirfenidone 2403 mg/day in the three Phase 3 trials had a higher incidence of elevations in ALT or AST ≥3 × ULN than placebo patients (3.7% vs. 0.8%, respectively). Elevations ≥10 × ULN in ALT or AST occurred in 0.3% of patients in the pirfenidone 2403 mg/day group and in 0.2% of patients in the placebo group. Increases in ALT and AST ≥3 × ULN were reversible with dose modification or treatment discontinuation. No cases of liver transplant or death due to liver failure that were related to pirfenidone have been reported. However, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury, that could lead to death or the need for liver transplants in some patients. Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with pirfenidone in all patients, then monthly for the first 6 months and every 3 months thereafter. Dosage modifications or interruption may be necessary for liver enzyme elevations.
### Photosensitivity Reaction or Rash
Patients treated with pirfenidone 2403 mg/day in the three Phase 3 studies had a higher incidence of photosensitivity reactions (9%) compared with patients treated with placebo (1%). The majority of the photosensitivity reactions occurred during the initial 6 months. Instruct patients to avoid or minimize exposure to sunlight (including sunlamps), to use a sunblock (SPF 50 or higher), and to wear clothing that protects against sun exposure. Additionally, instruct patients to avoid concomitant medications known to cause photosensitivity. Dosage reduction or discontinuation may be necessary in some cases of photosensitivity reaction or rash.
### Gastrointestinal Disorders
In the clinical studies, gastrointestinal events of nausea, diarrhea, dyspepsia, vomiting, gastroesophageal reflux disease, and abdominal pain were more frequently reported by patients in the pirfenidone treatment groups than in those taking placebo. Dosage reduction or interruption for gastrointestinal events was required in 18.5% of patients in the 2403 mg/day group, as compared to 5.8% of patients in the placebo group; 2.2% of patients in the pirfenidone 2403 mg/day group discontinued treatment due to a gastrointestinal event, as compared to 1.0% in the placebo group. The most common (>2%) gastrointestinal events that led to dosage reduction or interruption were nausea, diarrhea, vomiting, and dyspepsia. The incidence of gastrointestinal events was highest early in the course of treatment (with highest incidence occurring during the initial 3 months) and decreased over time. Dosage modifications may be necessary in some cases of gastrointestinal adverse reactions.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of pirfenidone has been evaluated in more than 1400 subjects with over 170 subjects exposed to pirfenidone for more than 5 years in clinical trials.
pirfenidone was studied in 3 randomized, double-blind, placebo-controlled trials (Studies 1, 2, and 3) in which a total of 623 patients received 2403 mg/day of pirfenidone and 624 patients received placebo. Subjects ages ranged from 40 to 80 years (mean age of 67 years). Most patients were male (74%) and Caucasian (95%). The mean duration of exposure to pirfenidone was 62 weeks (range: 2 to 118 weeks) in these 3 trials.
At the recommended dosage of 2403 mg/day, 14.6% of patients on pirfenidone compared to 9.6% on placebo permanently discontinued treatment because of an adverse event. The most common (>1%) adverse reactions leading to discontinuation were rash and nausea. The most common (>3%) adverse reactions leading to dosage reduction or interruption were rash, nausea, diarrhea, and photosensitivity reaction.
The most common adverse reactions with an incidence of ≥10% and more frequent in the pirfenidone than placebo treatment group are listed in TABLE 2.
Adverse reactions occurring in ≥5 to <10% of pirfenidone-treated patients and more commonly than placebo are photosensitivity reaction (9% vs. 1%), decreased appetite (8% vs. 3%), pruritus (8% vs. 5%), asthenia (6% vs. 4%), dysgeusia (6% vs. 2%), and non-cardiac chest pain (5% vs. 4%).
## Postmarketing Experience
In addition to adverse reactions identified from clinical trials the following adverse reactions have been identified during postapproval use of pirfenidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
- Blood and Lymphatic System Disorders
- Agranulocytosis
- Immune System Disorders
- Angioedema
- Hepatobiliary Disorders
- Bilirubin increased in combination with increases of ALT and AST
# Drug Interactions
### CYP1A2 Inhibitors
Pirfenidone is metabolized primarily (70 to 80%) via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1.
The concomitant administration of pirfenidone and fluvoxamine or other strong CYP1A2 inhibitors (e.g., enoxacin) is not recommended because it significantly increases exposure to pirfenidone. Use of fluvoxamine or other strong CYP1A2 inhibitors should be discontinued prior to administration of pirfenidone and avoided during pirfenidone treatment. In the event that fluvoxamine or other strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended. Monitor for adverse reactions and consider discontinuation of pirfenidone as needed.
Concomitant administration of pirfenidone and ciprofloxacin (a moderate inhibitor of CYP1A2) moderately increases exposure to pirfenidone. If ciprofloxacin at the dosage of 750 mg twice daily cannot be avoided, dosage reductions are recommended. Monitor patients closely when ciprofloxacin is used at a dosage of 250 mg or 500 mg once daily.
Agents or combinations of agents that are moderate or strong inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (i.e., CYP2C9, 2C19, 2D6, and 2E1) should be discontinued prior to and avoided during pirfenidone treatment.
### CYP1A2 Inducers
The concomitant use of pirfenidone and a CYP1A2 inducer may decrease the exposure of pirfenidone and this may lead to loss of efficacy. Therefore, discontinue use of strong CYP1A2 inducers prior to pirfenidone treatment and avoid the concomitant use of pirfenidone and a strong CYP1A2 inducer.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies of pirfenidone in pregnant women. Pirfenidone was not teratogenic in rats and rabbits. Because animal reproduction studies are not always predictive of human response, pirfenidone should be used during pregnancy only if the benefit outweighs the risk to the patient.
A fertility and embryo-fetal development study with rats and an embryo-fetal development study with rabbits that received oral doses up to 3 and 2 times, respectively, the maximum recommended daily dose (MRDD) in adults (on mg/m2 basis at maternal doses up to 1000 and 300 mg/kg/day, respectively) revealed no evidence of impaired fertility or harm to the fetus due to pirfenidone. In the presence of maternal toxicity, acyclic/irregular cycles (e.g., prolonged estrous cycle) were seen in rats at doses approximately equal to and higher than the MRDD in adults (on a mg/m2 basis at maternal doses of 450 mg/kg/day and higher). In a pre- and post-natal development study, prolongation of the gestation period, decreased numbers of live newborn, and reduced pup viability and body weights were seen in rats at an oral dosage approximately 3 times the MRDD in adults (on a mg/m2 basis at a maternal dose of 1000 mg/kg/day).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pirfenidone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pirfenidone during labor and delivery.
### Nursing Mothers
A study with radio-labeled pirfenidone in rats has shown that pirfenidone or its metabolites are excreted in milk. It is not known whether pirfenidone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue pirfenidone, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness of pirfenidone in pediatric patients have not been established.
### Geriatic Use
Of the total number of subjects in the clinical studies receiving pirfenidone, 714 (67%) were 65 years old and over, while 231 (22%) were 75 years old and over. No overall differences in safety or effectiveness were observed between older and younger patients. No dosage adjustment is required based upon age.
### Gender
Results of population pharmacokinetic analysis of pirfenidone showed no significant differences in pharmacokinetics between males and females.
### Race
Population pharmacokinetic analysis showed that race has no significant effect on the pharmacokinetics of pirfenidone.
### Renal Impairment
Pirfenidone should be used with caution in patients with mild (CLcr 50–80 mL/min), moderate (CLcr 30–50 mL/min), or severe (CLcr less than 30 mL/min) renal impairment. Monitor for adverse reactions and consider dosage modification or discontinuation of pirfenidone as needed. The safety, efficacy, and pharmacokinetics of pirfenidone have not been studied in patients with end-stage renal disease requiring dialysis. Use of pirfenidone in patients with end-stage renal diseases requiring dialysis is not recommended.
### Hepatic Impairment
Pirfenidone should be used with caution in patients with mild (Child Pugh Class A) to moderate (Child Pugh Class B) hepatic impairment. Monitor for adverse reactions and consider dosage modification or discontinuation of pirfenidone as needed.
The safety, efficacy, and pharmacokinetics of pirfenidone have not been studied in patients with severe hepatic impairment. Pirfenidone is not recommended for use in patients with severe (Child Pugh Class C) hepatic impairment.
### Females of Reproductive Potential and Males
Pirfenidone had no effects on fertility and reproductive performance in rats at dosages up to 1000 mg/kg/day (approximately 3 times the MRDD in adults on a mg/m2 basis).
### Immunocompromised Patients
There is no FDA guidance one the use of Pirfenidone in patients who are immunocompromised.
### Smokers
Smoking causes decreased exposure to pirfenidone, which may alter the efficacy profile of pirfenidone. Instruct patients to stop smoking prior to treatment with pirfenidone and to avoid smoking when using pirfenidone.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Pirfenidone Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Pirfenidone and IV administrations.
# Overdosage
There is limited clinical experience with overdosage. Multiple dosages of pirfenidone up to a maximum tolerated dose of 4005 mg per day were administered as five 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation.
In the event of a suspected overdosage, appropriate supportive medical care should be provided, including monitoring of vital signs and observation of the clinical status of the patient.
# Pharmacology
## Mechanism of Action
The mechanism of action of pirfenidone in the treatment of IPF has not been established.
## Structure
The chemical name of pirfenidone is 5-methyl-1-phenyl-2-1(H)-pyridone. It has a molecular formula of C12H11NO and a molecular weight of 185.23. The structural formula of pirfenidone is:
## Pharmacodynamics
### Cardiac Electrophysiology
The effect of pirfenidone on QT interval was evaluated in a randomized, placebo, and positive controlled parallel study in 160 healthy adult volunteers. Volunteers received pirfenidone 2403 mg/day (recommended dose) and 4005 mg/day (1.6 times recommended dose) or placebo for 10 days or a single dose of 400 mg moxifloxacin (active control).
Relative to placebo, the maximum mean change from baseline in study-specific QT interval was 3.2 milliseconds (ms) and 2.2 ms for pirfenidone 2403 mg/day and 4005 mg/day, respectively. No volunteer had a QTc interval greater than 480 ms or change from baseline greater than 60 ms. Although there was no evidence that pirfenidone prolonged the QTc interval in this study, a definitive conclusion may not be drawn as the positive control (moxifloxacin) did not perform as expected in this study, and pirfenidone at 4005 mg/day (1.7 times the maximum recommended dose) did not cover the maximum pirfenidone exposure increase with co-administration of fluvoxamine, a strong CYP1A2 inhibitor.
## Pharmacokinetics
### Absorption
After single oral-dose administration of 801 mg pirfenidone, the maximum observed plasma concentration (Cmax) was achieved between 30 minutes and 4 hours (median time of 0.5 hours). Food decreased the rate and extent of absorption. Median Tmax increased from 0.5 hours to 3 hours with food. Maximum plasma concentrations and AUC0-inf decreased by approximately 49% and 16% with food, respectively. A reduced incidence of adverse reactions was observed in the fed group when compared to the fasted group. In controlled studies with IPF patients, pirfenidone was taken with food.
The absolute bioavailability of pirfenidone has not been determined in humans.
### Distribution
pirfenidone binds to human plasma proteins, primarily to serum albumin, in a concentration-independent manner over the range of concentrations observed in clinical trials. The overall mean binding was 58% at concentrations observed in clinical studies (1 to 10 µg/mL). Mean apparent oral volume of distribution is approximately 59 to 71 liters.
### Metabolism
In vitro profiling studies in hepatocytes and liver microsomes have shown that pirfenidone is primarily metabolized in the liver by CYP1A2 and multiple other CYPs (CYP2C9, 2C19, 2D6, and 2E1). Oral administration of pirfenidone results in the formation of four metabolites. In humans, only pirfenidone and 5-carboxy-pirfenidone are present in plasma in significant quantities. The mean metabolite-to-parent ratio ranged from approximately 0.6 to 0.7.
No formal radiolabeled studies have assessed the metabolism of pirfenidone in humans. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
### Elimination
The mean terminal half-life is approximately 3 hours in healthy subjects. Pirfenidone is excreted predominantly as metabolite 5-carboxy-pirfenidone, mainly in the urine (approximately 80% of the dose). The majority of pirfenidone was excreted as the 5-carboxy metabolite (approximately 99.6% of that recovered).
## Nonclinical Toxicology
### Carcinogenesis
Long-term studies were conducted in mice and rats with admixture of pirfenidone to the diet to evaluate its carcinogenic potential.
In a 24-month carcinogenicity study in B6C3F1 mice, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma and hepatoblastoma in male mice at doses of 800 mg/kg and above (AUC exposure approximately 0.4 times adult exposure at the MRDD). There were statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in female mice at doses of 2000 mg/kg and above (AUC exposure approximately 0.7 times adult exposure at the MRDD).
In a 24-month carcinogenicity study in Fischer rats, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in male rats at doses of 750 mg/kg and above (AUC exposure approximately 1.9 times adult exposure at the MRDD). There were statistically significant increases of the combination of hepatocellular adenoma and carcinoma and the combination of uterine adenocarcinoma and adenoma at a dose of 1500 mg/kg/day (AUC exposure approximately 3.0 times adult exposure at the MRDD).
The relevance of these tumor findings in rodents to humans is unknown.
### Mutagenesis
Pirfenidone was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, a chromosomal aberration test in Chinese hamster lung cells, and a micronucleus test in mice.
# Clinical Studies
The efficacy of pirfenidone was evaluated in patients with IPF in three phase 3, randomized, double-blind, placebo-controlled, multicenter trials (Studies 1, 2, and 3).
Study 1 was a 52-week trial comparing pirfenidone 2403 mg/day (n=278) versus placebo (n=277) in patients with IPF. Study 2 and Study 3 were nearly identical to each other in design, with few exceptions, including an intermediate dose treatment arm in Study 2. Study 2 compared treatment with either pirfenidone 2403 mg/day (n=174) or pirfenidone 1197 mg/day (n=87) to placebo (n=174), while Study 3 compared pirfenidone 2403 mg/day (n=171) to placebo (n=173). Study drug was administered three times daily with food for a minimum of 72 weeks. Patients continued on treatment until the last patient completed 72 weeks of treatment, which included observations to approximately 120 weeks of study treatment. The primary endpoint was the change in percent predicted forced vital capacity (%FVC) from baseline to study end, measured at 52 weeks in Study 1, and at 72 weeks in Studies 2 and 3.
Studies 1, 2 and 3 enrolled adult patients who had a clinical and radiographic diagnosis of IPF (with or without accompanying surgical lung biopsy), without evidence or suspicion of an alternative diagnosis for interstitial lung disease. Eligible patients were to have %FVC greater than or equal to 50% at baseline and a percent predicted diffusing capacity of the lungs for carbon monoxide (%DLCO) greater than or equal to 30% (Study 1) or 35% (Studies 2 and 3) at baseline. In all three trials, over 80% of patients completed study treatment.
A total of 1247 patients with IPF were randomized to receive pirfenidone 2403 mg/day (n=623) or placebo (n=624) in these three trials. Baseline characteristics were generally balanced across treatment groups. The study population ranged from 40 to 80 years of age (mean age 67 years). Most patients were male (74%), white (95%), and current or former smokers (65%). Approximately 93% of patients met criteria for definite IPF on high resolution computed tomography (HRCT). Baseline mean %FVC and %DLCO were 72% and 46%, respectively. Approximately 15% subjects discontinued from each treatment group.
### Change from Baseline in Percent Predicted Forced Vital Capacity
In Study 1, the primary efficacy analysis for the change in %FVC from baseline to Week 52 demonstrated a statistically significant treatment effect of pirfenidone 2403 mg/day (n=278) compared with placebo (n=277) using a rank ANCOVA with the lowest rank imputation for missing data due to death. In Study 2, there was a statistically significant difference at Week 72 for the change in %FVC from baseline. In Study 3, there was no statistically significant difference at Week 72 for the change in %FVC from baseline.
FIGURE 1 presents the cumulative distribution for all cut-offs for the change from baseline in %FVC at Week 52 for Study 1. For all categorical declines in lung function, the proportion of patients declining was lower on pirfenidone than on placebo. Study 2 showed similar results.
### Mean Change from Baseline in FVC (mL)
In Study 1, a reduction in the mean decline in FVC (in mL) was observed in patients receiving pirfenidone 2403 mg/day (-235 mL) compared to placebo (-428 mL) (mean treatment difference 193 mL) at Week 52 (see FIGURE 2). In Study 2, a reduction in the decline in FVC volume was also observed in patients receiving pirfenidone 2403 mg/day compared with placebo (mean treatment difference 157 mL) at Week 72. There was no statistically significant difference in decline in FVC volume seen in Study 3.
### Survival
Survival was evaluated for pirfenidone compared to placebo in Studies 1, 2, and 3 as an exploratory analysis to support the primary endpoint (FVC). All-cause mortality was assessed over the study duration and available follow-up period, irrespective of cause of death and whether patients continued treatment. All-cause mortality did not show a statistically significant difference (see FIGURE 3).
# How Supplied
Bottle for a 30-day supply
- Bottle containing 270 capsules and closed with a child-resistant closure
- NDC 64116-121-01
14-day Titration Blister Pack
- Carton containing a total of 63 capsules in two blister cards
- NDC 64116-121-02
4-Week Maintenance Blister Pack
- Carton containing a total of 252 capsules in four blister cards
- NDC 64116-121-03
## Storage
Store at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Liver Enzyme Elevations
Advise patients that they may be required to undergo liver function testing periodically. Instruct patients to immediately report any symptoms of a liver problem (e.g., skin or the white of eyes turn yellow, urine turns dark or brown [tea colored], pain on the right side of stomach, bleed or bruise more easily than normal, lethargy).
### Photosensitivity Reaction or Rash
Advise patients to avoid or minimize exposure to sunlight (including sunlamps) during use of pirfenidone because of concern for photosensitivity reactions or rash. Instruct patients to use a sunblock and to wear clothing that protects against sun exposure. Instruct patients to report symptoms of photosensitivity reaction or rash to their physician. Temporary dosage reductions or discontinuations may be required.
### Gastrointestinal Events
Instruct patients to report symptoms of persistent gastrointestinal effects including nausea, diarrhea, dyspepsia, vomiting, gastroesophageal reflux disease, and abdominal pain. Temporary dosage reductions or discontinuations may be required.
### Smokers
Encourage patients to stop smoking prior to treatment with pirfenidone and to avoid smoking when using pirfenidone.
### Take with Food
Instruct patients to take pirfenidone with food to help decrease nausea and dizziness.
# Precautions with Alcohol
Alcohol-Pirfenidone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Esbriet [2]
# Look-Alike Drug Names
There is limited information regarding Pirfenidone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Esbriet | |
5b2ae1ed65fb0ef369595955058ac9ab6d52a016 | wikidoc | Escharotomy | Escharotomy
An escharotomy is a surgical procedure used to treat full thickness (third-degree) circumferential burns. Since full thickness burns are characterized by tough, leathery eschar, an escharotomy is used primarily to combat compartment syndrome. Following a full thickness burn, as the underlying tissues are re hydrated, they become constricted due to the eschar's loss of elasticity, leading to impaired circulation distal to the wound.
An escharotomy is performed by making an incision through the eschar to expose the fatty tissue below. Due to the residual pressure, the incision will often widen substantially.
Physiotherapy input - move limb when bleeding ceases and aim to maximise breathing mechanics. | Escharotomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
An escharotomy is a surgical procedure used to treat full thickness (third-degree) circumferential burns. Since full thickness burns are characterized by tough, leathery eschar, an escharotomy is used primarily to combat compartment syndrome. Following a full thickness burn, as the underlying tissues are re hydrated, they become constricted due to the eschar's loss of elasticity, leading to impaired circulation distal to the wound.
An escharotomy is performed by making an incision through the eschar to expose the fatty tissue below. Due to the residual pressure, the incision will often widen substantially.
Physiotherapy input - move limb when bleeding ceases and aim to maximise breathing mechanics.
# External links
- A basic primer on the procedure
- Journal of Burns and Wounds - online open-access journal featuring articles on burn care and related research
Template:Operations and other procedures of the integumentary system
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Escharotomy | |
0a8b450edaa84cf1f33e0d27073d4257c5f6d378 | wikidoc | Eszopiclone | Eszopiclone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Eszopiclone is a nonbarbiturate hypnotic that is FDA approved for the {{{indicationType}}} of insomnia. Common adverse reactions include unpleasant taste, headache, somnolence, respiratory infection, dizziness, dry mouth, rash, anxiety, hallucinations, and viral infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Dosage in Adults
- The recommended starting dose is 1 mg. Dosing can be raised to 2 mg or 3 mg if clinically indicated. In some patients, the higher morning blood levels of LUNESTA following use of the 2 mg or 3 mg dose increase the risk of next day impairment of driving and other activities that require full alertness. The total dose of LUNESTA should not exceed 3 mg, once daily immediately before bedtime.
- Geriatric or Debilitated Patients
- The total dose of LUNESTA should not exceed 2 mg in elderly or debilitated patients.
- Patients with Severe Hepatic Impairment, or Taking Potent CYP3A4 Inhibitors
- In patients with severe hepatic impairment, or in patients coadministered LUNESTA with potent CYP3A4 inhibitors, the total dose of LUNESTA should not exceed 2 mg.
- Use with CNS Depressants
- Dosage adjustments may be necessary when LUNESTA is combined with other CNS depressant drugs because of the potentially additive effects.
- Administration with Food
- Taking LUNESTA with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of LUNESTA on sleep latency.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eszopiclone in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Eszopiclone 3 mg prior to polysomnography.
- Dosing Information
- Eszopiclone 3 mg each night for 8 weeks.
- Dosing Information
- Eszopiclone 3 mg for 8 weeks.
- Dosing Information
- Eszopiclone 3 mg per day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Eszopiclone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eszopiclone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eszopiclone in pediatric patients.
# Contraindications
- LUNESTA is contraindicated in patients with known hypersensitivity to eszopiclone. Hypersensitivity reactions include anaphylaxis and angioedema.
# Warnings
### Precautions
- CNS Depressant Effects and Next-Day Impairment
- Eszopiclone is a central nervous system (CNS) depressant and can impair daytime function in some patients at the higher doses (2 mg or 3 mg), even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of symptoms (or even with subjective improvement), and impairment may not be reliably detected by ordinary clinical exam (i.e., less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of eszopiclone may develop, patients using 3 mg eszopiclone should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.
- Additive effects occur with concomitant use of other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of eszopiclone and concomitant CNS depressants should be considered.
- The use of eszopiclone with other sedative-hypnotics at bedtime or the middle of the night is not recommended.
- The risk of next-day psychomotor impairment is increased if eszopiclone is taken with less than a full night of sleep remaining (7- to 8 hours); if higher than the recommended dose is taken; if co- administered with other CNS depressants; or co-administered with other drugs that increase the blood levels of eszopiclone.
- Need to Evaluate for Co-Morbid Diagnoses
- Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including eszopiclone. Because some of the important adverse effects of eszopiclone appear to be dose-related, it is important to use the lowest possible effective dose, especially in the elderly.
- Severe Anaphylactic and Anaphylactoid Reactions
- Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including eszopiclone. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with eszopiclone should not be rechallenged with the drug.
- Abnormal Thinking and Behavioral Changes
- A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS depressants. Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.
- Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with eszopiclone alone at therapeutic doses, the use of alcohol and other CNS depressants with eszopiclone appears to increase the risk of such behaviors, as does the use of eszopiclone at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of eszopiclone should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.
- It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above are drug-induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
- Withdrawal Effects
- Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs.
- Timing of Drug Administration
- Eszopiclone should be taken immediately before bedtime. Taking a sedative/hypnotic while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness.
- Special Populations
- Use in Elderly and/or Debilitated Patients
Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. The dose should not exceed 2 mg in elderly or debilitated patients.
- Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. The dose should not exceed 2 mg in elderly or debilitated patients.
- Use in Patients with Concomitant Illness
Clinical experience with eszopiclone in patients with concomitant illness is limited. Eszopiclone should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
A study in healthy volunteers did not reveal respiratory-depressant effects at doses 2.5-fold higher (7 mg) than the recommended dose of eszopiclone. Caution is advised, however, if eszopiclone is prescribed to patients with compromised respiratory function.
The dose of eszopiclone should not exceed 2 mg in patients with severe hepatic impairment, because systemic exposure is doubled in such subjects. No dose adjustment appears necessary for subjects with mild or moderate hepatic impairment. No dose adjustment appears necessary in subjects with any degree of renal impairment, since less than 10% of eszopiclone is excreted unchanged in the urine.
The dose of eszopiclone should be reduced in patients who are administered potent inhibitors of CYP3A4, such as ketoconazole, while taking eszopiclone. Downward dose adjustment is also recommended when eszopiclone is administered with agents having known CNS-depressant effects.
- Clinical experience with eszopiclone in patients with concomitant illness is limited. Eszopiclone should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
- A study in healthy volunteers did not reveal respiratory-depressant effects at doses 2.5-fold higher (7 mg) than the recommended dose of eszopiclone. Caution is advised, however, if eszopiclone is prescribed to patients with compromised respiratory function.
- The dose of eszopiclone should not exceed 2 mg in patients with severe hepatic impairment, because systemic exposure is doubled in such subjects. No dose adjustment appears necessary for subjects with mild or moderate hepatic impairment. No dose adjustment appears necessary in subjects with any degree of renal impairment, since less than 10% of eszopiclone is excreted unchanged in the urine.
- The dose of eszopiclone should be reduced in patients who are administered potent inhibitors of CYP3A4, such as ketoconazole, while taking eszopiclone. Downward dose adjustment is also recommended when eszopiclone is administered with agents having known CNS-depressant effects.
- Use in Patients with Depression
Sedative/hypnotic drugs should be administered with caution to patients exhibiting signs and symptoms of depression. Suicidal tendencies may be present in such patients, and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.
- Sedative/hypnotic drugs should be administered with caution to patients exhibiting signs and symptoms of depression. Suicidal tendencies may be present in such patients, and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.
# Adverse Reactions
## Clinical Trials Experience
- Adverse Reactions Resulting in Discontinuation of Treatment
- In placebo-controlled, parallel-group clinical trials in the elderly, 3.8% of 208 patients who received placebo, 2.3% of 215 patients who received 2 mg eszopiclone, and 1.4% of 72 patients who received 1 mg eszopiclone discontinued treatment due to an adverse reaction. In the 6‑week parallel-group study in adults, no patients in the 3 mg arm discontinued because of an adverse reaction. In the long-term 6-month study in adult insomnia patients, 7.2% of 195 patients who received placebo and 12.8% of 593 patients who received 3 mg eszopiclone discontinued due to an adverse reaction. No reaction that resulted in discontinuation occurred at a rate of greater than 2%.
- Adverse Reactions Observed at an Incidence of ≥2% in Controlled Trials
- Table 1 shows the incidence of adverse reactions from a Phase 3 placebo-controlled study of eszopiclone at doses of 2 or 3 mg in non-elderly adults. Treatment duration in this trial was 44 days. The table includes only reactions that occurred in 2% or more of patients treated with eszopiclone 2 mg or 3 mg in which the incidence in patients treated with eszopiclone was greater than the incidence in placebo-treated patients.
- Adverse reactions from Table 1 that suggest a dose-response relationship in adults include viral infection, dry mouth, dizziness, hallucinations, infection, rash, and unpleasant taste, with this relationship clearest for unpleasant taste.
- Table 2 shows the incidence of adverse reactions from combined Phase 3 placebo-controlled studies of eszopiclone at doses of 1 or 2 mg in elderly adults (ages 65 to 86). Treatment duration in these trials was 14 days. The table includes only reactions that occurred in 2% or more of patients treated with eszopiclone 1 mg or 2 mg in which the incidence in patients treated with eszopiclone was greater than the incidence in placebo-treated patients.
- Adverse reactions from Table 2 that suggest a dose-response relationship in elderly adults include pain, dry mouth, and unpleasant taste, with this relationship again clearest for unpleasant taste.
- These figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice because patient characteristics and other factors may differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contributions of drug and non-drug factors to the adverse reaction incidence rate in the population studied.
- Other Reactions Observed During the Premarketing Evaluation of Eszopiclone
- Following is a list of modified COSTART terms that reflect adverse reactions as defined in the introduction to the Adverse Reactions section and reported by approximately 1550 subjects treated with eszopiclone at doses in the range of 1 to 3.5 mg/day during Phase 2 and 3 clinical trials throughout the United States and Canada. All reported reactions are included except those already listed in Tables 1 and 2 or elsewhere in labeling, minor reactions common in the general population, and reactions unlikely to be drug-related. Although the reactions reported occurred during treatment with eszopiclone, they were not necessarily caused by it.
- Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those that occurred on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those that occurred in fewer than 1/100 patients but in at least 1/1,000 patients; rare adverse reactions are those that occurred in fewer than 1/1,000 patients. Gender-specific reactions are categorized based on their incidence for the appropriate gender.
- Body as a Whole: Frequent: chest pain; Infrequent: allergic reaction, cellulitis, face edema, fever, halitosis, heat stroke, hernia, malaise, neck rigidity, photosensitivity.
- Cardiovascular System: Frequent: migraine; Infrequent: hypertension; Rare: thrombophlebitis.
- Digestive System: Infrequent: anorexia, cholelithiasis, increased appetite, melena, mouth ulceration, thirst, ulcerative stomatitis; Rare: colitis, dysphagia, gastritis, hepatitis, hepatomegaly, liver damage, stomach ulcer, stomatitis, tongue edema, rectal hemorrhage.
- Hemic and Lymphatic System: Infrequent: anemia, lymphadenopathy.
- Metabolic and Nutritional: Frequent: peripheral edema; Infrequent: hypercholesteremia, weight gain, weight loss; Rare: dehydration, gout, hyperlipemia, hypokalemia.
- Musculoskeletal System: Infrequent: arthritis, bursitis, joint disorder (mainly swelling, stiffness, and pain), leg cramps, myasthenia, twitching; Rare: arthrosis, myopathy, ptosis.
- Nervous System: Infrequent: agitation, apathy, ataxia, emotional lability, hostility, hypertonia, hypesthesia, incoordination, insomnia, memory impairment, neurosis, nystagmus, paresthesia, reflexes decreased, thinking abnormal (mainly difficulty concentrating), vertigo; Rare: abnormal gait, euphoria, hyperesthesia, hypokinesia, neuritis, neuropathy, stupor, tremor.
- Respiratory System: Infrequent: asthma, bronchitis, dyspnea, epistaxis, hiccup, laryngitis.
- Skin and Appendages: Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, skin discoloration, sweating, urticaria; Rare: erythema multiforme, furunculosis, herpes zoster, hirsutism, maculopapular rash, vesiculobullous rash.
- Special Senses: Infrequent: conjunctivitis, dry eyes, ear pain, otitis externa, otitis media, tinnitus, vestibular disorder; Rare: hyperacusis, iritis, mydriasis, photophobia.
- Urogenital System: Infrequent: amenorrhea, breast engorgement, breast enlargement, breast neoplasm, breast pain, cystitis, dysuria, female lactation, hematuria, kidney calculus, kidney pain, mastitis, menorrhagia, metrorrhagia, urinary frequency, urinary incontinence, uterine hemorrhage, vaginal hemorrhage, vaginitis; Rare: oliguria, pyelonephritis, urethritis.
## Postmarketing Experience
- In addition to the adverse reactions observed during clinical trials, dysosmia, an olfactory dysfunction that is characterized by distortion of the sense of smell, has been reported during post-marketing surveillance with eszopiclone. Because this event is reported spontaneously from a population of unknown size, it is not possible to estimate the frequency of this event.
# Drug Interactions
- CNS Active Drugs
- Ethanol: An additive effect on psychomotor performance was seen with coadministration of eszopiclone and ethanol.
- Olanzapine: Coadministration of eszopiclone and olanzapine produced a decrease in DSST scores. The interaction was pharmacodynamic; there was no alteration in the pharmacokinetics of either drug.
- Drugs that Inhibit or Induce CYP3A4
- Drugs That Inhibit CYP3A4 (Ketoconazole): CYP3A4 is a major metabolic pathway for elimination of eszopiclone. The exposure of eszopiclone was increased by coadministration of ketoconazole, a potent inhibitor of CYP3A4. Other strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, nelfinavir) would be expected to behave similarly. Dose reduction of eszopiclone is needed for patient co-administered eszopiclone with potent CYP3A4 inhibitors.
- Drugs that Induce CYP3A4 (Rifampicin): Racemic zopiclone exposure was decreased 80% by concomitant use of rifampicin, a potent inducer of CYP3A4. A similar effect would be expected with eszopiclone. Combination use with CYP3A4 inducer may decrease exposure and effects of eszopiclone
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. Eszopiclone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oral administration of eszopiclone to pregnant rats (62.5, 125, or 250 mg/kg/day) and rabbits (4, 8, or 16 mg/kg/day) throughout organogenesis showed no evidence of teratogenicity up to the highest doses tested. In rats, reduced fetal weight and increased incidences of skeletal variations and/or delayed ossification were observed at the mid and high doses. The no-observed-effect dose for adverse effects on embryofetal development is 200 times the maximum recommended human dose (MRHD) of 3 mg/day on a mg/m2 basis. No effects on embryofetal development were observed in rabbits; the highest dose tested is approximately 100 times the MRHD on a mg/m2 basis.
- Oral administration of eszopiclone (60, 120, or 180 mg/kg/day) to pregnant rats throughout the pregnancy and lactation resulted in increased post-implantation loss, decreased postnatal pup weights and survival, and increased pup startle response at all doses. The lowest dose tested is approximately 200 times the MRHD on a mg/m2 basis. Eszopiclone had no effects on other developmental measures or reproductive function in the offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eszopiclone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eszopiclone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Eszopiclone with respect to nursing mothers.
### Pediatric Use
- Safety and effectiveness have not been established in pediatric patients.
- The labeling for Sunovion Pharmaceutical Inc.’s eszopiclone tablets includes additional information from a clinical study in which efficacy was not demonstrated in pediatric patients. However, due to Sunovion Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
- In studies in which eszopiclone (2 to 300 mg/kg/day) was orally administered to young rats from weaning through sexual maturity, neurobehavioral impairment (altered auditory startle response) and reproductive toxicity (adverse effects on male reproductive organ weights and histopathology) were observed at doses ≥ 5 mg/kg/day. Delayed sexual maturation was noted in males and females at ≥ 10 mg/kg/day. The no-effect dose (2 mg/kg) was associated with plasma exposures (AUC) for eszopiclone and metabolite (S)-desmethylzopiclone approximately 2 times plasma exposures in humans at the maximum recommended dose (MRHD) in adults (3 mg/day).
- When eszopiclone (doses from 1 to 50 mg/kg/day) was orally administered to young dogs from weaning through sexual maturity, neurotoxicity (convulsions) was observed at doses ≥ 5 mg/kg/day. Hepatotoxicity (elevated liver enzymes and hepatocellular vacuolation and degeneration) and reproductive toxicity (adverse effects on male reproductive organ weights and histopathology) were noted at dose ≥ 10 mg/kg/day. The no-effect dose (1 mg/kg) was associated with plasma exposures (AUC) to eszopiclone and (S)-DMZ approximately 3 and 2 times, respectively, plasma exposures in humans at the MRHD in adults.
### Geriatic Use
- A total of 287 subjects in double-blind, parallel-group, placebo-controlled clinical trials who received eszopiclone were 65 to 86 years of age. The overall pattern of adverse events for elderly subjects (median age = 71 years) in 2-week studies with nighttime dosing of 2 mg eszopiclone was not different from that seen in younger adults. Eszopiclone 2 mg exhibited significant reduction in sleep latency and improvement in sleep maintenance in the elderly population. Compared with non-elderly adults, subjects 65 years and older had longer elimination and higher total exposure to eszopiclone. Therefore, dose reduction is recommended in the elderly patients.
### Gender
There is no FDA guidance on the use of Eszopiclone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eszopiclone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Eszopiclone in patients with renal impairment.
### Hepatic Impairment
- No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Exposure was increased in severely impaired patients compared with the healthy volunteers. The dose of eszopiclone should not exceed 2 mg in patients with severe hepatic impairment. Eszopiclone should be used with caution in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eszopiclone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eszopiclone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Eszopiclone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Eszopiclone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing. Impairment of consciousness ranging from somnolence to coma has been described. Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agents.
### Management
- General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Flumazenil may be useful. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. The value of dialysis in the treatment of overdosage has not been determined.
- As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Eszopiclone in the drug label.
# Pharmacology
## Mechanism of Action
- The precise mechanism of action of eszopiclone as a hypnotic is unknown, but its effect is believed to result from its interaction with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors. Eszopiclone is a nonbenzodiazepine hypnotic that is a pyrrolopyrazine derivative of the cyclopyrrolone class with a chemical structure unrelated to pyrazolopyrimidines, imidazopyridines, benzodiazepines, barbiturates, or other drugs with known hypnotic properties.
## Structure
- Eszopiclone Tablets are a nonbenzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrolone class. The chemical name of eszopiclone is (+)-(5S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo pyrazin-5-yl 4-methylpiperazine-1-carboxylate. Its molecular weight is 388.81, and its empirical formula is C17H17ClN6O3. Eszopiclone has a single chiral center with an (S)-configuration. It has the following chemical structure:
- Eszopiclone is a white to light-yellow crystalline solid. Eszopiclone is very slightly soluble in water, slightly soluble in ethanol, and soluble in phosphate buffer (pH 3.2).
- Eszopiclone is formulated as film-coated tablets for oral administration. Eszopiclone Tablets contain 1 mg, 2 mg, or 3 mg eszopiclone and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose (anhydrous), magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, titanium dioxide, and triacetin.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Eszopiclone in the drug label.
## Pharmacokinetics
- The pharmacokinetics of eszopiclone have been investigated in healthy subjects (adult and elderly) and in patients with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic profile was examined after single doses of up to 7.5 mg and after once-daily administration of 1, 3, and 6 mg for 7 days. Eszopiclone is rapidly absorbed, with a time to peak concentration (tmax) of approximately 1 hour and a terminal-phase elimination half-life (t1/2) of approximately 6 hours. In healthy adults, eszopiclone does not accumulate with once-daily administration, and its exposure is dose-proportional over the range of 1 to 6 mg.
- Absorption and Distribution
- Eszopiclone is rapidly absorbed following oral administration. Peak plasma concentrations are achieved within approximately 1 hour after oral administration. Eszopiclone is weakly bound to plasma protein (52 to 59%). The large free fraction suggests that eszopiclone disposition should not be affected by drug-drug interactions caused by protein binding. The blood-to-plasma ratio for eszopiclone is less than one, indicating no selective uptake by red blood cells.
- Metabolism
- Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes.
- Elimination
- After oral administration, eszopiclone is eliminated with a mean t1/2 of approximately 6 hours. Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites. A similar excretion profile would be expected for eszopiclone, the S-isomer of racemic zopiclone. Less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug.
- Effect of Food
- In healthy adults, administration of a 3 mg dose of eszopiclone after a high-fat meal resulted in no change in AUC, a reduction in mean Cmax of 21%, and delayed tmax by approximately 1 hour. The half-life remained unchanged, approximately 6 hours. The effects of eszopiclone on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal.
- Specific Populations
- Age
- Compared with non-elderly adults, subjects 65 years and older had an increase of 41% in total exposure (AUC) and a slightly prolonged elimination of eszopiclone (t1/2 approximately 9 hours). Cmax was unchanged. Therefore, in elderly patients the dose should not exceed 2 mg.
- Gender
- The pharmacokinetics of eszopiclone in men and women are similar.
- Race
- In an analysis of data on all subjects participating in Phase 1 studies of eszopiclone, the pharmacokinetics for all races studied appeared similar.
- Hepatic Impairment
- Pharmacokinetics of a 2 mg eszopiclone dose were assessed in 16 healthy volunteers and in 8 subjects with mild, moderate, and severe liver disease. Exposure was increased 2-fold in severely impaired patients compared with the healthy volunteers. Cmax and tmax were unchanged. No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Dose reduction is recommended for patients with severe hepatic impairment. Eszopiclone should be used with caution in patients with hepatic impairment.
- Renal Impairment
- The pharmacokinetics of eszopiclone were studied in 24 patients with mild, moderate, or severe renal impairment. AUC and Cmax were similar in the patients compared with demographically matched healthy control subjects. No dose adjustment is necessary in patients with renal impairment, since less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug.
- Drug Interactions
- Eszopiclone is metabolized by CYP3A4 and CYP2E1 via demethylation and oxidation. There were no pharmacokinetic or pharmacodynamic interactions between eszopiclone and paroxetine. When eszopiclone was coadministered with olanzapine, no pharmacokinetic interaction was detected in levels of eszopiclone or olanzapine, but a pharmacodynamic interaction was seen on a measure of psychomotor function. Eszopiclone and lorazepam decreased each other’s Cmax by 22%. Coadministration of eszopiclone 3 mg to subjects receiving ketoconazole, a potent inhibitor of CYP3A4, 400 mg daily for 5 days, resulted in a 2.2-fold increase in exposure to eszopiclone. Cmax and t1/2 were increased 1.4-fold and 1.3-fold, respectively. Eszopiclone would not be expected to alter the clearance of drugs metabolized by common CYP450 enzymes.
- Paroxetine
- Coadministration of single dose of eszopiclone and paroxetine produced no pharmacokinetic or pharmacodynamic interaction. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.
- Lorazepam
- Coadministration of single doses of eszopiclone and lorazepam did not have clinically relevant effects on the pharmacodynamics or pharmacokinetics of either drug. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.
- Drugs with a Narrow Therapeutic Index
- Digoxin
- A single dose of eszopiclone 3 mg did not affect the pharmacokinetics of digoxin measured at steady state following dosing of 0.5 mg twice daily for one day and 0.25 mg daily for the next 6 days.
- Warfarin
- Eszopiclone 3 mg administered daily for 5 days did not affect the pharmacokinetics of (R)- or (S)-warfarin, nor were there any changes in the pharmacodynamic profile (prothrombin time) following a single 25 mg oral dose of warfarin.
- Drugs Highly Bound to Plasma Protein
- Eszopiclone is not highly bound to plasma proteins (52 to 59% bound); therefore, the disposition of eszopiclone is not expected to be sensitive to alterations in protein binding. Administration of eszopiclone 3 mg to a patient taking another drug that is highly protein-bound would not be expected to cause an alteration in the free concentration of either drug.
## Nonclinical Toxicology
- Carcinogenesis
- In a carcinogenicity study in rats, oral administration of eszopiclone for 97 (males) or 104 (females) weeks resulted in no increases in tumors; plasma levels (AUC) of eszopiclone at the highest dose tested (16 mg/kg/day) are approximately 80 (females) and 20 (males) times those in humans at the maximum recommended human dose (MRHD) of 3 mg/day. However, in a 2-year carcinogenicity study in rats, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) resulted in increases in mammary gland adenocarcinomas (females) and thyroid gland follicular cell adenomas and carcinomas (males) at the highest dose tested. Plasma levels of eszopiclone at this dose are approximately 150 (females) and 70 (males) times those in humans at the MRHD of eszopiclone. The mechanism for the increase in mammary adenocarcinomas is unknown. The increase in thyroid tumors is thought to be due to increased levels of TSH secondary to increased metabolism of circulating thyroid hormones, a mechanism not considered relevant to humans.
- In a 2-year carcinogenicity study in mice, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) produced increases in pulmonary carcinomas and carcinomas plus adenomas (females) and skin fibromas and sarcomas (males) at the highest dose tested. The skin tumors were due to skin lesions induced by aggressive behavior, a mechanism not relevant to humans. A carcinogenicity study of eszopiclone was conducted in mice at oral doses up to 100 mg/kg/day. Although this study did not reach a maximum tolerated dose, and was thus inadequate for overall assessment of carcinogenic potential, no increases in either pulmonary or skin tumors were seen at doses producing plasma levels of eszopiclone approximately 90 times those in humans at the MRHD of eszopiclone (and 12 times the exposure in the racemate study).
- Eszopiclone did not increase tumors in a p53 transgenic mouse bioassay at oral doses up to 300 mg/kg/day.
- Mutagenesis
- Eszopiclone was clastogenic in in vitro (mouse lymphoma and chromosomal aberration) assays in mammalian cells. Eszopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo micronucleus assay.
- (S)-N-desmethyl zopiclone, a metabolite of eszopiclone, was positive in in vitro chromosomal aberration assays in mammalian cells. (S)-N-desmethyl zopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo chromosomal aberration and micronucleus assay.
- Impairment of Fertility
- Oral administration of eszopiclone to rats prior to and during mating, and continuing in females to day 7 of gestation (doses up to 45 mg/kg/day to males and females or up to 180 mg/kg/day to females only) resulted in decreased fertility, with no pregnancy at the highest dose tested when both males and females were treated. In females, there was an increase in abnormal estrus cycles at the highest dose tested. In males, decreases in sperm number and motility and increases in morphologically abnormal sperm were observed at the mid and high doses. The no-effect dose for adverse effects on fertility (5 mg/kg/day) is 16 times the MRHD on a mg/m2 basis.
# Clinical Studies
- The effect of eszopiclone on reducing sleep latency and improving sleep maintenance was established in studies with 2100 subjects (ages 18 to 86) with chronic and transient insomnia in six placebo-controlled trials of up to 6 months’ duration. Two of these trials were in elderly patients (n=523). Overall, at the recommended adult dose (2 to 3 mg) and elderly dose (1 to 2 mg), eszopiclone significantly decreased sleep latency and improved measures of sleep maintenance (objectively measured as wake time after sleep onset and subjectively measured as total sleep time).
- Transient Insomnia
- Healthy adults were evaluated in a model of transient insomnia (n=436) in a sleep laboratory in a double-blind, parallel-group, single-night trial comparing two doses of eszopiclone and placebo. Eszopiclone 3 mg was superior to placebo on measures of sleep latency and sleep maintenance, including polysomnographic (PSG) parameters of latency to persistent sleep (LPS) and WASO.
- Chronic Insomnia (Adults and Elderly)
- The effectiveness of eszopiclone was established in five controlled studies in chronic insomnia. Three controlled studies were in adult subjects, and two controlled studies were in elderly subjects with chronic insomnia.
- Adults
In the first study, adults with chronic insomnia (n=308) were evaluated in a double-blind, parallel-group trial of 6 weeks’ duration comparing eszopiclone 2 mg and 3 mg with placebo. Objective endpoints were measured for 4 weeks. Both 2 mg and 3 mg were superior to placebo on LPS at 4 weeks. The 3 mg dose was superior to placebo on WASO.
In the second study, adults with chronic insomnia (n=788) were evaluated using subjective measures in a double-blind, parallel-group trial comparing the safety and efficacy of eszopiclone 3 mg with placebo administered nightly for 6 months. Eszopiclone was superior to placebo on subjective measures of sleep latency, total sleep time, and WASO.
In addition, a 6-period cross-over PSG study evaluating eszopiclone doses of 1 to 3 mg, each given over a 2-day period, demonstrated effectiveness of all doses on LPS, and of 3 mg on WASO. In this trial, the response was dose-related.
- In the first study, adults with chronic insomnia (n=308) were evaluated in a double-blind, parallel-group trial of 6 weeks’ duration comparing eszopiclone 2 mg and 3 mg with placebo. Objective endpoints were measured for 4 weeks. Both 2 mg and 3 mg were superior to placebo on LPS at 4 weeks. The 3 mg dose was superior to placebo on WASO.
- In the second study, adults with chronic insomnia (n=788) were evaluated using subjective measures in a double-blind, parallel-group trial comparing the safety and efficacy of eszopiclone 3 mg with placebo administered nightly for 6 months. Eszopiclone was superior to placebo on subjective measures of sleep latency, total sleep time, and WASO.
- In addition, a 6-period cross-over PSG study evaluating eszopiclone doses of 1 to 3 mg, each given over a 2-day period, demonstrated effectiveness of all doses on LPS, and of 3 mg on WASO. In this trial, the response was dose-related.
- Elderly
Elderly subjects (ages 65 to 86) with chronic insomnia were evaluated in two double-blind, parallel-group trials of 2 weeks duration. One study (n=231) compared the effects of eszopiclone with placebo on subjective outcome measures, and the other (n=292) on objective and subjective outcome measures. The first study compared 1 mg and 2 mg of eszopiclone with placebo, while the second study compared 2 mg of eszopiclone with placebo. All doses were superior to placebo on measures of sleep latency. In both studies, 2 mg of eszopiclone was superior to placebo on measures of sleep maintenance.
- Elderly subjects (ages 65 to 86) with chronic insomnia were evaluated in two double-blind, parallel-group trials of 2 weeks duration. One study (n=231) compared the effects of eszopiclone with placebo on subjective outcome measures, and the other (n=292) on objective and subjective outcome measures. The first study compared 1 mg and 2 mg of eszopiclone with placebo, while the second study compared 2 mg of eszopiclone with placebo. All doses were superior to placebo on measures of sleep latency. In both studies, 2 mg of eszopiclone was superior to placebo on measures of sleep maintenance.
- Studies Pertinent to Safety Concerns for Sedative Hypnotic Drugs
- Next Day Residual Effects
In a double-blind study of 91 healthy adults age 25- to 40 years, the effects of eszopiclone 3 mg on psychomotor function were assessed between 7.5 and 11.5 hours the morning after dosing. Measures included tests of psychomotor coordination that are correlated with ability to maintain a motor vehicle in the driving lane, tests of working memory, and subjective perception of sedation and coordination. Compared with placebo, eszopiclone 3 mg was associated with next- morning psychomotor and memory impairment that was most severe at 7.5 hours, but still present and potentially clinically meaningful at 11.5 hours. Subjective perception of sedation and coordination from eszopiclone 3 mg was not consistently different from placebo, even though subjects were objectively impaired.
In a 6-month double-blind, placebo-controlled trial of nightly administered eszopiclone 3 mg, memory impairment was reported by 1.3% (8/593) of subjects treated with eszopiclone 3 mg compared to 0% (0/195) of subjects treated with placebo. In a 6-week adult study of nightly administered eszopiclone confusion was reported by 3% of patients treated with eszopiclone 3 mg, compared to 0% of subjects treated with placebo. In the same study, memory impairment was reported by 1% of patents treated with either 2 mg or 3 mg eszopiclone, compared to 0% treated with placebo.
In a 2-week study of 264 elderly insomniacs, 1.5% of patients treated with eszopiclone 2 mg reported memory impairment compared to 0% treated with placebo. In another 2-week study of 231 elderly insomniacs, 2.5% of patients treated with eszopiclone 2 mg reported confusion compared to 0% treated with placebo.
A study of normal subjects exposed to single fixed doses of eszopiclone from 1 to 7.5 mg using the DSST to assess sedation and psychomotor function at fixed times after dosing (hourly up to 16 hours) found the expected sedation and reduction in psychomotor function. This was maximal at 1 hour and present up to 4 hours, but was no longer present by 5 hours.
In another study, patients with insomnia were given 2 or 3 mg doses of eszopiclone nightly, with DSST assessed on the mornings following days 1, 15, and 29 of treatment. While both the placebo and eszopiclone 3 mg groups showed an improvement in DSST scores relative to baseline the following morning (presumably due to a learning effect), the improvement in the placebo group was greater and reached statistical significance on night 1, although not on nights 15 and 29. For the eszopiclone 2 mg group, DSST change scores were not significantly different from placebo at any time point.
- In a double-blind study of 91 healthy adults age 25- to 40 years, the effects of eszopiclone 3 mg on psychomotor function were assessed between 7.5 and 11.5 hours the morning after dosing. Measures included tests of psychomotor coordination that are correlated with ability to maintain a motor vehicle in the driving lane, tests of working memory, and subjective perception of sedation and coordination. Compared with placebo, eszopiclone 3 mg was associated with next- morning psychomotor and memory impairment that was most severe at 7.5 hours, but still present and potentially clinically meaningful at 11.5 hours. Subjective perception of sedation and coordination from eszopiclone 3 mg was not consistently different from placebo, even though subjects were objectively impaired.
- In a 6-month double-blind, placebo-controlled trial of nightly administered eszopiclone 3 mg, memory impairment was reported by 1.3% (8/593) of subjects treated with eszopiclone 3 mg compared to 0% (0/195) of subjects treated with placebo. In a 6-week adult study of nightly administered eszopiclone confusion was reported by 3% of patients treated with eszopiclone 3 mg, compared to 0% of subjects treated with placebo. In the same study, memory impairment was reported by 1% of patents treated with either 2 mg or 3 mg eszopiclone, compared to 0% treated with placebo.
- In a 2-week study of 264 elderly insomniacs, 1.5% of patients treated with eszopiclone 2 mg reported memory impairment compared to 0% treated with placebo. In another 2-week study of 231 elderly insomniacs, 2.5% of patients treated with eszopiclone 2 mg reported confusion compared to 0% treated with placebo.
- A study of normal subjects exposed to single fixed doses of eszopiclone from 1 to 7.5 mg using the DSST to assess sedation and psychomotor function at fixed times after dosing (hourly up to 16 hours) found the expected sedation and reduction in psychomotor function. This was maximal at 1 hour and present up to 4 hours, but was no longer present by 5 hours.
- In another study, patients with insomnia were given 2 or 3 mg doses of eszopiclone nightly, with DSST assessed on the mornings following days 1, 15, and 29 of treatment. While both the placebo and eszopiclone 3 mg groups showed an improvement in DSST scores relative to baseline the following morning (presumably due to a learning effect), the improvement in the placebo group was greater and reached statistical significance on night 1, although not on nights 15 and 29. For the eszopiclone 2 mg group, DSST change scores were not significantly different from placebo at any time point.
- Withdrawal-Emergent Anxiety and Insomnia
During nightly use for an extended period, pharmacodynamic tolerance or adaptation has been observed with other hypnotics. If a drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night’s use. This is believed to be responsible for two clinical findings reported to occur after several weeks of nightly use of other rapidly eliminated hypnotics: increased wakefulness during the last quarter of the night and the appearance of increased signs of daytime anxiety.
In a 6-month double-blind, placebo-controlled study of nightly administration of eszopiclone 3 mg, rates of anxiety reported as an adverse event were 2.1% in the placebo arm and 3.7% in the eszopiclone arm. In a 6-week adult study of nightly administration, anxiety was reported as an adverse event in 0%, 2.9%, and 1% of the placebo, 2 mg, and 3 mg treatment arms, respectively. In this study, single-blind placebo was administered on nights 45 and 46, the first and second days of withdrawal from study drug. New adverse events were recorded during the withdrawal period, beginning with day 45, up to 14 days after discontinuation. During this withdrawal period, 105 subjects previously taking nightly eszopiclone 3 mg for 44 nights spontaneously reported anxiety (1%), abnormal dreams (1.9%), hyperesthesia (1%), and neurosis (1%), while none of 99 subjects previously taking placebo reported any of these adverse events during the withdrawal period.
Rebound insomnia, defined as a dose-dependent temporary worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. Rebound insomnia following discontinuation of eszopiclone relative to placebo and baseline was examined objectively in a 6-week adult study on the first 2 nights of discontinuation (nights 45 and 46) following 44 nights of active treatment with 2 mg or 3 mg. In the eszopiclone 2 mg group, compared with baseline, there was a significant increase in WASO and a decrease in sleep efficiency, both occurring only on the first night after discontinuation of treatment. No changes from baseline were noted in the eszopiclone 3 mg group on the first night after discontinuation, and there was a significant improvement in LPS and sleep efficiency compared with baseline following the second night of discontinuation. Comparisons of changes from baseline between eszopiclone and placebo were also performed. On the first night after discontinuation of eszopiclone 2 mg, LPS and WASO were significantly increased and sleep efficiency was reduced; there were no significant differences on the second night. On the first night following discontinuation of eszopiclone 3 mg, sleep efficiency was significantly reduced. No other differences from placebo were noted in any other sleep parameter on either the first or second night following discontinuation. For both doses, the discontinuation-emergent effect was mild, had the characteristics of the return of the symptoms of chronic insomnia, and appeared to resolve by the second night after eszopiclone discontinuation.
- During nightly use for an extended period, pharmacodynamic tolerance or adaptation has been observed with other hypnotics. If a drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night’s use. This is believed to be responsible for two clinical findings reported to occur after several weeks of nightly use of other rapidly eliminated hypnotics: increased wakefulness during the last quarter of the night and the appearance of increased signs of daytime anxiety.
- In a 6-month double-blind, placebo-controlled study of nightly administration of eszopiclone 3 mg, rates of anxiety reported as an adverse event were 2.1% in the placebo arm and 3.7% in the eszopiclone arm. In a 6-week adult study of nightly administration, anxiety was reported as an adverse event in 0%, 2.9%, and 1% of the placebo, 2 mg, and 3 mg treatment arms, respectively. In this study, single-blind placebo was administered on nights 45 and 46, the first and second days of withdrawal from study drug. New adverse events were recorded during the withdrawal period, beginning with day 45, up to 14 days after discontinuation. During this withdrawal period, 105 subjects previously taking nightly eszopiclone 3 mg for 44 nights spontaneously reported anxiety (1%), abnormal dreams (1.9%), hyperesthesia (1%), and neurosis (1%), while none of 99 subjects previously taking placebo reported any of these adverse events during the withdrawal period.
- Rebound insomnia, defined as a dose-dependent temporary worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. Rebound insomnia following discontinuation of eszopiclone relative to placebo and baseline was examined objectively in a 6-week adult study on the first 2 nights of discontinuation (nights 45 and 46) following 44 nights of active treatment with 2 mg or 3 mg. In the eszopiclone 2 mg group, compared with baseline, there was a significant increase in WASO and a decrease in sleep efficiency, both occurring only on the first night after discontinuation of treatment. No changes from baseline were noted in the eszopiclone 3 mg group on the first night after discontinuation, and there was a significant improvement in LPS and sleep efficiency compared with baseline following the second night of discontinuation. Comparisons of changes from baseline between eszopiclone and placebo were also performed. On the first night after discontinuation of eszopiclone 2 mg, LPS and WASO were significantly increased and sleep efficiency was reduced; there were no significant differences on the second night. On the first night following discontinuation of eszopiclone 3 mg, sleep efficiency was significantly reduced. No other differences from placebo were noted in any other sleep parameter on either the first or second night following discontinuation. For both doses, the discontinuation-emergent effect was mild, had the characteristics of the return of the symptoms of chronic insomnia, and appeared to resolve by the second night after eszopiclone discontinuation.
# How Supplied
- Eszopiclone tablets are round, white, film-coated tablets and are supplied as follows:
- The 1 mg tablets are debossed with product identification “54 746” on one side and plain on the other side.
- NDC 0054-0290-13 1 mg, bottle of 30
- NDC 0054-0290-25 1 mg, bottle of 100
- The 2 mg tablets are debossed with product identification “54 029” on one side and plain on the other side.
- NDC 0054-0291-25 2 mg, bottle of 100
- The 3 mg tablets are debossed with product identification “54 396” on one side and plain on the other side.
- NDC 0054-0292-25 3 mg, bottle of 100
- Storage
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
## Storage
There is limited information regarding Eszopiclone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients and their families about the benefits and risks of treatment with eszopiclone. Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with eszopiclone and with each prescription refill. Review the eszopiclone Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that eszopiclone should be taken only as prescribed.
- CNS depressant effects and next-day impairment: Tell patients that eszopiclone can cause next-day impairment even when used as prescribed, and that this risk is increased if dosing instructions are not carefully followed. Caution patients taking the 3 mg dose against driving and other activities requiring complete mental alertness the day after use. Inform patients that impairment can be present despite feeling fully awake.
- Severe anaphylactic and anaphylactoid reactions: Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with eszopiclone. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur.
- “Sleep-Driving” and other complex behaviors: Instruct patients and their families that sedative hypnotics can cause abnormal thinking and behavior change, including "sleep driving" and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you immediately if they develop any of these symptoms.
- Suicide: Tell patients to immediately report any suicidal thoughts.
- Alcohol and Other Drugs: Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use eszopiclone if they drank alcohol that evening or before bed.
- Tolerance, Abuse, and Dependence: Tell patients not to increase the dose of eszopiclone on their own, and to inform you if they believe the drug "does not work".
- Administration Instructions: Patients should be counseled to take eszopiclone right before they get into bed and only when they are able to stay in bed a full night (7–8 hours) before being active again. Eszopiclone tablets should not be taken with or immediately after a meal. Advise patients NOT to take eszopiclone if they drank alcohol that evening.
# Precautions with Alcohol
- Advise patients not to use eszopiclone if they drank alcohol that evening or before bed.
# Brand Names
- Lunesta
# Look-Alike Drug Names
- Lunesta® — Neulasta®
# Drug Shortage Status
# Price | Eszopiclone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
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# Overview
Eszopiclone is a nonbarbiturate hypnotic that is FDA approved for the {{{indicationType}}} of insomnia. Common adverse reactions include unpleasant taste, headache, somnolence, respiratory infection, dizziness, dry mouth, rash, anxiety, hallucinations, and viral infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Dosage in Adults
- The recommended starting dose is 1 mg. Dosing can be raised to 2 mg or 3 mg if clinically indicated. In some patients, the higher morning blood levels of LUNESTA following use of the 2 mg or 3 mg dose increase the risk of next day impairment of driving and other activities that require full alertness. The total dose of LUNESTA should not exceed 3 mg, once daily immediately before bedtime.
- Geriatric or Debilitated Patients
- The total dose of LUNESTA should not exceed 2 mg in elderly or debilitated patients.
- Patients with Severe Hepatic Impairment, or Taking Potent CYP3A4 Inhibitors
- In patients with severe hepatic impairment, or in patients coadministered LUNESTA with potent CYP3A4 inhibitors, the total dose of LUNESTA should not exceed 2 mg.
- Use with CNS Depressants
- Dosage adjustments may be necessary when LUNESTA is combined with other CNS depressant drugs because of the potentially additive effects.
- Administration with Food
- Taking LUNESTA with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of LUNESTA on sleep latency.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eszopiclone in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Eszopiclone 3 mg prior to polysomnography.[1]
- Dosing Information
- Eszopiclone 3 mg each night for 8 weeks.[2]
- Dosing Information
- Eszopiclone 3 mg for 8 weeks.[3]
- Dosing Information
- Eszopiclone 3 mg per day.[4]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Eszopiclone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eszopiclone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eszopiclone in pediatric patients.
# Contraindications
- LUNESTA is contraindicated in patients with known hypersensitivity to eszopiclone. Hypersensitivity reactions include anaphylaxis and angioedema.
# Warnings
### Precautions
- CNS Depressant Effects and Next-Day Impairment
- Eszopiclone is a central nervous system (CNS) depressant and can impair daytime function in some patients at the higher doses (2 mg or 3 mg), even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of symptoms (or even with subjective improvement), and impairment may not be reliably detected by ordinary clinical exam (i.e., less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of eszopiclone may develop, patients using 3 mg eszopiclone should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.
- Additive effects occur with concomitant use of other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of eszopiclone and concomitant CNS depressants should be considered.
- The use of eszopiclone with other sedative-hypnotics at bedtime or the middle of the night is not recommended.
- The risk of next-day psychomotor impairment is increased if eszopiclone is taken with less than a full night of sleep remaining (7- to 8 hours); if higher than the recommended dose is taken; if co- administered with other CNS depressants; or co-administered with other drugs that increase the blood levels of eszopiclone.
- Need to Evaluate for Co-Morbid Diagnoses
- Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including eszopiclone. Because some of the important adverse effects of eszopiclone appear to be dose-related, it is important to use the lowest possible effective dose, especially in the elderly.
- Severe Anaphylactic and Anaphylactoid Reactions
- Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including eszopiclone. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with eszopiclone should not be rechallenged with the drug.
- Abnormal Thinking and Behavioral Changes
- A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS depressants. Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.
- Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with eszopiclone alone at therapeutic doses, the use of alcohol and other CNS depressants with eszopiclone appears to increase the risk of such behaviors, as does the use of eszopiclone at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of eszopiclone should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.
- It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above are drug-induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
- Withdrawal Effects
- Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs.
- Timing of Drug Administration
- Eszopiclone should be taken immediately before bedtime. Taking a sedative/hypnotic while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness.
- Special Populations
- Use in Elderly and/or Debilitated Patients
Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. The dose should not exceed 2 mg in elderly or debilitated patients.
- Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. The dose should not exceed 2 mg in elderly or debilitated patients.
- Use in Patients with Concomitant Illness
Clinical experience with eszopiclone in patients with concomitant illness is limited. Eszopiclone should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
A study in healthy volunteers did not reveal respiratory-depressant effects at doses 2.5-fold higher (7 mg) than the recommended dose of eszopiclone. Caution is advised, however, if eszopiclone is prescribed to patients with compromised respiratory function.
The dose of eszopiclone should not exceed 2 mg in patients with severe hepatic impairment, because systemic exposure is doubled in such subjects. No dose adjustment appears necessary for subjects with mild or moderate hepatic impairment. No dose adjustment appears necessary in subjects with any degree of renal impairment, since less than 10% of eszopiclone is excreted unchanged in the urine.
The dose of eszopiclone should be reduced in patients who are administered potent inhibitors of CYP3A4, such as ketoconazole, while taking eszopiclone. Downward dose adjustment is also recommended when eszopiclone is administered with agents having known CNS-depressant effects.
- Clinical experience with eszopiclone in patients with concomitant illness is limited. Eszopiclone should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
- A study in healthy volunteers did not reveal respiratory-depressant effects at doses 2.5-fold higher (7 mg) than the recommended dose of eszopiclone. Caution is advised, however, if eszopiclone is prescribed to patients with compromised respiratory function.
- The dose of eszopiclone should not exceed 2 mg in patients with severe hepatic impairment, because systemic exposure is doubled in such subjects. No dose adjustment appears necessary for subjects with mild or moderate hepatic impairment. No dose adjustment appears necessary in subjects with any degree of renal impairment, since less than 10% of eszopiclone is excreted unchanged in the urine.
- The dose of eszopiclone should be reduced in patients who are administered potent inhibitors of CYP3A4, such as ketoconazole, while taking eszopiclone. Downward dose adjustment is also recommended when eszopiclone is administered with agents having known CNS-depressant effects.
- Use in Patients with Depression
Sedative/hypnotic drugs should be administered with caution to patients exhibiting signs and symptoms of depression. Suicidal tendencies may be present in such patients, and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.
- Sedative/hypnotic drugs should be administered with caution to patients exhibiting signs and symptoms of depression. Suicidal tendencies may be present in such patients, and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.
# Adverse Reactions
## Clinical Trials Experience
- Adverse Reactions Resulting in Discontinuation of Treatment
- In placebo-controlled, parallel-group clinical trials in the elderly, 3.8% of 208 patients who received placebo, 2.3% of 215 patients who received 2 mg eszopiclone, and 1.4% of 72 patients who received 1 mg eszopiclone discontinued treatment due to an adverse reaction. In the 6‑week parallel-group study in adults, no patients in the 3 mg arm discontinued because of an adverse reaction. In the long-term 6-month study in adult insomnia patients, 7.2% of 195 patients who received placebo and 12.8% of 593 patients who received 3 mg eszopiclone discontinued due to an adverse reaction. No reaction that resulted in discontinuation occurred at a rate of greater than 2%.
- Adverse Reactions Observed at an Incidence of ≥2% in Controlled Trials
- Table 1 shows the incidence of adverse reactions from a Phase 3 placebo-controlled study of eszopiclone at doses of 2 or 3 mg in non-elderly adults. Treatment duration in this trial was 44 days. The table includes only reactions that occurred in 2% or more of patients treated with eszopiclone 2 mg or 3 mg in which the incidence in patients treated with eszopiclone was greater than the incidence in placebo-treated patients.
- Adverse reactions from Table 1 that suggest a dose-response relationship in adults include viral infection, dry mouth, dizziness, hallucinations, infection, rash, and unpleasant taste, with this relationship clearest for unpleasant taste.
- Table 2 shows the incidence of adverse reactions from combined Phase 3 placebo-controlled studies of eszopiclone at doses of 1 or 2 mg in elderly adults (ages 65 to 86). Treatment duration in these trials was 14 days. The table includes only reactions that occurred in 2% or more of patients treated with eszopiclone 1 mg or 2 mg in which the incidence in patients treated with eszopiclone was greater than the incidence in placebo-treated patients.
- Adverse reactions from Table 2 that suggest a dose-response relationship in elderly adults include pain, dry mouth, and unpleasant taste, with this relationship again clearest for unpleasant taste.
- These figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice because patient characteristics and other factors may differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contributions of drug and non-drug factors to the adverse reaction incidence rate in the population studied.
- Other Reactions Observed During the Premarketing Evaluation of Eszopiclone
- Following is a list of modified COSTART terms that reflect adverse reactions as defined in the introduction to the Adverse Reactions section and reported by approximately 1550 subjects treated with eszopiclone at doses in the range of 1 to 3.5 mg/day during Phase 2 and 3 clinical trials throughout the United States and Canada. All reported reactions are included except those already listed in Tables 1 and 2 or elsewhere in labeling, minor reactions common in the general population, and reactions unlikely to be drug-related. Although the reactions reported occurred during treatment with eszopiclone, they were not necessarily caused by it.
- Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those that occurred on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those that occurred in fewer than 1/100 patients but in at least 1/1,000 patients; rare adverse reactions are those that occurred in fewer than 1/1,000 patients. Gender-specific reactions are categorized based on their incidence for the appropriate gender.
- Body as a Whole: Frequent: chest pain; Infrequent: allergic reaction, cellulitis, face edema, fever, halitosis, heat stroke, hernia, malaise, neck rigidity, photosensitivity.
- Cardiovascular System: Frequent: migraine; Infrequent: hypertension; Rare: thrombophlebitis.
- Digestive System: Infrequent: anorexia, cholelithiasis, increased appetite, melena, mouth ulceration, thirst, ulcerative stomatitis; Rare: colitis, dysphagia, gastritis, hepatitis, hepatomegaly, liver damage, stomach ulcer, stomatitis, tongue edema, rectal hemorrhage.
- Hemic and Lymphatic System: Infrequent: anemia, lymphadenopathy.
- Metabolic and Nutritional: Frequent: peripheral edema; Infrequent: hypercholesteremia, weight gain, weight loss; Rare: dehydration, gout, hyperlipemia, hypokalemia.
- Musculoskeletal System: Infrequent: arthritis, bursitis, joint disorder (mainly swelling, stiffness, and pain), leg cramps, myasthenia, twitching; Rare: arthrosis, myopathy, ptosis.
- Nervous System: Infrequent: agitation, apathy, ataxia, emotional lability, hostility, hypertonia, hypesthesia, incoordination, insomnia, memory impairment, neurosis, nystagmus, paresthesia, reflexes decreased, thinking abnormal (mainly difficulty concentrating), vertigo; Rare: abnormal gait, euphoria, hyperesthesia, hypokinesia, neuritis, neuropathy, stupor, tremor.
- Respiratory System: Infrequent: asthma, bronchitis, dyspnea, epistaxis, hiccup, laryngitis.
- Skin and Appendages: Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, skin discoloration, sweating, urticaria; Rare: erythema multiforme, furunculosis, herpes zoster, hirsutism, maculopapular rash, vesiculobullous rash.
- Special Senses: Infrequent: conjunctivitis, dry eyes, ear pain, otitis externa, otitis media, tinnitus, vestibular disorder; Rare: hyperacusis, iritis, mydriasis, photophobia.
- Urogenital System: Infrequent: amenorrhea, breast engorgement, breast enlargement, breast neoplasm, breast pain, cystitis, dysuria, female lactation, hematuria, kidney calculus, kidney pain, mastitis, menorrhagia, metrorrhagia, urinary frequency, urinary incontinence, uterine hemorrhage, vaginal hemorrhage, vaginitis; Rare: oliguria, pyelonephritis, urethritis.
## Postmarketing Experience
- In addition to the adverse reactions observed during clinical trials, dysosmia, an olfactory dysfunction that is characterized by distortion of the sense of smell, has been reported during post-marketing surveillance with eszopiclone. Because this event is reported spontaneously from a population of unknown size, it is not possible to estimate the frequency of this event.
# Drug Interactions
- CNS Active Drugs
- Ethanol: An additive effect on psychomotor performance was seen with coadministration of eszopiclone and ethanol.
- Olanzapine: Coadministration of eszopiclone and olanzapine produced a decrease in DSST scores. The interaction was pharmacodynamic; there was no alteration in the pharmacokinetics of either drug.
- Drugs that Inhibit or Induce CYP3A4
- Drugs That Inhibit CYP3A4 (Ketoconazole): CYP3A4 is a major metabolic pathway for elimination of eszopiclone. The exposure of eszopiclone was increased by coadministration of ketoconazole, a potent inhibitor of CYP3A4. Other strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, nelfinavir) would be expected to behave similarly. Dose reduction of eszopiclone is needed for patient co-administered eszopiclone with potent CYP3A4 inhibitors.
- Drugs that Induce CYP3A4 (Rifampicin): Racemic zopiclone exposure was decreased 80% by concomitant use of rifampicin, a potent inducer of CYP3A4. A similar effect would be expected with eszopiclone. Combination use with CYP3A4 inducer may decrease exposure and effects of eszopiclone
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. Eszopiclone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oral administration of eszopiclone to pregnant rats (62.5, 125, or 250 mg/kg/day) and rabbits (4, 8, or 16 mg/kg/day) throughout organogenesis showed no evidence of teratogenicity up to the highest doses tested. In rats, reduced fetal weight and increased incidences of skeletal variations and/or delayed ossification were observed at the mid and high doses. The no-observed-effect dose for adverse effects on embryofetal development is 200 times the maximum recommended human dose (MRHD) of 3 mg/day on a mg/m2 basis. No effects on embryofetal development were observed in rabbits; the highest dose tested is approximately 100 times the MRHD on a mg/m2 basis.
- Oral administration of eszopiclone (60, 120, or 180 mg/kg/day) to pregnant rats throughout the pregnancy and lactation resulted in increased post-implantation loss, decreased postnatal pup weights and survival, and increased pup startle response at all doses. The lowest dose tested is approximately 200 times the MRHD on a mg/m2 basis. Eszopiclone had no effects on other developmental measures or reproductive function in the offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eszopiclone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eszopiclone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Eszopiclone with respect to nursing mothers.
### Pediatric Use
- Safety and effectiveness have not been established in pediatric patients.
- The labeling for Sunovion Pharmaceutical Inc.’s eszopiclone tablets includes additional information from a clinical study in which efficacy was not demonstrated in pediatric patients. However, due to Sunovion Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
- In studies in which eszopiclone (2 to 300 mg/kg/day) was orally administered to young rats from weaning through sexual maturity, neurobehavioral impairment (altered auditory startle response) and reproductive toxicity (adverse effects on male reproductive organ weights and histopathology) were observed at doses ≥ 5 mg/kg/day. Delayed sexual maturation was noted in males and females at ≥ 10 mg/kg/day. The no-effect dose (2 mg/kg) was associated with plasma exposures (AUC) for eszopiclone and metabolite (S)-desmethylzopiclone [(S)-DMZ] approximately 2 times plasma exposures in humans at the maximum recommended dose (MRHD) in adults (3 mg/day).
- When eszopiclone (doses from 1 to 50 mg/kg/day) was orally administered to young dogs from weaning through sexual maturity, neurotoxicity (convulsions) was observed at doses ≥ 5 mg/kg/day. Hepatotoxicity (elevated liver enzymes and hepatocellular vacuolation and degeneration) and reproductive toxicity (adverse effects on male reproductive organ weights and histopathology) were noted at dose ≥ 10 mg/kg/day. The no-effect dose (1 mg/kg) was associated with plasma exposures (AUC) to eszopiclone and (S)-DMZ approximately 3 and 2 times, respectively, plasma exposures in humans at the MRHD in adults.
### Geriatic Use
- A total of 287 subjects in double-blind, parallel-group, placebo-controlled clinical trials who received eszopiclone were 65 to 86 years of age. The overall pattern of adverse events for elderly subjects (median age = 71 years) in 2-week studies with nighttime dosing of 2 mg eszopiclone was not different from that seen in younger adults. Eszopiclone 2 mg exhibited significant reduction in sleep latency and improvement in sleep maintenance in the elderly population. Compared with non-elderly adults, subjects 65 years and older had longer elimination and higher total exposure to eszopiclone. Therefore, dose reduction is recommended in the elderly patients.
### Gender
There is no FDA guidance on the use of Eszopiclone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eszopiclone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Eszopiclone in patients with renal impairment.
### Hepatic Impairment
- No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Exposure was increased in severely impaired patients compared with the healthy volunteers. The dose of eszopiclone should not exceed 2 mg in patients with severe hepatic impairment. Eszopiclone should be used with caution in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eszopiclone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eszopiclone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Eszopiclone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Eszopiclone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing. Impairment of consciousness ranging from somnolence to coma has been described. Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agents.
### Management
- General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Flumazenil may be useful. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. The value of dialysis in the treatment of overdosage has not been determined.
- As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Eszopiclone in the drug label.
# Pharmacology
## Mechanism of Action
- The precise mechanism of action of eszopiclone as a hypnotic is unknown, but its effect is believed to result from its interaction with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors. Eszopiclone is a nonbenzodiazepine hypnotic that is a pyrrolopyrazine derivative of the cyclopyrrolone class with a chemical structure unrelated to pyrazolopyrimidines, imidazopyridines, benzodiazepines, barbiturates, or other drugs with known hypnotic properties.
## Structure
- Eszopiclone Tablets are a nonbenzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrolone class. The chemical name of eszopiclone is (+)-(5S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazin-5-yl 4-methylpiperazine-1-carboxylate. Its molecular weight is 388.81, and its empirical formula is C17H17ClN6O3. Eszopiclone has a single chiral center with an (S)-configuration. It has the following chemical structure:
- Eszopiclone is a white to light-yellow crystalline solid. Eszopiclone is very slightly soluble in water, slightly soluble in ethanol, and soluble in phosphate buffer (pH 3.2).
- Eszopiclone is formulated as film-coated tablets for oral administration. Eszopiclone Tablets contain 1 mg, 2 mg, or 3 mg eszopiclone and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose (anhydrous), magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, titanium dioxide, and triacetin.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Eszopiclone in the drug label.
## Pharmacokinetics
- The pharmacokinetics of eszopiclone have been investigated in healthy subjects (adult and elderly) and in patients with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic profile was examined after single doses of up to 7.5 mg and after once-daily administration of 1, 3, and 6 mg for 7 days. Eszopiclone is rapidly absorbed, with a time to peak concentration (tmax) of approximately 1 hour and a terminal-phase elimination half-life (t1/2) of approximately 6 hours. In healthy adults, eszopiclone does not accumulate with once-daily administration, and its exposure is dose-proportional over the range of 1 to 6 mg.
- Absorption and Distribution
- Eszopiclone is rapidly absorbed following oral administration. Peak plasma concentrations are achieved within approximately 1 hour after oral administration. Eszopiclone is weakly bound to plasma protein (52 to 59%). The large free fraction suggests that eszopiclone disposition should not be affected by drug-drug interactions caused by protein binding. The blood-to-plasma ratio for eszopiclone is less than one, indicating no selective uptake by red blood cells.
- Metabolism
- Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes.
- Elimination
- After oral administration, eszopiclone is eliminated with a mean t1/2 of approximately 6 hours. Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites. A similar excretion profile would be expected for eszopiclone, the S-isomer of racemic zopiclone. Less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug.
- Effect of Food
- In healthy adults, administration of a 3 mg dose of eszopiclone after a high-fat meal resulted in no change in AUC, a reduction in mean Cmax of 21%, and delayed tmax by approximately 1 hour. The half-life remained unchanged, approximately 6 hours. The effects of eszopiclone on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal.
- Specific Populations
- Age
- Compared with non-elderly adults, subjects 65 years and older had an increase of 41% in total exposure (AUC) and a slightly prolonged elimination of eszopiclone (t1/2 approximately 9 hours). Cmax was unchanged. Therefore, in elderly patients the dose should not exceed 2 mg.
- Gender
- The pharmacokinetics of eszopiclone in men and women are similar.
- Race
- In an analysis of data on all subjects participating in Phase 1 studies of eszopiclone, the pharmacokinetics for all races studied appeared similar.
- Hepatic Impairment
- Pharmacokinetics of a 2 mg eszopiclone dose were assessed in 16 healthy volunteers and in 8 subjects with mild, moderate, and severe liver disease. Exposure was increased 2-fold in severely impaired patients compared with the healthy volunteers. Cmax and tmax were unchanged. No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Dose reduction is recommended for patients with severe hepatic impairment. Eszopiclone should be used with caution in patients with hepatic impairment.
- Renal Impairment
- The pharmacokinetics of eszopiclone were studied in 24 patients with mild, moderate, or severe renal impairment. AUC and Cmax were similar in the patients compared with demographically matched healthy control subjects. No dose adjustment is necessary in patients with renal impairment, since less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug.
- Drug Interactions
- Eszopiclone is metabolized by CYP3A4 and CYP2E1 via demethylation and oxidation. There were no pharmacokinetic or pharmacodynamic interactions between eszopiclone and paroxetine. When eszopiclone was coadministered with olanzapine, no pharmacokinetic interaction was detected in levels of eszopiclone or olanzapine, but a pharmacodynamic interaction was seen on a measure of psychomotor function. Eszopiclone and lorazepam decreased each other’s Cmax by 22%. Coadministration of eszopiclone 3 mg to subjects receiving ketoconazole, a potent inhibitor of CYP3A4, 400 mg daily for 5 days, resulted in a 2.2-fold increase in exposure to eszopiclone. Cmax and t1/2 were increased 1.4-fold and 1.3-fold, respectively. Eszopiclone would not be expected to alter the clearance of drugs metabolized by common CYP450 enzymes.
- Paroxetine
- Coadministration of single dose of eszopiclone and paroxetine produced no pharmacokinetic or pharmacodynamic interaction. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.
- Lorazepam
- Coadministration of single doses of eszopiclone and lorazepam did not have clinically relevant effects on the pharmacodynamics or pharmacokinetics of either drug. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.
- Drugs with a Narrow Therapeutic Index
- Digoxin
- A single dose of eszopiclone 3 mg did not affect the pharmacokinetics of digoxin measured at steady state following dosing of 0.5 mg twice daily for one day and 0.25 mg daily for the next 6 days.
- Warfarin
- Eszopiclone 3 mg administered daily for 5 days did not affect the pharmacokinetics of (R)- or (S)-warfarin, nor were there any changes in the pharmacodynamic profile (prothrombin time) following a single 25 mg oral dose of warfarin.
- Drugs Highly Bound to Plasma Protein
- Eszopiclone is not highly bound to plasma proteins (52 to 59% bound); therefore, the disposition of eszopiclone is not expected to be sensitive to alterations in protein binding. Administration of eszopiclone 3 mg to a patient taking another drug that is highly protein-bound would not be expected to cause an alteration in the free concentration of either drug.
## Nonclinical Toxicology
- Carcinogenesis
- In a carcinogenicity study in rats, oral administration of eszopiclone for 97 (males) or 104 (females) weeks resulted in no increases in tumors; plasma levels (AUC) of eszopiclone at the highest dose tested (16 mg/kg/day) are approximately 80 (females) and 20 (males) times those in humans at the maximum recommended human dose (MRHD) of 3 mg/day. However, in a 2-year carcinogenicity study in rats, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) resulted in increases in mammary gland adenocarcinomas (females) and thyroid gland follicular cell adenomas and carcinomas (males) at the highest dose tested. Plasma levels of eszopiclone at this dose are approximately 150 (females) and 70 (males) times those in humans at the MRHD of eszopiclone. The mechanism for the increase in mammary adenocarcinomas is unknown. The increase in thyroid tumors is thought to be due to increased levels of TSH secondary to increased metabolism of circulating thyroid hormones, a mechanism not considered relevant to humans.
- In a 2-year carcinogenicity study in mice, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) produced increases in pulmonary carcinomas and carcinomas plus adenomas (females) and skin fibromas and sarcomas (males) at the highest dose tested. The skin tumors were due to skin lesions induced by aggressive behavior, a mechanism not relevant to humans. A carcinogenicity study of eszopiclone was conducted in mice at oral doses up to 100 mg/kg/day. Although this study did not reach a maximum tolerated dose, and was thus inadequate for overall assessment of carcinogenic potential, no increases in either pulmonary or skin tumors were seen at doses producing plasma levels of eszopiclone approximately 90 times those in humans at the MRHD of eszopiclone (and 12 times the exposure in the racemate study).
- Eszopiclone did not increase tumors in a p53 transgenic mouse bioassay at oral doses up to 300 mg/kg/day.
- Mutagenesis
- Eszopiclone was clastogenic in in vitro (mouse lymphoma and chromosomal aberration) assays in mammalian cells. Eszopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo micronucleus assay.
- (S)-N-desmethyl zopiclone, a metabolite of eszopiclone, was positive in in vitro chromosomal aberration assays in mammalian cells. (S)-N-desmethyl zopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo chromosomal aberration and micronucleus assay.
- Impairment of Fertility
- Oral administration of eszopiclone to rats prior to and during mating, and continuing in females to day 7 of gestation (doses up to 45 mg/kg/day to males and females or up to 180 mg/kg/day to females only) resulted in decreased fertility, with no pregnancy at the highest dose tested when both males and females were treated. In females, there was an increase in abnormal estrus cycles at the highest dose tested. In males, decreases in sperm number and motility and increases in morphologically abnormal sperm were observed at the mid and high doses. The no-effect dose for adverse effects on fertility (5 mg/kg/day) is 16 times the MRHD on a mg/m2 basis.
# Clinical Studies
- The effect of eszopiclone on reducing sleep latency and improving sleep maintenance was established in studies with 2100 subjects (ages 18 to 86) with chronic and transient insomnia in six placebo-controlled trials of up to 6 months’ duration. Two of these trials were in elderly patients (n=523). Overall, at the recommended adult dose (2 to 3 mg) and elderly dose (1 to 2 mg), eszopiclone significantly decreased sleep latency and improved measures of sleep maintenance (objectively measured as wake time after sleep onset [WASO] and subjectively measured as total sleep time).
- Transient Insomnia
- Healthy adults were evaluated in a model of transient insomnia (n=436) in a sleep laboratory in a double-blind, parallel-group, single-night trial comparing two doses of eszopiclone and placebo. Eszopiclone 3 mg was superior to placebo on measures of sleep latency and sleep maintenance, including polysomnographic (PSG) parameters of latency to persistent sleep (LPS) and WASO.
- Chronic Insomnia (Adults and Elderly)
- The effectiveness of eszopiclone was established in five controlled studies in chronic insomnia. Three controlled studies were in adult subjects, and two controlled studies were in elderly subjects with chronic insomnia.
- Adults
In the first study, adults with chronic insomnia (n=308) were evaluated in a double-blind, parallel-group trial of 6 weeks’ duration comparing eszopiclone 2 mg and 3 mg with placebo. Objective endpoints were measured for 4 weeks. Both 2 mg and 3 mg were superior to placebo on LPS at 4 weeks. The 3 mg dose was superior to placebo on WASO.
In the second study, adults with chronic insomnia (n=788) were evaluated using subjective measures in a double-blind, parallel-group trial comparing the safety and efficacy of eszopiclone 3 mg with placebo administered nightly for 6 months. Eszopiclone was superior to placebo on subjective measures of sleep latency, total sleep time, and WASO.
In addition, a 6-period cross-over PSG study evaluating eszopiclone doses of 1 to 3 mg, each given over a 2-day period, demonstrated effectiveness of all doses on LPS, and of 3 mg on WASO. In this trial, the response was dose-related.
- In the first study, adults with chronic insomnia (n=308) were evaluated in a double-blind, parallel-group trial of 6 weeks’ duration comparing eszopiclone 2 mg and 3 mg with placebo. Objective endpoints were measured for 4 weeks. Both 2 mg and 3 mg were superior to placebo on LPS at 4 weeks. The 3 mg dose was superior to placebo on WASO.
- In the second study, adults with chronic insomnia (n=788) were evaluated using subjective measures in a double-blind, parallel-group trial comparing the safety and efficacy of eszopiclone 3 mg with placebo administered nightly for 6 months. Eszopiclone was superior to placebo on subjective measures of sleep latency, total sleep time, and WASO.
- In addition, a 6-period cross-over PSG study evaluating eszopiclone doses of 1 to 3 mg, each given over a 2-day period, demonstrated effectiveness of all doses on LPS, and of 3 mg on WASO. In this trial, the response was dose-related.
- Elderly
Elderly subjects (ages 65 to 86) with chronic insomnia were evaluated in two double-blind, parallel-group trials of 2 weeks duration. One study (n=231) compared the effects of eszopiclone with placebo on subjective outcome measures, and the other (n=292) on objective and subjective outcome measures. The first study compared 1 mg and 2 mg of eszopiclone with placebo, while the second study compared 2 mg of eszopiclone with placebo. All doses were superior to placebo on measures of sleep latency. In both studies, 2 mg of eszopiclone was superior to placebo on measures of sleep maintenance.
- Elderly subjects (ages 65 to 86) with chronic insomnia were evaluated in two double-blind, parallel-group trials of 2 weeks duration. One study (n=231) compared the effects of eszopiclone with placebo on subjective outcome measures, and the other (n=292) on objective and subjective outcome measures. The first study compared 1 mg and 2 mg of eszopiclone with placebo, while the second study compared 2 mg of eszopiclone with placebo. All doses were superior to placebo on measures of sleep latency. In both studies, 2 mg of eszopiclone was superior to placebo on measures of sleep maintenance.
- Studies Pertinent to Safety Concerns for Sedative Hypnotic Drugs
- Next Day Residual Effects
In a double-blind study of 91 healthy adults age 25- to 40 years, the effects of eszopiclone 3 mg on psychomotor function were assessed between 7.5 and 11.5 hours the morning after dosing. Measures included tests of psychomotor coordination that are correlated with ability to maintain a motor vehicle in the driving lane, tests of working memory, and subjective perception of sedation and coordination. Compared with placebo, eszopiclone 3 mg was associated with next- morning psychomotor and memory impairment that was most severe at 7.5 hours, but still present and potentially clinically meaningful at 11.5 hours. Subjective perception of sedation and coordination from eszopiclone 3 mg was not consistently different from placebo, even though subjects were objectively impaired.
In a 6-month double-blind, placebo-controlled trial of nightly administered eszopiclone 3 mg, memory impairment was reported by 1.3% (8/593) of subjects treated with eszopiclone 3 mg compared to 0% (0/195) of subjects treated with placebo. In a 6-week adult study of nightly administered eszopiclone confusion was reported by 3% of patients treated with eszopiclone 3 mg, compared to 0% of subjects treated with placebo. In the same study, memory impairment was reported by 1% of patents treated with either 2 mg or 3 mg eszopiclone, compared to 0% treated with placebo.
In a 2-week study of 264 elderly insomniacs, 1.5% of patients treated with eszopiclone 2 mg reported memory impairment compared to 0% treated with placebo. In another 2-week study of 231 elderly insomniacs, 2.5% of patients treated with eszopiclone 2 mg reported confusion compared to 0% treated with placebo.
A study of normal subjects exposed to single fixed doses of eszopiclone from 1 to 7.5 mg using the DSST to assess sedation and psychomotor function at fixed times after dosing (hourly up to 16 hours) found the expected sedation and reduction in psychomotor function. This was maximal at 1 hour and present up to 4 hours, but was no longer present by 5 hours.
In another study, patients with insomnia were given 2 or 3 mg doses of eszopiclone nightly, with DSST assessed on the mornings following days 1, 15, and 29 of treatment. While both the placebo and eszopiclone 3 mg groups showed an improvement in DSST scores relative to baseline the following morning (presumably due to a learning effect), the improvement in the placebo group was greater and reached statistical significance on night 1, although not on nights 15 and 29. For the eszopiclone 2 mg group, DSST change scores were not significantly different from placebo at any time point.
- In a double-blind study of 91 healthy adults age 25- to 40 years, the effects of eszopiclone 3 mg on psychomotor function were assessed between 7.5 and 11.5 hours the morning after dosing. Measures included tests of psychomotor coordination that are correlated with ability to maintain a motor vehicle in the driving lane, tests of working memory, and subjective perception of sedation and coordination. Compared with placebo, eszopiclone 3 mg was associated with next- morning psychomotor and memory impairment that was most severe at 7.5 hours, but still present and potentially clinically meaningful at 11.5 hours. Subjective perception of sedation and coordination from eszopiclone 3 mg was not consistently different from placebo, even though subjects were objectively impaired.
- In a 6-month double-blind, placebo-controlled trial of nightly administered eszopiclone 3 mg, memory impairment was reported by 1.3% (8/593) of subjects treated with eszopiclone 3 mg compared to 0% (0/195) of subjects treated with placebo. In a 6-week adult study of nightly administered eszopiclone confusion was reported by 3% of patients treated with eszopiclone 3 mg, compared to 0% of subjects treated with placebo. In the same study, memory impairment was reported by 1% of patents treated with either 2 mg or 3 mg eszopiclone, compared to 0% treated with placebo.
- In a 2-week study of 264 elderly insomniacs, 1.5% of patients treated with eszopiclone 2 mg reported memory impairment compared to 0% treated with placebo. In another 2-week study of 231 elderly insomniacs, 2.5% of patients treated with eszopiclone 2 mg reported confusion compared to 0% treated with placebo.
- A study of normal subjects exposed to single fixed doses of eszopiclone from 1 to 7.5 mg using the DSST to assess sedation and psychomotor function at fixed times after dosing (hourly up to 16 hours) found the expected sedation and reduction in psychomotor function. This was maximal at 1 hour and present up to 4 hours, but was no longer present by 5 hours.
- In another study, patients with insomnia were given 2 or 3 mg doses of eszopiclone nightly, with DSST assessed on the mornings following days 1, 15, and 29 of treatment. While both the placebo and eszopiclone 3 mg groups showed an improvement in DSST scores relative to baseline the following morning (presumably due to a learning effect), the improvement in the placebo group was greater and reached statistical significance on night 1, although not on nights 15 and 29. For the eszopiclone 2 mg group, DSST change scores were not significantly different from placebo at any time point.
- Withdrawal-Emergent Anxiety and Insomnia
During nightly use for an extended period, pharmacodynamic tolerance or adaptation has been observed with other hypnotics. If a drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night’s use. This is believed to be responsible for two clinical findings reported to occur after several weeks of nightly use of other rapidly eliminated hypnotics: increased wakefulness during the last quarter of the night and the appearance of increased signs of daytime anxiety.
In a 6-month double-blind, placebo-controlled study of nightly administration of eszopiclone 3 mg, rates of anxiety reported as an adverse event were 2.1% in the placebo arm and 3.7% in the eszopiclone arm. In a 6-week adult study of nightly administration, anxiety was reported as an adverse event in 0%, 2.9%, and 1% of the placebo, 2 mg, and 3 mg treatment arms, respectively. In this study, single-blind placebo was administered on nights 45 and 46, the first and second days of withdrawal from study drug. New adverse events were recorded during the withdrawal period, beginning with day 45, up to 14 days after discontinuation. During this withdrawal period, 105 subjects previously taking nightly eszopiclone 3 mg for 44 nights spontaneously reported anxiety (1%), abnormal dreams (1.9%), hyperesthesia (1%), and neurosis (1%), while none of 99 subjects previously taking placebo reported any of these adverse events during the withdrawal period.
Rebound insomnia, defined as a dose-dependent temporary worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. Rebound insomnia following discontinuation of eszopiclone relative to placebo and baseline was examined objectively in a 6-week adult study on the first 2 nights of discontinuation (nights 45 and 46) following 44 nights of active treatment with 2 mg or 3 mg. In the eszopiclone 2 mg group, compared with baseline, there was a significant increase in WASO and a decrease in sleep efficiency, both occurring only on the first night after discontinuation of treatment. No changes from baseline were noted in the eszopiclone 3 mg group on the first night after discontinuation, and there was a significant improvement in LPS and sleep efficiency compared with baseline following the second night of discontinuation. Comparisons of changes from baseline between eszopiclone and placebo were also performed. On the first night after discontinuation of eszopiclone 2 mg, LPS and WASO were significantly increased and sleep efficiency was reduced; there were no significant differences on the second night. On the first night following discontinuation of eszopiclone 3 mg, sleep efficiency was significantly reduced. No other differences from placebo were noted in any other sleep parameter on either the first or second night following discontinuation. For both doses, the discontinuation-emergent effect was mild, had the characteristics of the return of the symptoms of chronic insomnia, and appeared to resolve by the second night after eszopiclone discontinuation.
- During nightly use for an extended period, pharmacodynamic tolerance or adaptation has been observed with other hypnotics. If a drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night’s use. This is believed to be responsible for two clinical findings reported to occur after several weeks of nightly use of other rapidly eliminated hypnotics: increased wakefulness during the last quarter of the night and the appearance of increased signs of daytime anxiety.
- In a 6-month double-blind, placebo-controlled study of nightly administration of eszopiclone 3 mg, rates of anxiety reported as an adverse event were 2.1% in the placebo arm and 3.7% in the eszopiclone arm. In a 6-week adult study of nightly administration, anxiety was reported as an adverse event in 0%, 2.9%, and 1% of the placebo, 2 mg, and 3 mg treatment arms, respectively. In this study, single-blind placebo was administered on nights 45 and 46, the first and second days of withdrawal from study drug. New adverse events were recorded during the withdrawal period, beginning with day 45, up to 14 days after discontinuation. During this withdrawal period, 105 subjects previously taking nightly eszopiclone 3 mg for 44 nights spontaneously reported anxiety (1%), abnormal dreams (1.9%), hyperesthesia (1%), and neurosis (1%), while none of 99 subjects previously taking placebo reported any of these adverse events during the withdrawal period.
- Rebound insomnia, defined as a dose-dependent temporary worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. Rebound insomnia following discontinuation of eszopiclone relative to placebo and baseline was examined objectively in a 6-week adult study on the first 2 nights of discontinuation (nights 45 and 46) following 44 nights of active treatment with 2 mg or 3 mg. In the eszopiclone 2 mg group, compared with baseline, there was a significant increase in WASO and a decrease in sleep efficiency, both occurring only on the first night after discontinuation of treatment. No changes from baseline were noted in the eszopiclone 3 mg group on the first night after discontinuation, and there was a significant improvement in LPS and sleep efficiency compared with baseline following the second night of discontinuation. Comparisons of changes from baseline between eszopiclone and placebo were also performed. On the first night after discontinuation of eszopiclone 2 mg, LPS and WASO were significantly increased and sleep efficiency was reduced; there were no significant differences on the second night. On the first night following discontinuation of eszopiclone 3 mg, sleep efficiency was significantly reduced. No other differences from placebo were noted in any other sleep parameter on either the first or second night following discontinuation. For both doses, the discontinuation-emergent effect was mild, had the characteristics of the return of the symptoms of chronic insomnia, and appeared to resolve by the second night after eszopiclone discontinuation.
# How Supplied
- Eszopiclone tablets are round, white, film-coated tablets and are supplied as follows:
- The 1 mg tablets are debossed with product identification “54 746” on one side and plain on the other side.
- NDC 0054-0290-13 1 mg, bottle of 30
- NDC 0054-0290-25 1 mg, bottle of 100
- The 2 mg tablets are debossed with product identification “54 029” on one side and plain on the other side.
- NDC 0054-0291-25 2 mg, bottle of 100
- The 3 mg tablets are debossed with product identification “54 396” on one side and plain on the other side.
- NDC 0054-0292-25 3 mg, bottle of 100
- Storage
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
## Storage
There is limited information regarding Eszopiclone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients and their families about the benefits and risks of treatment with eszopiclone. Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with eszopiclone and with each prescription refill. Review the eszopiclone Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that eszopiclone should be taken only as prescribed.
- CNS depressant effects and next-day impairment: Tell patients that eszopiclone can cause next-day impairment even when used as prescribed, and that this risk is increased if dosing instructions are not carefully followed. Caution patients taking the 3 mg dose against driving and other activities requiring complete mental alertness the day after use. Inform patients that impairment can be present despite feeling fully awake.
- Severe anaphylactic and anaphylactoid reactions: Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with eszopiclone. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur.
- “Sleep-Driving” and other complex behaviors: Instruct patients and their families that sedative hypnotics can cause abnormal thinking and behavior change, including "sleep driving" and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you immediately if they develop any of these symptoms.
- Suicide: Tell patients to immediately report any suicidal thoughts.
- Alcohol and Other Drugs: Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use eszopiclone if they drank alcohol that evening or before bed.
- Tolerance, Abuse, and Dependence: Tell patients not to increase the dose of eszopiclone on their own, and to inform you if they believe the drug "does not work".
- Administration Instructions: Patients should be counseled to take eszopiclone right before they get into bed and only when they are able to stay in bed a full night (7–8 hours) before being active again. Eszopiclone tablets should not be taken with or immediately after a meal. Advise patients NOT to take eszopiclone if they drank alcohol that evening.
# Precautions with Alcohol
- Advise patients not to use eszopiclone if they drank alcohol that evening or before bed.
# Brand Names
- Lunesta[6]
# Look-Alike Drug Names
- Lunesta® — Neulasta®[7]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Eszopiclone | |
54e5b468c10f8489eecba08d9e7ff9ef93a8b8fc | wikidoc | Ethanethiol | Ethanethiol
Ethanethiol, commonly known as ethyl mercaptan is the organic compound with the formula CH3CH2SH. It consists of an ethyl group, CH3CH2, attached to a thiol group, SH. The compound is structurally similar to ethanol by replacement of O by S. This change leads to many different properties, the most infamous of which is the strong odour of EtSH. Ethanethiol is also more volatile than ethanol due to its diminished ability to engage in hydrogen bonding. Ethanethiol is toxic. It occurs naturally as a minor component of petroleum, and may be added to liquefied petroleum gas (LPG) to warn of a gas leak. At these concentrations, ethanethiol is not harmful.
# Odour
Ethanethiol has a strongly disagreeable odour that humans can detect in minute concentrations. The threshold for human detection is as low as one part in 2.8 billion parts of air. Its odour resembles that of leeks. Ethanethiol is intentionally added to butane and propane (see: LPG) to impart an easily noticed smell to these odourless fuels, that otherwise pose the threat of fire and explosion.
According to the 2000 edition of the Guinness Book Of World Records, ethanethiol is the "smelliest substance" in existence. Other more specialized chemicals were probably not examined, however. Most volatile thiols are comparably offensive. Thiols can be oxidized, and thus de-odourized, using bleach or related oxidants.
# Reactions
Ethanethiol is a valued reagent in organic synthesis. In the presence of sodium hydroxide, it forms the powerful nucleophile NaSEt. The salt can also be generated quantitatively by reaction with sodium hydride.
Oxidation of EtSH gives the disulfide, diethyl disulfide:
Like other thiols, it behaves comparably to hydrogen sulfide. For example, it binds, concomitant with deprotonation to "soft" transition metal cations, such a Hg2+, Cu+, and Ni2+ to give polymeric thiolato complexes, Hg(SEt)2, CuSEt, and Ni(SEt)2, respectively. | Ethanethiol
Template:Chembox new
Ethanethiol, commonly known as ethyl mercaptan is the organic compound with the formula CH3CH2SH. It consists of an ethyl group, CH3CH2, attached to a thiol group, SH. The compound is structurally similar to ethanol by replacement of O by S. This change leads to many different properties, the most infamous of which is the strong odour of EtSH. Ethanethiol is also more volatile than ethanol due to its diminished ability to engage in hydrogen bonding. Ethanethiol is toxic. It occurs naturally as a minor component of petroleum, and may be added to liquefied petroleum gas (LPG) to warn of a gas leak. At these concentrations, ethanethiol is not harmful.
# Odour
Ethanethiol has a strongly disagreeable odour that humans can detect in minute concentrations. The threshold for human detection is as low as one part in 2.8 billion parts of air. Its odour resembles that of leeks. Ethanethiol is intentionally added to butane and propane (see: LPG) to impart an easily noticed smell to these odourless fuels, that otherwise pose the threat of fire and explosion.
According to the 2000 edition of the Guinness Book Of World Records, ethanethiol is the "smelliest substance" in existence. Other more specialized chemicals were probably not examined, however. Most volatile thiols are comparably offensive. Thiols can be oxidized, and thus de-odourized, using bleach or related oxidants.
# Reactions
Ethanethiol is a valued reagent in organic synthesis. In the presence of sodium hydroxide, it forms the powerful nucleophile NaSEt. The salt can also be generated quantitatively by reaction with sodium hydride.[1]
Oxidation of EtSH gives the disulfide, diethyl disulfide:
Like other thiols, it behaves comparably to hydrogen sulfide. For example, it binds, concomitant with deprotonation to "soft" transition metal cations, such a Hg2+, Cu+, and Ni2+ to give polymeric thiolato complexes, Hg(SEt)2, CuSEt, and Ni(SEt)2, respectively. | https://www.wikidoc.org/index.php/Ethanethiol | |
c5c8636db4d283eeab47d753e8f65cc751616f60 | wikidoc | Ether lipid | Ether lipid
Ether lipids are lipids in which one or more of the carbon atoms on glycerol is bonded to an alkyl chain via an ether linkage, as opposed to the usual ester linkage.
# Types
Ether lipids are called plasmalogens (1-O-1'-alkenyl-2-acylglycerophospholipids) if these are glycerol-containing phospholipids with an unsaturated O-(1-alkenyl) (vinyl ether) group at the first position on the glycerol chain.
Platelet-activating factor is an ether lipid which has an acetyl group instead of an acyl chain at the second position (SN-2).
# Biosynthesis
The formation of the ether bond in mammals requires two enzymes, dihydoxyacetonephosphate acyltransferase (DHAPAT) and alkyldihydroxyacetonephosphate synthase (ADAPS), that reside in the peroxisome. Accordingly, peroxisomal defects often lead to impairment of ether-lipid production.
# Functions
## Structural
Plasmalogens as well as some 1-O-alkyl lipids are ubiquitous and sometimes major parts of the cell membranes in mammals and anaerobic bacteria. In archaea, ether lipids are the major polar lipids in the cell envelope and their abundance is one of the major characteristics that separate this group of prokaryotes from the bacteria. In these cells, diphytanylglycerolipids or bipolar macrocyclic tetraethers can form covalently linked 'bilayers'.
## Second messenger
Differences between the catabolism of ether glycerophospholipids by specific phospholipases enzymes might be involved in the generation of lipid second messenger systems such as prostaglandins and arachidonic acid that are important in signal transduction. Ether lipids can also act directly in cell signaling, as the platelet-activating factor is an ether lipid signaling molecule that is involved in leukocyte function in the mammalian immune system.
## Antioxidant
Another possible function of the plasmalogen ether lipids is as antioxidants, as protective effects against oxidative stress have been demonstrated in cell culture and these lipids might therefore play a role in serum lipoprotein metabolism. This antioxidant activity comes from the enol ether double bond being targeted by a variety of reactive oxygen species.
# Synthetic ether lipid analogs
Synthetic ether lipid analogs have cytostatic and cytotoxic properties, probably by disrupting membrane structure and acting as inhibitors of enzymes within signal transmission pathways, such as protein kinase C and phospholipase C.
A toxic ether lipid analogue miltefosine has recently been introduced as an oral treatment for the tropical disease leishmaniasis, which is caused by leishmania, a protozoal parasite with a particularly high ether lipid content in its membranes. | Ether lipid
Ether lipids are lipids in which one or more of the carbon atoms on glycerol is bonded to an alkyl chain via an ether linkage, as opposed to the usual ester linkage.
# Types
Ether lipids are called plasmalogens (1-O-1'-alkenyl-2-acylglycerophospholipids) if these are glycerol-containing phospholipids with an unsaturated O-(1-alkenyl) (vinyl ether) group at the first position on the glycerol chain.
Platelet-activating factor is an ether lipid which has an acetyl group instead of an acyl chain at the second position (SN-2).
# Biosynthesis
The formation of the ether bond in mammals requires two enzymes, dihydoxyacetonephosphate acyltransferase (DHAPAT) and alkyldihydroxyacetonephosphate synthase (ADAPS), that reside in the peroxisome. [1] Accordingly, peroxisomal defects often lead to impairment of ether-lipid production.
# Functions
## Structural
Plasmalogens as well as some 1-O-alkyl lipids are ubiquitous and sometimes major parts of the cell membranes in mammals and anaerobic bacteria.[2] In archaea, ether lipids are the major polar lipids in the cell envelope and their abundance is one of the major characteristics that separate this group of prokaryotes from the bacteria. In these cells, diphytanylglycerolipids or bipolar macrocyclic tetraethers can form covalently linked 'bilayers'.[3]
## Second messenger
Differences between the catabolism of ether glycerophospholipids by specific phospholipases enzymes might be involved in the generation of lipid second messenger systems such as prostaglandins and arachidonic acid that are important in signal transduction.[4] Ether lipids can also act directly in cell signaling, as the platelet-activating factor is an ether lipid signaling molecule that is involved in leukocyte function in the mammalian immune system.[5]
## Antioxidant
Another possible function of the plasmalogen ether lipids is as antioxidants, as protective effects against oxidative stress have been demonstrated in cell culture and these lipids might therefore play a role in serum lipoprotein metabolism.[6] This antioxidant activity comes from the enol ether double bond being targeted by a variety of reactive oxygen species.[7]
# Synthetic ether lipid analogs
Synthetic ether lipid analogs have cytostatic and cytotoxic properties, probably by disrupting membrane structure and acting as inhibitors of enzymes within signal transmission pathways, such as protein kinase C and phospholipase C.
A toxic ether lipid analogue miltefosine has recently been introduced as an oral treatment for the tropical disease leishmaniasis, which is caused by leishmania, a protozoal parasite with a particularly high ether lipid content in its membranes.[8] | https://www.wikidoc.org/index.php/Ether_lipid | |
185ba06f7d2b3d0d1024d6eb373c8649c9b70bf5 | wikidoc | Ethionamide | Ethionamide
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Ethionamide is an antitubercular that is FDA approved for the treatment of tuberculosis. Common adverse reactions include abdominal pain, diarrhea, metallic taste, nausea, stomatitis, vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Trecator is primarily indicated for the treatment of active tuberculosis in patients with M. tuberculosis resistant to isoniazid or rifampin, or when there is intolerance on the part of the patient to other drugs. Its use alone in the treatment of tuberculosis results in the rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility tests. If the susceptibility tests indicate that the patient's organism is resistant to one of the first-line antituberculosis drugs (i.e., isoniazid or rifampin) yet susceptible to ethionamide, ethionamide should be accompanied by at least one drug to which the M. tuberculosis isolate is known to be susceptible.3 If the tuberculosis is resistant to both isoniazid and rifampin, yet susceptible to ethionamide, ethionamide should be accompanied by at least two other drugs to which the M. tuberculosis isolate is known to be susceptible.3
- Patient nonadherence to prescribed treatment can result in treatment failure and in the development of drug-resistant tuberculosis, which can be life-threatening and lead to other serious health risks. It is, therefore, essential that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended for all patients receiving treatment for tuberculosis. Patients in whom drug-resistant M. tuberculosis organisms are isolated should be managed in consultation with an expert in the treatment of drug-resistant tuberculosis.
# Dosage
In the treatment of tuberculosis, a major cause of the emergence of drug-resistant organisms, and thus treatment failure, is patient nonadherence to prescribed treatment. Treatment failure and drug-resistant organisms can be life-threatening and may result in other serious health risks. It is, therefore, important that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended when patients are receiving treatment for tuberculosis. Consultation with an expert in the treatment of drug-resistant tuberculosis is advised for patients in whom drug-resistant tuberculosis is suspected or likely. Ethionamide should be administered with at least one, sometimes two, other drugs to which the organism is known to be susceptible (see INDICATIONS AND USAGE).
- Trecator is administered orally. The usual adult dose is 15 to 20 mg/kg/day, administered once daily or, if patient exhibits poor gastrointestinal tolerance, in divided doses, with a maximum daily dosage of 1 gram.
- Trecator tablets have been reformulated from a sugar-coated tablet to a film-coated tablet. Patients should be monitored and have their dosage retitrated when switching from the sugar-coated tablet to the film-coated tablet.
- Therapy should be initiated at a dose of 250 mg daily, with gradual titration to optimal doses as tolerated by the patient. A regimen of 250 mg daily for 1 or 2 days, followed by 250 mg twice daily for 1 or 2 days with a subsequent increase to 1 gm in 3 or 4 divided doses has been reported.4,5 Thus far, there is insufficient evidence to indicate the lowest effective dosage levels. Therefore, in order to minimize the risk of resistance developing to the drug or to the companion drug, the principle of giving the highest tolerated dose (based on gastrointestinal intolerance) has been followed. In the adult this would seem to be between 0.5 and 1.0 gm daily, with an average of 0.75 gm daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethionamide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethionamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications For Pediatric,12 Yrs And older
- Trecator is primarily indicated for the treatment of active tuberculosis in patients with M. tuberculosis resistant to isoniazid or rifampin, or when there is intolerance on the part of the patient to other drugs. Its use alone in the treatment of tuberculosis results in the rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility tests. If the susceptibility tests indicate that the patient's organism is resistant to one of the first-line antituberculosis drugs (i.e., isoniazid or rifampin) yet susceptible to ethionamide, ethionamide should be accompanied by at least one drug to which the M. tuberculosis isolate is known to be susceptible.3 If the tuberculosis is resistant to both isoniazid and rifampin, yet susceptible to ethionamide, ethionamide should be accompanied by at least two other drugs to which the M. tuberculosis isolate is known to be susceptible.3
- Patient nonadherence to prescribed treatment can result in treatment failure and in the development of drug-resistant tuberculosis, which can be life-threatening and lead to other serious health risks. It is, therefore, essential that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended for all patients receiving treatment for tuberculosis. Patients in whom drug-resistant M. tuberculosis organisms are isolated should be managed in consultation with an expert in the treatment of drug-resistant tuberculosis.
# Dosage For Pediatrics 12 Yrs And Older
The optimum dosage for pediatric patients has not been established. However, pediatric dosages of 10 to 20 mg/kg p.o. daily in 2 or 3 divided doses given after meals or 15 mg/kg/24 hrs as a single daily dose have been recommended.1,2 As with adults, ethionamide may be administered to pediatric patients once daily. It should be noted that in patients with concomitant tuberculosis and HIV infection, malabsorption syndrome may be present. Drug malabsorption should be suspected in patients who adhere to therapy, but who fail to respond appropriately. In such cases, consideration should be given to therapeutic drug monitoring.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethionamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethionamide in pediatric patients.
# Contraindications
- Ethionamide is contraindicated in patients with severe hepatic impairment and in patients who are hypersensitive to the drug.
# Warnings
- The use of Trecator alone in the treatment of tuberculosis results in rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility testing. However, therapy may be initiated prior to receiving the results of susceptibility tests as deemed appropriate by the physician. Ethionamide should be administered with at least one, sometimes two, other drugs to which the organism is known to be susceptible. Drugs which have been used as companion agents are rifampin, ethambutol, pyrazinamide, cycloserine, kanamycin, streptomycin, and isoniazid. The usual warnings, precautions, and dosage regimens for these companion drugs should be observed.
- Patient compliance is essential to the success of the antituberculosis therapy and to prevent the emergence of drug-resistant organisms. Therefore, patients should adhere to the drug regimen for the full duration of treatment. It is recommended that directly observed therapy be practiced when patients are receiving antituberculous medication. Additional consultation from experts in the treatment of drug-resistant tuberculosis is recommended when patients develop drug-resistant organisms.
# Adverse Reactions
## Clinical Trials Experience
Gastrointestinal: The most common side effects of ethionamide are gastrointestinal disturbances including nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia and weight loss. Adverse gastrointestinal effects appear to be dose related, with approximately 50% of patients unable to tolerate 1 gm as a single dose. Gastrointestinal effects may be minimized by decreasing dosage, by changing the time of drug administration, or by the concurrent administration of an antiemetic agent.
Nervous System: Psychotic disturbances (including mental depression), drowsiness, dizziness, restlessness, headache, and postural hypotension have been reported with ethionamide. Rare reports of peripheral neuritis, optic neuritis, diplopia, blurred vision, and a pellagra-like syndrome also have been reported. Concurrent administration of pyridoxine has been recommended to prevent or relieve neurotoxic effects.
Hepatic: Transient increases in serum bilirubin, SGOT, SGPT; Hepatitis (with or without jaundice).
Other: Hypersensitivity reactions including rash, photosensitivity, thrombocytopenia and purpura have been reported rarely. Hypoglycemia, hypothyroidism, gynecomastia, impotence, and acne also have occurred. The management of patients with diabetes mellitus may become more difficult in those receiving ethionamide.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ethionamide in the drug label.
# Drug Interactions
- Trecator has been found to temporarily raise serum concentrations of isoniazid. Trecator may potentiate the adverse effects of other antituberculous drugs administered concomitantly. In particular, convulsions have been reported when ethionamide is administered with cycloserine and special care should be taken when the treatment regimen includes both of these drugs. Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Teratogenic Effects: Pregnancy Category C
- Animal studies conducted with Trecator indicate that the drug has teratogenic potential in rabbits and rats. The doses used in these studies on a mg/kg basis were considerably in excess of those recommended in humans. There are no adequate and well-controlled studies in pregnant women. Because of these animal studies, however, it must be recommended that Trecator be withheld from women who are pregnant, or who are likely to become pregnant while under therapy, unless the prescribing physician considers it to be an essential part of the treatment.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ethionamide in women who are pregnant.
### Labor and Delivery
- The effect of Trecator on labor and delivery in pregnant women is unknown.
### Nursing Mothers
- Because no information is available on the excretion of ethionamide in human milk, Trecator should be administered to nursing mothers only if the benefits outweigh the risks. Newborns who are breast-fed by mothers who are taking Trecator should be monitored for adverse effects.
### Pediatric Use
- Due to the fact that pulmonary tuberculosis resistant to primary therapy is rarely found in neonates, infants, and children, investigations have been limited in these age groups. At present, the drug should not be used in pediatric patients under 12 years of age except when the organisms are definitely resistant to primary therapy and systemic dissemination of the disease, or other life-threatening complications of tuberculosis, is judged to be imminent.
### Geriatic Use
There is no FDA guidance on the use of Ethionamide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Ethionamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ethionamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ethionamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ethionamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ethionamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ethionamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ethionamide in the drug
# IV Compatibility
There is limited information regarding IV Compatibility of Ethionamide in the drug label.
# Overdosage
- No specific information is available on the treatment of overdosage with Trecator. If it should occur, standard procedures to evacuate gastric contents and to support vital functions should be employed.
# Pharmacology
## Mechanism of Action
- Ethionamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. The exact mechanism of action of ethionamide has not been fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms.
## Structure
- Trecator® (ethionamide tablets, USP) is used in the treatment of tuberculosis. The chemical name for ethionamide is 2-ethylthioisonicotinamide with the following structural formula:
- Ethionamide is a yellow crystalline, nonhygroscopic compound with a faint to moderate sulfide odor and a melting point of 162°C. It is practically insoluble in water and ether, but soluble in methanol and ethanol. It has a partition coefficient (octanol/water) Log P value of 0.3699. Trecator tablets contain 250 mg of ethionamide. The inactive ingredients present are croscarmellose sodium, FD&C Yellow #6, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, silicon dioxide, talc, and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ethionamide in the drug label.
## Pharmacokinetics
Absorption
- Ethionamide is essentially completely absorbed following oral administration and is not subjected to any appreciable first pass metabolism. Ethionamide tablets may be administered without regard to the timing of meals.
- The pharmacokinetic parameters of ethionamide following single oral-dose administration of 250 mg of Trecator film-coated tablets under fasted conditions to 40 healthy adult volunteers are provided below.
- Trecator tablets have been reformulated from a sugar-coated tablet to a film-coated tablet. The Cmax for the film-coated tablets (2.16 µg/mL) was significantly higher than that of sugar-coated tablets (1.48 µg/mL).
Distribution
- Ethionamide is rapidly and widely distributed into body tissues and fluids following administration of a sugar-coated tablet, with concentrations in plasma and various organs being approximately equal. Significant concentrations are also present in cerebrospinal fluid following administration of a sugar-coated tablet. Distribution of ethionamide into the same body tissues and fluids, including cerebrospinal fluid following administration of the film-coated tablet, has not been studied, but is not expected to differ significantly from that of the sugar-coated tablet. The drug is approximately 30% bound to proteins. The mean (SD) apparent oral volume of distribution observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 93.5 (19.2) L.
Metabolism
- Ethionamide is extensively metabolized to active and inactive metabolites. Metabolism is presumed to occur in the liver and thus far 6 metabolites have been isolated: 2-ethylisonicotinamide, carbonyl-dihydropyridine, thiocarbonyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso-nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis.
Elimination
- The mean (SD) half-life observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 1.92 (0.27) hours. Less than 1% of the oral dose is excreted as ethionamide in urine.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ethionamide in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Ethionamide in the drug label.
# How Supplied
- Trecator® (ethionamide tablets, USP) are supplied in bottles of 100 tablets as follows:
- 250 mg, orange film-coated tablet marked "W" on one side and "4117" on reverse side, NDC 0008-4117-01.
## Storage
- Store at controlled room temperature 20° to 25°C (68° to 77°F). Dispense in a tight container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised to consult their physician should blurred vision or any loss of vision, with or without eye pain, occur during treatment.
- Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported.
# Precautions with Alcohol
- Alcohol-Ethionamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TRECATOR
# Look-Alike Drug Names
There is limited information regarding Ethionamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ethionamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Ethionamide is an antitubercular that is FDA approved for the treatment of tuberculosis. Common adverse reactions include abdominal pain, diarrhea, metallic taste, nausea, stomatitis, vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Trecator is primarily indicated for the treatment of active tuberculosis in patients with M. tuberculosis resistant to isoniazid or rifampin, or when there is intolerance on the part of the patient to other drugs. Its use alone in the treatment of tuberculosis results in the rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility tests. If the susceptibility tests indicate that the patient's organism is resistant to one of the first-line antituberculosis drugs (i.e., isoniazid or rifampin) yet susceptible to ethionamide, ethionamide should be accompanied by at least one drug to which the M. tuberculosis isolate is known to be susceptible.3 If the tuberculosis is resistant to both isoniazid and rifampin, yet susceptible to ethionamide, ethionamide should be accompanied by at least two other drugs to which the M. tuberculosis isolate is known to be susceptible.3
- Patient nonadherence to prescribed treatment can result in treatment failure and in the development of drug-resistant tuberculosis, which can be life-threatening and lead to other serious health risks. It is, therefore, essential that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended for all patients receiving treatment for tuberculosis. Patients in whom drug-resistant M. tuberculosis organisms are isolated should be managed in consultation with an expert in the treatment of drug-resistant tuberculosis.
# Dosage
In the treatment of tuberculosis, a major cause of the emergence of drug-resistant organisms, and thus treatment failure, is patient nonadherence to prescribed treatment. Treatment failure and drug-resistant organisms can be life-threatening and may result in other serious health risks. It is, therefore, important that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended when patients are receiving treatment for tuberculosis. Consultation with an expert in the treatment of drug-resistant tuberculosis is advised for patients in whom drug-resistant tuberculosis is suspected or likely. Ethionamide should be administered with at least one, sometimes two, other drugs to which the organism is known to be susceptible (see INDICATIONS AND USAGE).
- Trecator is administered orally. The usual adult dose is 15 to 20 mg/kg/day, administered once daily or, if patient exhibits poor gastrointestinal tolerance, in divided doses, with a maximum daily dosage of 1 gram.
- Trecator tablets have been reformulated from a sugar-coated tablet to a film-coated tablet. Patients should be monitored and have their dosage retitrated when switching from the sugar-coated tablet to the film-coated tablet.
- Therapy should be initiated at a dose of 250 mg daily, with gradual titration to optimal doses as tolerated by the patient. A regimen of 250 mg daily for 1 or 2 days, followed by 250 mg twice daily for 1 or 2 days with a subsequent increase to 1 gm in 3 or 4 divided doses has been reported.4,5 Thus far, there is insufficient evidence to indicate the lowest effective dosage levels. Therefore, in order to minimize the risk of resistance developing to the drug or to the companion drug, the principle of giving the highest tolerated dose (based on gastrointestinal intolerance) has been followed. In the adult this would seem to be between 0.5 and 1.0 gm daily, with an average of 0.75 gm daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethionamide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethionamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications For Pediatric,12 Yrs And older
- Trecator is primarily indicated for the treatment of active tuberculosis in patients with M. tuberculosis resistant to isoniazid or rifampin, or when there is intolerance on the part of the patient to other drugs. Its use alone in the treatment of tuberculosis results in the rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility tests. If the susceptibility tests indicate that the patient's organism is resistant to one of the first-line antituberculosis drugs (i.e., isoniazid or rifampin) yet susceptible to ethionamide, ethionamide should be accompanied by at least one drug to which the M. tuberculosis isolate is known to be susceptible.3 If the tuberculosis is resistant to both isoniazid and rifampin, yet susceptible to ethionamide, ethionamide should be accompanied by at least two other drugs to which the M. tuberculosis isolate is known to be susceptible.3
- Patient nonadherence to prescribed treatment can result in treatment failure and in the development of drug-resistant tuberculosis, which can be life-threatening and lead to other serious health risks. It is, therefore, essential that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended for all patients receiving treatment for tuberculosis. Patients in whom drug-resistant M. tuberculosis organisms are isolated should be managed in consultation with an expert in the treatment of drug-resistant tuberculosis.
# Dosage For Pediatrics 12 Yrs And Older
The optimum dosage for pediatric patients has not been established. However, pediatric dosages of 10 to 20 mg/kg p.o. daily in 2 or 3 divided doses given after meals or 15 mg/kg/24 hrs as a single daily dose have been recommended.1,2 As with adults, ethionamide may be administered to pediatric patients once daily. It should be noted that in patients with concomitant tuberculosis and HIV infection, malabsorption syndrome may be present. Drug malabsorption should be suspected in patients who adhere to therapy, but who fail to respond appropriately. In such cases, consideration should be given to therapeutic drug monitoring.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethionamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethionamide in pediatric patients.
# Contraindications
- Ethionamide is contraindicated in patients with severe hepatic impairment and in patients who are hypersensitive to the drug.
# Warnings
- The use of Trecator alone in the treatment of tuberculosis results in rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility testing. However, therapy may be initiated prior to receiving the results of susceptibility tests as deemed appropriate by the physician. Ethionamide should be administered with at least one, sometimes two, other drugs to which the organism is known to be susceptible. Drugs which have been used as companion agents are rifampin, ethambutol, pyrazinamide, cycloserine, kanamycin, streptomycin, and isoniazid. The usual warnings, precautions, and dosage regimens for these companion drugs should be observed.
- Patient compliance is essential to the success of the antituberculosis therapy and to prevent the emergence of drug-resistant organisms. Therefore, patients should adhere to the drug regimen for the full duration of treatment. It is recommended that directly observed therapy be practiced when patients are receiving antituberculous medication. Additional consultation from experts in the treatment of drug-resistant tuberculosis is recommended when patients develop drug-resistant organisms.
# Adverse Reactions
## Clinical Trials Experience
Gastrointestinal: The most common side effects of ethionamide are gastrointestinal disturbances including nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia and weight loss. Adverse gastrointestinal effects appear to be dose related, with approximately 50% of patients unable to tolerate 1 gm as a single dose. Gastrointestinal effects may be minimized by decreasing dosage, by changing the time of drug administration, or by the concurrent administration of an antiemetic agent.
Nervous System: Psychotic disturbances (including mental depression), drowsiness, dizziness, restlessness, headache, and postural hypotension have been reported with ethionamide. Rare reports of peripheral neuritis, optic neuritis, diplopia, blurred vision, and a pellagra-like syndrome also have been reported. Concurrent administration of pyridoxine has been recommended to prevent or relieve neurotoxic effects.
Hepatic: Transient increases in serum bilirubin, SGOT, SGPT; Hepatitis (with or without jaundice).
Other: Hypersensitivity reactions including rash, photosensitivity, thrombocytopenia and purpura have been reported rarely. Hypoglycemia, hypothyroidism, gynecomastia, impotence, and acne also have occurred. The management of patients with diabetes mellitus may become more difficult in those receiving ethionamide.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ethionamide in the drug label.
# Drug Interactions
- Trecator has been found to temporarily raise serum concentrations of isoniazid. Trecator may potentiate the adverse effects of other antituberculous drugs administered concomitantly. In particular, convulsions have been reported when ethionamide is administered with cycloserine and special care should be taken when the treatment regimen includes both of these drugs. Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Teratogenic Effects: Pregnancy Category C
- Animal studies conducted with Trecator indicate that the drug has teratogenic potential in rabbits and rats. The doses used in these studies on a mg/kg basis were considerably in excess of those recommended in humans. There are no adequate and well-controlled studies in pregnant women. Because of these animal studies, however, it must be recommended that Trecator be withheld from women who are pregnant, or who are likely to become pregnant while under therapy, unless the prescribing physician considers it to be an essential part of the treatment.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ethionamide in women who are pregnant.
### Labor and Delivery
- The effect of Trecator on labor and delivery in pregnant women is unknown.
### Nursing Mothers
- Because no information is available on the excretion of ethionamide in human milk, Trecator should be administered to nursing mothers only if the benefits outweigh the risks. Newborns who are breast-fed by mothers who are taking Trecator should be monitored for adverse effects.
### Pediatric Use
- Due to the fact that pulmonary tuberculosis resistant to primary therapy is rarely found in neonates, infants, and children, investigations have been limited in these age groups. At present, the drug should not be used in pediatric patients under 12 years of age except when the organisms are definitely resistant to primary therapy and systemic dissemination of the disease, or other life-threatening complications of tuberculosis, is judged to be imminent.
### Geriatic Use
There is no FDA guidance on the use of Ethionamide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Ethionamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ethionamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ethionamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ethionamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ethionamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ethionamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ethionamide in the drug
# IV Compatibility
There is limited information regarding IV Compatibility of Ethionamide in the drug label.
# Overdosage
- No specific information is available on the treatment of overdosage with Trecator. If it should occur, standard procedures to evacuate gastric contents and to support vital functions should be employed.
# Pharmacology
## Mechanism of Action
- Ethionamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. The exact mechanism of action of ethionamide has not been fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms.
## Structure
- Trecator® (ethionamide tablets, USP) is used in the treatment of tuberculosis. The chemical name for ethionamide is 2-ethylthioisonicotinamide with the following structural formula:
- Ethionamide is a yellow crystalline, nonhygroscopic compound with a faint to moderate sulfide odor and a melting point of 162°C. It is practically insoluble in water and ether, but soluble in methanol and ethanol. It has a partition coefficient (octanol/water) Log P value of 0.3699. Trecator tablets contain 250 mg of ethionamide. The inactive ingredients present are croscarmellose sodium, FD&C Yellow #6, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, silicon dioxide, talc, and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ethionamide in the drug label.
## Pharmacokinetics
Absorption
- Ethionamide is essentially completely absorbed following oral administration and is not subjected to any appreciable first pass metabolism. Ethionamide tablets may be administered without regard to the timing of meals.
- The pharmacokinetic parameters of ethionamide following single oral-dose administration of 250 mg of Trecator film-coated tablets under fasted conditions to 40 healthy adult volunteers are provided below.
- Trecator tablets have been reformulated from a sugar-coated tablet to a film-coated tablet. The Cmax for the film-coated tablets (2.16 µg/mL) was significantly higher than that of sugar-coated tablets (1.48 µg/mL).
Distribution
- Ethionamide is rapidly and widely distributed into body tissues and fluids following administration of a sugar-coated tablet, with concentrations in plasma and various organs being approximately equal. Significant concentrations are also present in cerebrospinal fluid following administration of a sugar-coated tablet. Distribution of ethionamide into the same body tissues and fluids, including cerebrospinal fluid following administration of the film-coated tablet, has not been studied, but is not expected to differ significantly from that of the sugar-coated tablet. The drug is approximately 30% bound to proteins. The mean (SD) apparent oral volume of distribution observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 93.5 (19.2) L.
Metabolism
- Ethionamide is extensively metabolized to active and inactive metabolites. Metabolism is presumed to occur in the liver and thus far 6 metabolites have been isolated: 2-ethylisonicotinamide, carbonyl-dihydropyridine, thiocarbonyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso-nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis.
Elimination
- The mean (SD) half-life observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 1.92 (0.27) hours. Less than 1% of the oral dose is excreted as ethionamide in urine.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ethionamide in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Ethionamide in the drug label.
# How Supplied
- Trecator® (ethionamide tablets, USP) are supplied in bottles of 100 tablets as follows:
- 250 mg, orange film-coated tablet marked "W" on one side and "4117" on reverse side, NDC 0008-4117-01.
## Storage
- Store at controlled room temperature 20° to 25°C (68° to 77°F). Dispense in a tight container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised to consult their physician should blurred vision or any loss of vision, with or without eye pain, occur during treatment.
- Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported.
# Precautions with Alcohol
- Alcohol-Ethionamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TRECATOR
# Look-Alike Drug Names
There is limited information regarding Ethionamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ethionamide | |
f1c74038c52746380bf3755cc9921c78e4432b78 | wikidoc | Ethisterone | Ethisterone
# Overview
Ethisterone (pregneninolone, 17α-ethynyltestosterone or 19–norandrostane) is a progestin. It is the 17α-ethynyl analog of testosterone, and was synthesized in 1938 by Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg, and Arthur Serini at Schering AG in Berlin and marketed in Germany in 1939 as Proluton C and by Schering in the U.S. in 1945 as Pranone. It was the first orally-active progestin.
Ethisterone was also marketed in the U.S. from the 1950s into the 1960s under a variety of trade names by other pharmaceutical companies that had been members of the pre-World War II European hormone cartel (Ciba, Organon, Roussel).
# Synthesis
Ethisterone is made by the ethynylation of androstenolone with acetylene and successive oxidation of the hydroxyl group at C3 of the steroid system. | Ethisterone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ethisterone (pregneninolone, 17α-ethynyltestosterone or 19–norandrostane) is a progestin. It is the 17α-ethynyl analog of testosterone, and was synthesized in 1938 by Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg, and Arthur Serini at Schering AG in Berlin and marketed in Germany in 1939 as Proluton C and by Schering in the U.S. in 1945 as Pranone. It was the first orally-active progestin.
Ethisterone was also marketed in the U.S. from the 1950s into the 1960s under a variety of trade names by other pharmaceutical companies that had been members of the pre-World War II European hormone cartel (Ciba, Organon, Roussel).
# Synthesis
Ethisterone is made by the ethynylation of androstenolone with acetylene and successive oxidation of the hydroxyl group at C3 of the steroid system. | https://www.wikidoc.org/index.php/Ethisterone | |
45e12863d3413b2c4a26a16dd997526ebfa04180 | wikidoc | Ethyl group | Ethyl group
In chemistry, an ethyl group is an alkyl functional group derived from ethane (C2H6). It has the formula -C2H5 and is very often abbreviated -Et.
"Ethyl" was also the common designation in North America for high-performance commercial gasoline containing lead in the mid 20th century. The term comes from the name of the company, Ethyl Corporation, which manufactured the antiknock organometallic agent tetraethyl lead added to the gasoline.
Ethylation is the formation of a compound by introduction of the ethyl functional group, C2H5.
da:Ætyl
de:Ethylgruppe
nl:Ethyl
fi:Etyyli
sv:Etylgrupp | Ethyl group
In chemistry, an ethyl group is an alkyl functional group derived from ethane (C2H6). It has the formula -C2H5 and is very often abbreviated -Et.
"Ethyl" was also the common designation in North America for high-performance commercial gasoline containing lead in the mid 20th century. The term comes from the name of the company, Ethyl Corporation, which manufactured the antiknock organometallic agent tetraethyl lead added to the gasoline.
Ethylation is the formation of a compound by introduction of the ethyl functional group, C2H5.
da:Ætyl
de:Ethylgruppe
nl:Ethyl
fi:Etyyli
sv:Etylgrupp
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Template:WS | https://www.wikidoc.org/index.php/Ethyl | |
c1a82b86b6738ed760168ac715f8dac129816ef2 | wikidoc | Ethyl Green | Ethyl Green
The dye Ethyl Green (Brilliant Green, C.I. 42590; C27H35N3ClBr), due to its powerful bacteriostatic properties, is commonly used along with iodine tincture as a topical antiseptic in Eastern Europe and Russia (common name, Russian tr.:Zelyonka), though not in the west due to its irritant properties and toxicity if ingested. It is soluble in water.
Ethyl green is made of crystal violet by adding an ethyl group; crystal violet is therefore a possible contaminant.
Methyl green is a closely related dye used as a stain in histology. Methyl green and ethyl green are very similar and probably interchangeable. | Ethyl Green
The dye Ethyl Green (Brilliant Green, C.I. 42590; C27H35N3ClBr), due to its powerful bacteriostatic properties, is commonly used along with iodine tincture as a topical antiseptic in Eastern Europe and Russia (common name, Russian tr.:Zelyonka), though not in the west due to its irritant properties and toxicity if ingested. It is soluble in water.
Template:SMILESCAS
Ethyl green is made of crystal violet by adding an ethyl group; crystal violet is therefore a possible contaminant.
Methyl green is a closely related dye used as a stain in histology. Methyl green and ethyl green are very similar and probably interchangeable.
# External links
- Chemical data
- Toxicity data
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Ethyl_Green | |
55cd078585f24667b8028a0d0f8eec270c66cd2e | wikidoc | Etonitazene | Etonitazene
Etonitazene is a highly potent narcotic analgesic (1000–1500x morphine). It's the one of several benzimidazole opioids, and is structurally related to clonitazene (where the p-ethoxybenzyl group is replaced by a p-chlorobenzyl group. However, clonitazene itself has only 3x the potency of morphine.).
It has a strong dependency potential similar to that of morphine and therefore is not used in humans. It is, however, useful in addiction studies on animals.
It is the most potent benzimidazole opioid currently known. Other analogues of considerable potency are as follows:
- Methyl (10x morphine)
- Ethyl (30x morphine)
- Propyl (50x morphine)
- Methoxy (100x morphine)
- Isopropoxy (500x morphine)
- Butoxy (200x morphine)
- Methylthio (50x morphine)
- Ethylthio (30x morphine)
These groups replace the p-ethoxy group - there are other possible modifications but these are the most significant.
The drug has proved very important in mapping out the opiate receptor and some experimental compounds in which phenolic groupings have been replaced with nitro groupings have proved more active than the parent compound.
Illicit production and sale of etonitazene has been limited. This compound was identified on the illegal drug market in Moscow in 1998, appeared to have been illicitly manufactured, and was primarily smoked. In another case a chemist at Morton Thiokol called Thomas K Highsmith Hovey produced the compound and placed it in a nasal inhaler. Such was the level of his addiction, insufficient amounts of methadone were given and he committed suicide before the case went to court | Etonitazene
Etonitazene is a highly potent narcotic analgesic (1000–1500x morphine). It's the one of several benzimidazole opioids, and is structurally related to clonitazene (where the p-ethoxybenzyl group is replaced by a p-chlorobenzyl group. However, clonitazene itself has only 3x the potency of morphine.).
It has a strong dependency potential similar to that of morphine and therefore is not used in humans. It is, however, useful in addiction studies on animals.
It is the most potent benzimidazole opioid currently known.[1] Other analogues of considerable potency are as follows:
- Methyl (10x morphine)
- Ethyl (30x morphine)
- Propyl (50x morphine)
- Methoxy (100x morphine)
- Isopropoxy (500x morphine)
- Butoxy (200x morphine)
- Methylthio (50x morphine)
- Ethylthio (30x morphine)
These groups replace the p-ethoxy group - there are other possible modifications but these are the most significant.
The drug has proved very important in mapping out the opiate receptor and some experimental compounds in which phenolic groupings have been replaced with nitro groupings have proved more active than the parent compound.[citation needed]
Illicit production and sale of etonitazene has been limited. This compound was identified on the illegal drug market in Moscow in 1998, appeared to have been illicitly manufactured, and was primarily smoked.[1] In another case a chemist at Morton Thiokol called Thomas K Highsmith Hovey [2] produced the compound and placed it in a nasal inhaler. Such was the level of his addiction, insufficient amounts of methadone were given and he committed suicide before the case went to court[citation needed] | https://www.wikidoc.org/index.php/Etonitazene | |
5cb498d52f2a35d5ab4b7995275af1773a12a38b | wikidoc | Euchromatin | Euchromatin
Euchromatin is a lightly packed form of chromatin that is rich in gene concentration, and is often (but not always) under active transcription. Unlike heterochromatin, it is found in both eukaryotes and prokaryotes.
# Structure
The structure of euchromatin is reminiscient of an unfolded set of beads along a string, where those beads represent nucleosomes. Nucleosomes consist of eight proteins known as histones, with approximately 146 base pairs of DNA wound around them; in euchromatin this wrapping is loose so that the raw DNA may be accessed. Each core histone possesses a `tail' structure which can vary in several ways; it is thought that these variations act as "master control switches" which determine the overall arrangement of the chromatin. In particular, it is believed that the presence of methylated lysine 4 on the histone tails acts as a general marker for euchromatin.
# Appearance
Euchromatin generally appears as light-colored bands when stained in GTG banding and observed under an optical microscope; in contrast to heterochromatin, which stains darkly. This lighter staining is due to the less compact structure of euchromatin. It should be noted that in prokaryotes, euchromatin is the only form of chromatin present; this indicates that the heterochromatin structure evolved later along with the nucleus, possibly as a mechanism to handle increasing genome size and therefore a decrease in safety/manageability.
# Function
Euchromatin participates in the active transcription of DNA to mRNA products. The unfolded structure allows gene regulatory proteins and RNA polymerase complexes to bind to the DNA sequence, which can then initiate the transcription process. Not all euchromatin is necessarily transcribed, but in general that which is not is transformed into heterochromatin to protect the genes while they are not in use. There is therefore a direct link to how actively productive a cell is and the amount of euchromatin that can be found in its nucleus. It is thought that the cell uses transformation from euchromatin into heterochromatin as a method of controlling gene expression and replication, since such processes behave differently on densely compacted chromatin- this is known as the `accessibility hypothesis'. | Euchromatin
Euchromatin is a lightly packed form of chromatin that is rich in gene concentration, and is often (but not always) under active transcription. Unlike heterochromatin, it is found in both eukaryotes and prokaryotes.
# Structure
The structure of euchromatin is reminiscient of an unfolded set of beads along a string, where those beads represent nucleosomes. Nucleosomes consist of eight proteins known as histones, with approximately 146 base pairs of DNA wound around them; in euchromatin this wrapping is loose so that the raw DNA may be accessed. Each core histone possesses a `tail' structure which can vary in several ways; it is thought that these variations act as "master control switches" which determine the overall arrangement of the chromatin. In particular, it is believed that the presence of methylated lysine 4 on the histone tails acts as a general marker for euchromatin.
# Appearance
Euchromatin generally appears as light-colored bands when stained in GTG banding and observed under an optical microscope; in contrast to heterochromatin, which stains darkly. This lighter staining is due to the less compact structure of euchromatin. It should be noted that in prokaryotes, euchromatin is the only form of chromatin present; this indicates that the heterochromatin structure evolved later along with the nucleus, possibly as a mechanism to handle increasing genome size and therefore a decrease in safety/manageability.
# Function
Euchromatin participates in the active transcription of DNA to mRNA products. The unfolded structure allows gene regulatory proteins and RNA polymerase complexes to bind to the DNA sequence, which can then initiate the transcription process. Not all euchromatin is necessarily transcribed, but in general that which is not is transformed into heterochromatin to protect the genes while they are not in use. There is therefore a direct link to how actively productive a cell is and the amount of euchromatin that can be found in its nucleus. It is thought that the cell uses transformation from euchromatin into heterochromatin as a method of controlling gene expression and replication, since such processes behave differently on densely compacted chromatin- this is known as the `accessibility hypothesis'.
# External links and references
- Research news in Euchromatin
- Zheng C, Hayes J (2003). "Structures and interactions of the core histone tail domains". Biopolymers. 68 (4): 539–46. PMID 12666178..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Muegge K (2003). "Modifications of histone cores and tails in V(D)J recombination". Genome Biol. 4 (4): 211. PMID 12702201. Article
- Histology image: 20102loa – Histology Learning System at Boston University
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d96846e88fa0fa8f92761b385089d717b5c398bc | wikidoc | Evaporation | Evaporation
Evaporation is the process by which molecules in a liquid state (e.g. water) spontaneously become gaseous (e.g. water vapor). It is the opposite of condensation. Generally, evaporation can be seen by the gradual disappearance of a liquid, when exposed to a significant volume of gas.
On average, the molecules do not have enough energy to escape from the liquid, or else the liquid would turn into vapor quickly. When the molecules collide, they transfer energy to each other in varying degrees, based on how they collide. Sometimes the transfer is so one-sided that one of the molecules ends up with enough energy to be considered past the boiling point of the liquid. If this happens near the surface of the liquid it may actually fly off into the gas and thus "evaporate".
Liquids that do not appear to evaporate visibly at a given temperature in a given gas (e.g. cooking oil at room temperature) have molecules that do not tend to transfer energy to each other in a pattern sufficient to frequently give a molecule the "escape velocity" - the heat energy - necessary to turn into vapor. However, these liquids are evaporating, it's just that the process is much slower and thus significantly less visible.
Evaporation is an essential part of the water cycle. Solar energy drives evaporation of water from oceans, lakes, moisture in the soil, and other sources of water. In hydrology, evaporation and transpiration (which involves evaporation within plant stomata) are collectively termed evapotranspiration.
# Theory
For molecules of a liquid to evaporate, they must be located near the surface, be moving in the proper direction, and have sufficient kinetic energy to overcome liquid-phase intermolecular forces. Only a small proportion of the molecules meet these criteria, so the rate of evaporation is limited. Since the kinetic energy of a molecule is proportional to its temperature, evaporation proceeds more quickly at higher temperature. As the faster-moving molecules escape, the remaining molecules have lower average kinetic energy, and the temperature of the liquid thus decreases. This phenomenon is also called evaporative cooling. This is why evaporating sweat cools the human body.
Evaporation also tends to proceed more quickly with higher flow rates between the gaseous and liquid phase and in liquids with higher vapor pressure. For example, laundry on a clothes line will dry (by evaporation) more rapidly on a windy day than on a still day.Three key parts to evaporation are heat, humidity and air movement.
## Evaporative equilibrium
If the evaporation takes place in a closed vessel, the escaping molecules accumulate as a vapor above the liquid. Many of the molecules return to the liquid, with returning molecules becoming more frequent as the density and pressure of the vapor increases. When the process of escape and return reaches an equilibrium, the vapor is said to be "saturated," and no further change in either vapor pressure and density or liquid temperature will occur. For a system consisting of vapor and liquid of a pure substance, this equilibrium state is directly related to the vapor pressure of the substance, as given by the Clausius-Clapeyron relation:
where P1, P2 are the vapor pressures at temperatures T1, T2 respectively, ΔHvap is the enthalpy of vaporization, and R is the universal gas constant. The rate of evaporation in an open system is related to the vapor pressure found in a closed system. If a liquid is heated, when the vapor pressure reaches the ambient pressure the liquid will boil.
The ability for a molecule of a liquid to evaporate is largely based on the amount of kinetic energy an individual particle may possess. Even at lower temperatures, individual molecules of a liquid can potentially evaporate if they have more than the minimum amount of kinetic energy required for vaporization!
# Factors influencing the rate of evaporation
- Concentration of the substance evaporating in the air: If the air already has a high concentration of the substance evaporating, then the given substance will evaporate more slowly.
- Concentration of other substances in the air: If the air is already saturated with other substances, it can have a lower capacity for the substance evaporating.
- Flow rate of air: This is in part related to the concentration points above. If fresh air is moving over the substance all the time, then the concentration of the substance in the air is less likely to go up with time, thus encouraging faster evaporation. This is result of the boundary layer at the evaporation surface decreasing with flow velocity, decreasing the diffusion distance in the stagnant layer.
- Concentration of other substances in the liquid: If the liquid contains other substances, it will have a lower capacity for evaporation.
- Temperature of the substance: If the substance is hotter, then evaporation will be faster.
- Inter-molecular forces: The stronger the forces keeping the molecules together in the liquid state the more energy that must be input in order to evaporate them.
- Surface Area: A substance which has a larger surface area will evaporate faster as there are more surface molecules which are able to escape.
# Applications
When clothes are hung on a laundry line, even though the ambient temperature is below the boiling point of water, water evaporates. This is accelerated by factors such as low humidity, heat (from the sun), and wind. In a clothes dryer hot air is blown through the clothes, allowing water to evaporate very rapidly.
## Combustion vaporization
Fuel droplets vaporize as they receive heat by mixing with the hot gases in the combustion chamber. Heat (energy) can also be received by radiation from any hot refractory wall of the combustion chamber.
## Film deposition
Thin films may be deposited by evaporating a substance and condensing it onto a substrate. | Evaporation
Evaporation is the process by which molecules in a liquid state (e.g. water) spontaneously become gaseous (e.g. water vapor). It is the opposite of condensation. Generally, evaporation can be seen by the gradual disappearance of a liquid, when exposed to a significant volume of gas.
On average, the molecules do not have enough energy to escape from the liquid, or else the liquid would turn into vapor quickly. When the molecules collide, they transfer energy to each other in varying degrees, based on how they collide. Sometimes the transfer is so one-sided that one of the molecules ends up with enough energy to be considered past the boiling point of the liquid. If this happens near the surface of the liquid it may actually fly off into the gas and thus "evaporate".
Liquids that do not appear to evaporate visibly at a given temperature in a given gas (e.g. cooking oil at room temperature) have molecules that do not tend to transfer energy to each other in a pattern sufficient to frequently give a molecule the "escape velocity" - the heat energy - necessary to turn into vapor. However, these liquids are evaporating, it's just that the process is much slower and thus significantly less visible.
Evaporation is an essential part of the water cycle. Solar energy drives evaporation of water from oceans, lakes, moisture in the soil, and other sources of water. In hydrology, evaporation and transpiration (which involves evaporation within plant stomata) are collectively termed evapotranspiration.
# Theory
For molecules of a liquid to evaporate, they must be located near the surface, be moving in the proper direction, and have sufficient kinetic energy to overcome liquid-phase intermolecular forces.[1] Only a small proportion of the molecules meet these criteria, so the rate of evaporation is limited. Since the kinetic energy of a molecule is proportional to its temperature, evaporation proceeds more quickly at higher temperature. As the faster-moving molecules escape, the remaining molecules have lower average kinetic energy, and the temperature of the liquid thus decreases. This phenomenon is also called evaporative cooling. This is why evaporating sweat cools the human body.
Evaporation also tends to proceed more quickly with higher flow rates between the gaseous and liquid phase and in liquids with higher vapor pressure. For example, laundry on a clothes line will dry (by evaporation) more rapidly on a windy day than on a still day.Three key parts to evaporation are heat, humidity and air movement.
## Evaporative equilibrium
If the evaporation takes place in a closed vessel, the escaping molecules accumulate as a vapor above the liquid. Many of the molecules return to the liquid, with returning molecules becoming more frequent as the density and pressure of the vapor increases. When the process of escape and return reaches an equilibrium,[1] the vapor is said to be "saturated," and no further change in either vapor pressure and density or liquid temperature will occur. For a system consisting of vapor and liquid of a pure substance, this equilibrium state is directly related to the vapor pressure of the substance, as given by the Clausius-Clapeyron relation:
where P1, P2 are the vapor pressures at temperatures T1, T2 respectively, ΔHvap is the enthalpy of vaporization, and R is the universal gas constant. The rate of evaporation in an open system is related to the vapor pressure found in a closed system. If a liquid is heated, when the vapor pressure reaches the ambient pressure the liquid will boil.
The ability for a molecule of a liquid to evaporate is largely based on the amount of kinetic energy an individual particle may possess. Even at lower temperatures, individual molecules of a liquid can potentially evaporate if they have more than the minimum amount of kinetic energy required for vaporization!
# Factors influencing the rate of evaporation
- Concentration of the substance evaporating in the air: If the air already has a high concentration of the substance evaporating, then the given substance will evaporate more slowly.
- Concentration of other substances in the air: If the air is already saturated with other substances, it can have a lower capacity for the substance evaporating.
- Flow rate of air: This is in part related to the concentration points above. If fresh air is moving over the substance all the time, then the concentration of the substance in the air is less likely to go up with time, thus encouraging faster evaporation. This is result of the boundary layer at the evaporation surface decreasing with flow velocity, decreasing the diffusion distance in the stagnant layer.
- Concentration of other substances in the liquid: If the liquid contains other substances, it will have a lower capacity for evaporation.
- Temperature of the substance: If the substance is hotter, then evaporation will be faster.
- Inter-molecular forces: The stronger the forces keeping the molecules together in the liquid state the more energy that must be input in order to evaporate them.
- Surface Area: A substance which has a larger surface area will evaporate faster as there are more surface molecules which are able to escape.
# Applications
When clothes are hung on a laundry line, even though the ambient temperature is below the boiling point of water, water evaporates. This is accelerated by factors such as low humidity, heat (from the sun), and wind. In a clothes dryer hot air is blown through the clothes, allowing water to evaporate very rapidly.
## Combustion vaporization
Fuel droplets vaporize as they receive heat by mixing with the hot gases in the combustion chamber. Heat (energy) can also be received by radiation from any hot refractory wall of the combustion chamber.
## Film deposition
Thin films may be deposited by evaporating a substance and condensing it onto a substrate. | https://www.wikidoc.org/index.php/Evaporated | |
971bcda40a429b37f31146a8ac40a62c9adfcc72 | wikidoc | Romosozumab | Romosozumab
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Romosozumab is a sclerostin inhibitor that is FDA approved for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include arthralgia and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Romosozumab is indicated for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.
Dosage
- Two separate syringes (and two separate subcutaneous injections) are needed to administer the total dose of 210 mg of romosozumab. Inject two 105 mg/1.17 mL prefilled syringes, one after the other.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding romosozumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding romosozumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of romosozumab have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding romosozumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding romosozumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
Romosozumab is contraindicated in patients with:
- Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with romosozumab.
- A history of systemic hypersensitivity to romosozumab or to any component of the product formulation. Reactions have included angioedema, erythema multiforme, and urticaria.
# Warnings
- In a randomized controlled trial in postmenopausal women, there was a higher rate of major adverse cardiac events (MACE), a composite endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, in patients treated with romosozumab compared to those treated with alendronate.
- Romosozumab should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year. Consider whether the benefits outweigh the risks in patients with other cardiovascular risk factors. Monitor for signs and symptoms of myocardial infarction and stroke and instruct patients to seek prompt medical attention if symptoms occur. If a patient experiences a myocardial infarction or stroke during therapy, romosozumab should be discontinued.
- Hypersensitivity reactions, including angioedema, erythema multiforme, dermatitis, rash, and urticaria have occurred in romosozumab-treated patients. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of romosozumab.
- Hypocalcemia has occurred in patients receiving romosozumab. Correct hypocalcemia prior to initiating romosozumab.
- Monitor patients for signs and symptoms of hypocalcemia. Patients should be adequately supplemented with calcium and vitamin D while on romosozumab.
- Patients with severe renal impairment (estimated glomerular filtration rate 15 to 29 mL/min/1.73 m2) or receiving dialysis are at greater risk of developing hypocalcemia. Monitor serum calcium and adequately supplement patients who have severe renal impairment or are receiving dialysis with calcium and vitamin D. Instruct patients with severe renal impairment, including those receiving dialysis, about the symptoms of hypocalcemia and the importance of maintaining calcium levels with adequate calcium and vitamin D supplementation.
- Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients receiving romosozumab. A routine oral examination should be performed by the prescriber prior to initiation of romosozumab treatment. Concomitant administration of drugs associated with ONJ (chemotherapy, bisphosphonates, denosumab, angiogenesis inhibitors, and corticosteroids) may increase the risk of developing ONJ. Other risk factors for ONJ include cancer, radiotherapy, poor oral hygiene, pre-existing dental disease or infection, anemia, and coagulopathy.
- For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on benefit-risk assessment. Patients who are suspected of having or who develop ONJ while on romosozumab should receive care by a dentist or an oral surgeon. In these patients, dental surgery to treat ONJ may exacerbate the condition. Discontinuation of romosozumab should be considered based on benefit-risk assessment.
- Atypical low-energy or low trauma fractures of the femoral shaft have been reported in patients receiving romosozumab. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated.
- Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs.
- During romosozumab treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of romosozumab therapy should be considered based on benefit-risk assessment.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of romosozumab for the treatment of postmenopausal osteoporosis was evaluated in a multicenter, randomized, double-blind, placebo-controlled study (Study 1, NCT01575834) of 7180 postmenopausal women aged 55 to 90 years (mean age of 71 years). A total of 3581 and 3576 women received at least one dose of romosozumab and placebo, respectively, administered once every month during the 12-month double-blind study period. Women received at least 500 mg calcium and 600 international units of vitamin D supplementation daily and 77% received a loading dose of 50,000 to 60,000 international units of vitamin D within one week of randomization (if serum 25-hydroxyvitamin D concentrations were 40 ng/mL or less).
- The safety of romosozumab for the treatment of postmenopausal osteoporosis in patients at high risk of fracture was evaluated in a multicenter, randomized, double-blind, alendronate-controlled study (Study 2, NCT01631214) of 4093 postmenopausal women aged 55 to 90 years (mean age of 74 years). A total of 2040 and 2014 women received at least one dose of romosozumab and alendronate, respectively, during the 12-month double-blind study period. Women received at least 500 mg calcium and 600 international units vitamin D supplementation daily and 74% received a loading dose of 50,000 to 60,000 international units of vitamin D within one week of randomization (if serum 25-hydroxyvitamin D concentrations were 40 ng/mL or less).
- In Study 1, during the 12-month double-blind treatment period, the incidence of all-cause mortality was 0.7% (24/3576) in the placebo group and 0.8% (29/3581) in the romosozumab group. The incidence of nonfatal serious adverse events was 8.3% in the placebo group and 9.1% in the romosozumab group. The percentage of patients who withdrew from the study due to adverse events was 1.1% in the placebo group and 1.1% in the romosozumab group. The most common adverse reactions reported with romosozumab (greater than or equal to 5% and at a higher incidence than placebo) were arthralgia and headache. The most common adverse reaction leading to discontinuation of romosozumab was arthralgia (6 subjects in the placebo group and 5 subjects in the romosozumab group).
- In Study 2, during the 12-month double-blind treatment period, the incidence of all-cause mortality was 1.1% (22/2014) in the alendronate group and 1.5% (30/2040) in the romosozumab group. The incidence of nonfatal serious adverse events was 13.3% in the alendronate group and 11.9% in the romosozumab group. The percentage of patients who withdrew from the study due to adverse events was 1.2% in the alendronate group and 1.2% in the romosozumab group. The most common adverse reactions reported with romosozumab (greater than or equal to 5%) were arthralgia and headache.
- Table 1 outlines the most common adverse reactions occurring in greater than or equal to 2% of romosozumab treated women in at least one study.
- The adverse reactions described below are from the 12-month treatment periods of Study 1 (placebo-controlled) and Study 2 (alendronate-controllmed).
Major Adverse Cardiac Events (MACE)
- During the 12-month double-blind treatment period of the placebo-controlled trial (Study 1), myocardial infarction occurred in 9 women (0.3%) in the romosozumab group and 8 (0.2%) women in the placebo group; stroke occurred in 8 women (0.2%) in the romosozumab group and 10 (0.3%) women in the placebo group. These events occurred in patients with and without a history of myocardial infarction or stroke. Cardiovascular death occurred in 17 women (0.5%) in the romosozumab group and 15 (0.4%) women in the placebo group. The number of women with positively adjudicated MACE was 30 (0.8%) in the romosozumab group and 29 (0.8%) in the placebo group, yielding a hazard ratio of 1.03 (95% confidence interval ) for romosozumab compared to placebo.
- During the 12-month double-blind treatment period of the active-controlled trial (Study 2), myocardial infarction occurred in 16 women (0.8%) in the romosozumab group and 5 (0.2%) women in the alendronate group; stroke occurred in 13 women (0.6%) in the romosozumab group and 7 (0.3%) women in the alendronate group. These events occurred in patients with and without a history of myocardial infarction or stroke. Cardiovascular death occurred in 17 women (0.8%) in the romosozumab group and 12 (0.6%) women in the alendronate group. The number of women with positively adjudicated MACE was 41 (2.0%) in the romosozumab group and 22 (1.1%) in the alendronate group, yielding a hazard ratio of 1.87 (95% confidence interval ) for romosozumab compared to alendronate.
Hypersensitivity Reactions
- Across both trials, hypersensitivity reactions were reported in 364 (6.5%) women in the romosozumab group and 365 (6.5%) women in the control group. Reported reactions included angioedema (3 women in the romosozumab group vs. 3 women in the control group), erythema multiforme (1 woman in the romosozumab group vs. no woman in the control group), dermatitis (32 women in the romosozumab group vs. 42 women in the control group), rash (60 women in the romosozumab group vs. 53 women in the control group), and urticaria (23 women in the romosozumab group vs. 27 women in the control group). Although angioedema, dermatitis and urticaria were not reported at a higher incidence with romosozumab than control, there were cases of angioedema, dermatitis and urticaria that were determined to be related to romosozumab use.
Hypocalcemia
- Across both trials, adverse events of hypocalcemia occurred in 2 romosozumab-treated women and in 1 woman in the control group. Decreases in albumin-adjusted serum calcium to below the lower limit of the reference range (8.3 mg/dL) were reported in 14 (0.2%) women in the romosozumab group and 10 (0.2%) women in the control group. No patient receiving romosozumab developed serum calcium less than 7.5 mg/dL. The nadir in albumin-adjusted serum calcium occurred by month 1 after romosozumab dosing in patients with normal renal function.
Injection Site Reactions
- Across both trials, injection site reactions occurred in 278 (4.9%) women in the romosozumab group and 157 (2.8%) women in the control group. The most common injection site reactions were pain (94 women in the romosozumab group; 70 in the control group) and erythema (80 women in the romosozumab group and 14 women in the control group). Injection site reactions resulted in discontinuation of treatment in 7 (0.1%) romosozumab-treated patients and 3 (< 0.1%) patients in the control group.
Osteonecrosis of the Jaw
- Across both trials, osteonecrosis of the jaw occurred in one patient during treatment with romosozumab.
Atypical Subtrochanteric and Diaphysial Fractures
- Across both trials, atypical femoral fracture occurred in one patient during treatment with romosozumab.
## Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other romosozumab products may be misleading.
- The immunogenicity of romosozumab was evaluated using an immunoassay for the detection of anti-romosozumab-aqqg antibodies. An in vitro biological assay was performed to detect neutralizing antibodies for those subjects whose sera tested positive for anti-romosozumab-aqqg antibodies.
- Among 5914 postmenopausal women treated with romosozumab 210 mg monthly, 18.1% of subjects developed antibodies to romosozumab-aqqg. Of the subjects who developed antibodies to romosozumab-aqqg, 4.7% had antibodies that were classified as neutralizing. Development of antibodies to romosozumab-aqqg was associated with lower serum romosozumab-aqqg concentrations. Antibodies to romosozumab-aqqg were generally not associated with changes in the efficacy or safety of romosozumab.
## Postmarketing Experience
There is limited information regarding Romosozumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Romosozumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Romosozumab is not indicated for use in women of reproductive potential. In animal reproduction studies, weekly administration of romosozumab-aqqg to pregnant rats during the period of organogenesis at exposures greater than 32 times the clinical exposure produced skeletal abnormalities in the offspring. Administration of romosozumab-aqqg to rats prior to mating and through to the end of lactation produced minimal to slight decreases in femoral bone mineral density and/or cortical circumferences in the offspring at 1.5 to 56 times the expected exposure in humans.
Animal Data
- Reproductive and developmental effects of romosozumab-aqqg were assessed in the rat in a preliminary and definitive embryo-fetal development study, a combined fertility and embryo-development study, and a pre- and postnatal development study.
- Skeletal malformations including syndactyly and polydactyly occurred in 1 out of 75 litters across all rat reproductive toxicity studies, in the litter of a dam given weekly subcutaneous romosozumab-aqqg doses of 300 mg/kg (equivalent to at least 32 times the clinical exposure observed in humans following a monthly subcutaneous dose of 210 mg, based on area under the concentration-time curve comparison).
- In the offspring of female rats given weekly romosozumab-aqqg doses from 6 weeks before cohabitation through mating and lactation, femoral periosteal and endocortical circumferences were slightly decreased at 10, 60, and 300 mg/kg (equivalent to 1.5, 19, and 56 times the clinical exposure following a monthly subcutaneous dose of 210 mg, based on AUC comparison). Cortical thickness was increased at 300 mg/kg (equivalent to 56 times expected clinical exposure). Femoral metaphysical bone mineral density was slightly decreased at 60 and 300 mg/kg (equivalent to 19 and 56 times expected clinical exposure).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Romosozumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Romosozumab during labor and delivery.
### Nursing Mothers
- Romosozumab is not indicated for use in women of reproductive potential. In animal studies where pregnant rats were given weekly doses of romosozumab-aqqg from 6 weeks before cohabitation through mating and lactation at 10, 60, or 300 mg/kg (equivalent to 1.5, 19 or 56 times the clinical exposure following a monthly subcutaneous dose of 210 mg, based on AUC comparison), romosozumab-aqqg was dose-dependently present in the serum of offspring on postnatal day 21 at 0.01 to 2.4 times maternal exposure due to gestational and/or lactational exposure.
### Pediatric Use
- Safety and effectiveness of romosozumab have not been established in pediatric patients.
### Geriatic Use
- Of the 6544 postmenopausal women with osteoporosis in the clinical studies of romosozumab, 5234 (80%) were age 65 years and over and 2390 (37%) were age 75 years and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
- Romosozumab is indicated for postmenopausal women.
### Race
There is no FDA guidance on the use of Romosozumab with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is required in patients with renal impairment.
- Patients with severe renal impairment (estimated glomerular filtration rate 15 to 29 mL/min/1.73 m2 by MDRD equation) or receiving dialysis are at greater risk of developing hypocalcemia. Monitor calcium concentrations and adequately supplement calcium and vitamin D in patients who have severe renal impairment or are receiving dialysis.
### Hepatic Impairment
There is no FDA guidance on the use of Romosozumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Romosozumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Romosozumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Two separate syringes (and two separate subcutaneous injections) are needed to administer the total dose of 210 mg of romosozumab. Inject two 105 mg/1.17 mL prefilled syringes, one after the other.
- Romosozumab should be administered by a healthcare provider.
- The recommended dose of romosozumab is 210 mg administered subcutaneously in the abdomen, thigh or upper arm. Administer romosozumab once every month.
- The treatment duration for romosozumab is 12 monthly doses.
- Patients should be adequately supplemented with calcium and vitamin D during treatment with romosozumab.
- If the romosozumab dose is missed, administer as soon as it can be rescheduled. Thereafter, romosozumab can be scheduled every month from the date of the last dose.
Step 1. Prior to Administration:
- Remove two syringes from the carton.
- Visually inspect romosozumab for particles and discoloration prior to administration. Romosozumab is a clear to opalescent, colorless to light yellow solution. Do not use if the solution is cloudy or discolored or contains particles.
- Do not use the syringe if:
any part appears cracked or broken
the gray needle cap is missing or not securely attached
the expiration date printed on the label has passed
- any part appears cracked or broken
- the gray needle cap is missing or not securely attached
- the expiration date printed on the label has passed
- Always hold the prefilled syringe by the syringe barrel to remove the syringe from the tray. See Figure A.
Do not grasp the plunger rod.
Do not grasp the gray needle cap.
Do not remove the gray needle cap until you are ready to inject.
- Do not grasp the plunger rod.
- Do not grasp the gray needle cap.
- Do not remove the gray needle cap until you are ready to inject.
- Allow romosozumab to sit at room temperature for at least 30 minutes before injecting. Do not warm in any other way.
Step 2: Select the Injection Site and Prepare the Syringe
- Prepare and clean two injection sites, one for each of the two injections. See Figure B.
- The recommended subcutaneous injection sites include:
The thigh
Abdomen, except for a two-inch area right around the navel
Outer area of upper arm
- The thigh
- Abdomen, except for a two-inch area right around the navel
- Outer area of upper arm
- Clean the injection sites with alcohol wipes. Let the skin dry.
Choose a different site each time you give an injection. If you want to use the same injection site, make sure it is not the same spot on the injection site you used for a previous injection.
Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.
- Choose a different site each time you give an injection. If you want to use the same injection site, make sure it is not the same spot on the injection site you used for a previous injection.
- Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.
- Choose the first syringe. Pull the gray needle cap straight off and away from your body when you are ready to inject. See Figure C.
- Do not put the gray needle cap back onto the syringe.
Step 3: Inject romosozumab
- Insert needle and inject all the liquid subcutaneously. Do not administer into muscle or blood vessel. See Figure D.
- When done, gently lift the syringe off of the skin.
Step 4: Syringe and Needle Cap Disposal
- Immediately dispose of the syringe and needle cap in the nearest sharps container.
Important: Repeat all steps with the second syringe to inject the full dose.
### Monitoring
- Monitor for signs and symptoms of myocardial infarction and stroke and instruct patients to seek prompt medical attention if symptoms occur.
- Monitor patients for signs and symptoms of hypocalcemia. Patients should be adequately supplemented with calcium and vitamin D while on romosozumab.
- Monitor calcium concentrations and adequately supplement calcium and vitamin D in patients who have severe renal impairment or are receiving dialysis.
# IV Compatibility
There is limited information regarding the compatibility of Romosozumab and IV administrations.
# Overdosage
There is limited information regarding Romosozumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Romosozumab inhibits the action of sclerostin, a regulatory factor in bone metabolism. Romosozumab increases bone formation and, to a lesser extent, decreases bone resorption. Animal studies showed that romosozumab-aqqg stimulates new bone formation on trabecular and cortical bone surfaces by stimulating osteoblastic activity resulting in increases in trabecular and cortical bone mass and improvements in bone structure and strength.
## Structure
There is limited information regarding Romosozumab Structure in the drug label.
## Pharmacodynamics
- In postmenopausal women with osteoporosis, romosozumab increased the bone formation marker procollagen type 1 N-telopeptide (P1NP) with a peak increase from baseline of approximately 145% compared to placebo 2 weeks after initiating treatment, followed by a return to concentrations seen with placebo at month 9 and a decline from baseline to approximately 15% below the concentration change seen with placebo at month 12.
- Romosozumab decreased the bone resorption marker type 1 collagen C-telopeptide (CTX) with a maximal reduction from baseline of approximately 55% compared to placebo 2 weeks after initiating treatment. CTX remained below concentrations seen with placebo and was approximately 25% below the concentration change seen with placebo at month 12.
- After discontinuation of romosozumab, P1NP levels returned to baseline within 12 months; CTX increased above baseline levels within 3 months and returned toward baseline levels by month 12.
## Pharmacokinetics
- Administration of a single dose of 210 mg romosozumab in healthy volunteers resulted in a mean (standard deviation ) maximum romosozumab-aqqg serum concentration (Cmax) of 22.2 (5.8) mcg/mL and a mean (SD) AUC of 389 (127) mcg*day/mL. Steady-state concentrations were achieved by month 3 following the monthly administration of 210 mg to postmenopausal women. The mean trough serum romosozumab-aqqg concentrations at months 3, 6, 9, and 12 ranged from 8 to 13 mcg/mL.
- Romosozumab-aqqg exhibited nonlinear pharmacokinetics with exposure increasing greater than dose proportionally (e.g., 550-fold increase in mean AUCinf for the 100-fold increase in subcutaneous doses ranging from 0.1 to 10 mg/kg [0.03 to 3.3 times the approved recommended dosage for a 70 kg woman).
Absorption
- The median time to maximum romosozumab-aqqg concentration (Tmax) is 5 days (range: 2 to 7 days).
Distribution
- The estimated volume of distribution at steady-state is approximately 3.92 L.
Elimination
- Romosozumab-aqqg exhibited nonlinear pharmacokinetics with the clearance of romosozumab-aqqg decreasing as the dose increased. The estimated mean systemic clearance (CL/F) of romosozumab-aqqg was 0.38 mL/hr/kg, following a single subcutaneous administration of 3 mg/kg (the approved recommended dosage for a 70 kg woman). The mean effective t1/2 was 12.8 days after 3 doses of 3 mg/kg (the approved recommended dosage for a 70 kg woman) every 4 weeks.
Metabolism
- The metabolic pathway of romosozumab-aqqg has not been characterized. As a humanized IgG2 monoclonal antibody, romosozumab-aqqg is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
Anti-Product Antibody Formation Affecting Pharmacokinetics
- Development of anti-romosozumab-aqqg antibodies was associated with reduced serum romosozumab-aqqg concentrations. The presence of anti-romosozumab-aqqg antibodies led to decreased mean romosozumab-aqqg concentrations up to 22%. The presence of neutralizing antibodies led to decreased mean romosozumab-aqqg concentrations up to 63%.
Specific Populations
- No clinically significant differences in the pharmacokinetics of romosozumab-aqqg were observed based on age (20-89 years), sex, race, disease state (low bone mass or osteoporosis), prior exposure to alendronate, or renal impairment including end-stage renal disease (ESRD) requiring dialysis. The effect of ESRD not requiring dialysis on the pharmacokinetics of romosozumab-aqqg is unknown.
Body Weight
- The exposure of romosozumab-aqqg decreases with increasing body weight.
## Nonclinical Toxicology
Carcinogenicity
- In a rat carcinogenicity study, once-weekly romosozumab-aqqg doses of 3, 10 or 50 mg/kg were administered by subcutaneous injection to Sprague-Dawley rats from 8 weeks up to 98 weeks of age, resulting in systemic exposures that were up to 19 times the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison). Romosozumab-aqqg caused a dose-dependent increase in bone mass with trabecular and cortical bone thickening at all doses. There were no effects of romosozumab-aqqg on mortality and romosozumab-aqqg did not cause significant increases in tumor incidence in male or female rats.
Mutagenicity
- Mutagenesis has not been evaluated, as monoclonal antibodies are not expected to alter DNA or chromosomes.
Impairment of Fertility
- No effects on fertility were observed in male and female rats given subcutaneous romosozumab-aqqg doses up to 300 mg/kg (up to 56 times the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab, based on AUC comparison). No effects were noted in reproductive organs in rats and cynomolgus monkeys dosed subcutaneously for 6 months with weekly doses up to 100 mg/kg (exposures up to 38 and 93 times, respectively, the systemic exposure observed in humans administered monthly subcutaneous doses of 210 mg based on AUC comparison).
- No adverse effects were noted in rats and monkeys after 26 once-weekly subcutaneous romosozumab-aqqg doses up to 100 mg/kg, equivalent to systemic exposures of 38 and 93 times, respectively, the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison).
- Bone safety studies of up to 12-month duration were conducted in ovariectomized rats and monkeys with once-weekly romosozumab-aqqg doses yielding exposures ranging from 1 to 22 times the systemic exposure in humans given monthly doses of 210 mg, based on AUC comparison. Romosozumab-aqqg increased bone mass and improved cancellous bone microarchitecture and cortical bone geometry by increasing bone formation on periosteal, endocortical, and trabecular surfaces, and decreasing bone resorption on trabecular and endocortical surfaces. The increases in bone mass were significantly correlated with increases in bone strength. In rats and monkeys, bone quality was maintained at all skeletal sites at doses ranging from 1 to 22 times human exposure, and slightly improved in vertebrae at 19 to 22 times human exposure. There was no evidence of mineralization defects, osteoid accumulation, or woven bone formation.
# Clinical Studies
Study 1 (NCT01575834) was a randomized, double-blind, placebo-controlled study of postmenopausal women aged 55 to 90 years (mean age of 71 years) with bone mineral density (BMD) T-score less than or equal to −2.5 at the total hip or femoral neck. Women were randomized to receive subcutaneous injections of either romosozumab (N = 3589) or placebo (N = 3591) for 12 months. At baseline, 18% of women had a vertebral fracture. After the 12-month treatment period, women in both arms transitioned to open-label anti-resorptive therapy (denosumab) for 12 months while remaining blinded to their initial treatment. Women received 500 to 1000 mg calcium and 600 to 800 international units vitamin D supplementation daily. The coprimary efficacy endpoints were new vertebral fracture at month 12 and month 24.
Effect on Fractures
- Romosozumab significantly reduced the incidence of new vertebral fractures through month 12 compared to placebo. In addition, the significant reduction in fracture risk persisted through the second year in women who received romosozumab during the first year and transitioned to denosumab compared to those who transitioned from placebo to denosumab (see Table 2).
- Romosozumab significantly reduced the incidence of clinical fracture (a composite endpoint of symptomatic vertebral fracture and nonvertebral fracture) at 12 months. However, 88% of these clinical fractures were nonvertebral fractures and the incidence of nonvertebral fractures was not statistically significantly different when comparing romosozumab-treated women to placebo-treated women at month 12 or month 24.
Effect on BMD
- Romosozumab significantly increased BMD at the lumbar spine, total hip, and femoral neck compared with placebo at month 12. The treatment differences in BMD were 12.7% at the lumbar spine, 5.8% at the total hip, and 5.2% at the femoral neck.
- Following the transition from romosozumab to denosumab at month 12, BMD continued to increase through month 24. In patients who transitioned from placebo to denosumab, BMD also increased with denosumab use. The differences in BMD achieved at month 12 between romosozumab and placebo patients were overall maintained at month 24, when comparing patients who transitioned from romosozumab to denosumab to those who transitioned from placebo to denosumab. There was no evidence of differences in effects on BMD at the lumbar spine or total hip across subgroups defined by baseline age, baseline BMD, or geographic region.
- After romosozumab discontinuation, BMD returns to approximately baseline levels within 12 months in the absence of follow-on antiresorptive therapy.
Bone Histology and Histomorphometry
- A total of 154 transiliac crest bone biopsy specimens were obtained from 139 postmenopausal women with osteoporosis at month 2, month 12, and/or month 24. All of these biopsies were adequate for qualitative histology and 138 (90%) were adequate for full quantitative histomorphometry assessment. Qualitative histology assessments from women treated with romosozumab showed normal bone architecture and quality at all time points. There was no evidence of woven bone, mineralization defects, or marrow fibrosis.
- Histomorphometry assessments on biopsies at months 2 and 12 compared the effect of romosozumab with placebo (15 specimens at month 2 and 39 specimens at month 12 in the romosozumab group, 14 specimens at month 2 and 31 specimens at month 12 in the placebo group). At month 2 in women treated with romosozumab, histomorphometric indices of bone formation at trabecular and endocortical surfaces were increased. These effects on bone formation were accompanied by a decrease in indices of bone resorption. At month 12, both bone formation and resorption indices were decreased with romosozumab, while bone volume, and trabecular and cortical thickness were increased.
Study 2 (NCT01631214) was a randomized, double-blind, alendronate-controlled study of postmenopausal women aged 55 to 90 years (mean age of 74 years) with BMD T-score less than or equal to −2.5 at the total hip or femoral neck and either one moderate or severe vertebral fracture or two mild vertebral fractures, or BMD T-score less than or equal to -2.0 at the total hip or femoral neck and either two moderate or severe vertebral fractures or a history of a proximal femur fracture. Women were randomized (1:1) to receive either monthly subcutaneous injections of romosozumab (N = 2046) or oral alendronate 70 mg weekly (N = 2047) for 12 months, with 500 to 1000 mg calcium and 600 to 800 international units vitamin D supplementation daily. After the 12-month treatment period, women in both arms transitioned to open-label alendronate 70 mg weekly while remaining blinded to their initial treatment.
- This was an event driven trial. The coprimary efficacy endpoints were the incidence of morphometric vertebral fracture at 24 months and time to the first clinical fracture through the primary analysis period, which ended when at least 330 subjects had a clinical fracture and all subjects had completed the 24-month visit. Clinical fracture was a composite endpoint of nonvertebral fracture and symptomatic vertebral fracture.
Effect on Fractures
- Romosozumab significantly reduced the incidence of new vertebral fracture at 24 months (see Table 3).
- Romosozumab significantly reduced the risk of clinical fracture through the end of the primary analysis period (see Table 4). This was an event-driven trial and the duration of follow-up varied across subjects. The median duration of subject follow-up for the primary analysis period was 33 months. Subjects with nonvertebral fracture comprised 83% of the subjects with clinical fracture during the primary analysis period.
- Romosozumab followed by alendronate also significantly reduced the risk of nonvertebral fracture through the primary analysis period (with a median follow-up of 33 months), with a hazard ratio of 0.81 (95% CI: 0.66, 0.99; p = 0.04) compared to alendronate alone.
Effect on Bone Mineral Density (BMD)
- Romosozumab significantly increased BMD at the lumbar spine, total hip, and femoral neck compared with alendronate at month 12. The treatment differences in BMD were 8.7% at the lumbar spine, 3.3% at the total hip, and 3.2% at the femoral neck.
- Twelve months of treatment with romosozumab followed by 12 months of treatment with alendronate significantly increased BMD compared with alendronate alone. The BMD increase with romosozumab over alendronate observed at month 12 was maintained at month 24. The treatment differences in BMD at month 24 were 8.1% at the lumbar spine, 3.8% at the total hip, and 3.8% at the femoral neck.
- There was no evidence of differences in effects on BMD at the lumbar spine or total hip across subgroups defined by baseline age, baseline BMD, or geographic region.
# How Supplied
- Romosozumab (romosozumab-aqqg) injection is a clear to opalescent, colorless to light yellow solution for subcutaneous injection supplied in a single-use prefilled syringe.
- Each single-use prefilled syringe contains 105 mg of romosozumab in a deliverable volume of 1.17 mL. To deliver a full dose, inject two 105 mg/1.17 mL romosozumab prefilled syringes, one after the other for a total dose of 210 mg.
## Storage
- Refrigerate romosozumab at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.
- If removed from the refrigerator, romosozumab can be kept at room temperature up to 25°C (77°F) in the original carton and must be used within 30 days. If not used within 30 days, discard romosozumab.
- Do not expose romosozumab to temperatures above 25°C (77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).
Major Adverse Cardiac Events
- Advise patients to seek immediate medical attention if they experience signs or symptoms of a myocardial infarction or stroke.
Hypersensitivity Reactions
- Advise patients to seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction including angioedema, erythema multiforme, dermatitis, rash, and urticaria.
Calcium and Vitamin D Supplements to Prevent Hypocalcemia
- Advise patients to take calcium and vitamin D supplements daily to reduce the risk of hypocalcemia. Advise patients to seek immediate medical attention for symptoms of hypocalcemia.
Osteonecrosis of the Jaw
- Advise patients to practice good oral hygiene during treatment with romosozumab and tell their dentist that they are receiving romosozumab before having dental work.
Atypical Femoral Fracture
- Advise patients to report signs and symptoms that could be consistent with impending atypical femoral fracture including new or unusual thigh, hip, or groin pain.
## Medication Guide
# Precautions with Alcohol
Alcohol-Romosozumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Evenity
# Look-Alike Drug Names
There is limited information regarding Romosozumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Romosozumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2]
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# Black Box Warning
# Overview
Romosozumab is a sclerostin inhibitor that is FDA approved for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include arthralgia and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Romosozumab is indicated for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.
Dosage
- Two separate syringes (and two separate subcutaneous injections) are needed to administer the total dose of 210 mg of romosozumab. Inject two 105 mg/1.17 mL prefilled syringes, one after the other.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding romosozumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding romosozumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of romosozumab have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding romosozumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding romosozumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
Romosozumab is contraindicated in patients with:
- Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with romosozumab.
- A history of systemic hypersensitivity to romosozumab or to any component of the product formulation. Reactions have included angioedema, erythema multiforme, and urticaria.
# Warnings
- In a randomized controlled trial in postmenopausal women, there was a higher rate of major adverse cardiac events (MACE), a composite endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, in patients treated with romosozumab compared to those treated with alendronate.
- Romosozumab should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year. Consider whether the benefits outweigh the risks in patients with other cardiovascular risk factors. Monitor for signs and symptoms of myocardial infarction and stroke and instruct patients to seek prompt medical attention if symptoms occur. If a patient experiences a myocardial infarction or stroke during therapy, romosozumab should be discontinued.
- Hypersensitivity reactions, including angioedema, erythema multiforme, dermatitis, rash, and urticaria have occurred in romosozumab-treated patients. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of romosozumab.
- Hypocalcemia has occurred in patients receiving romosozumab. Correct hypocalcemia prior to initiating romosozumab.
- Monitor patients for signs and symptoms of hypocalcemia. Patients should be adequately supplemented with calcium and vitamin D while on romosozumab.
- Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2) or receiving dialysis are at greater risk of developing hypocalcemia. Monitor serum calcium and adequately supplement patients who have severe renal impairment or are receiving dialysis with calcium and vitamin D. Instruct patients with severe renal impairment, including those receiving dialysis, about the symptoms of hypocalcemia and the importance of maintaining calcium levels with adequate calcium and vitamin D supplementation.
- Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients receiving romosozumab. A routine oral examination should be performed by the prescriber prior to initiation of romosozumab treatment. Concomitant administration of drugs associated with ONJ (chemotherapy, bisphosphonates, denosumab, angiogenesis inhibitors, and corticosteroids) may increase the risk of developing ONJ. Other risk factors for ONJ include cancer, radiotherapy, poor oral hygiene, pre-existing dental disease or infection, anemia, and coagulopathy.
- For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on benefit-risk assessment. Patients who are suspected of having or who develop ONJ while on romosozumab should receive care by a dentist or an oral surgeon. In these patients, dental surgery to treat ONJ may exacerbate the condition. Discontinuation of romosozumab should be considered based on benefit-risk assessment.
- Atypical low-energy or low trauma fractures of the femoral shaft have been reported in patients receiving romosozumab. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated.
- Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs.
- During romosozumab treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of romosozumab therapy should be considered based on benefit-risk assessment.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of romosozumab for the treatment of postmenopausal osteoporosis was evaluated in a multicenter, randomized, double-blind, placebo-controlled study (Study 1, NCT01575834) of 7180 postmenopausal women aged 55 to 90 years (mean age of 71 years). A total of 3581 and 3576 women received at least one dose of romosozumab and placebo, respectively, administered once every month during the 12-month double-blind study period. Women received at least 500 mg calcium and 600 international units of vitamin D supplementation daily and 77% received a loading dose of 50,000 to 60,000 international units of vitamin D within one week of randomization (if serum 25-hydroxyvitamin D concentrations were 40 ng/mL or less).
- The safety of romosozumab for the treatment of postmenopausal osteoporosis in patients at high risk of fracture was evaluated in a multicenter, randomized, double-blind, alendronate-controlled study (Study 2, NCT01631214) of 4093 postmenopausal women aged 55 to 90 years (mean age of 74 years). A total of 2040 and 2014 women received at least one dose of romosozumab and alendronate, respectively, during the 12-month double-blind study period. Women received at least 500 mg calcium and 600 international units vitamin D supplementation daily and 74% received a loading dose of 50,000 to 60,000 international units of vitamin D within one week of randomization (if serum 25-hydroxyvitamin D concentrations were 40 ng/mL or less).
- In Study 1, during the 12-month double-blind treatment period, the incidence of all-cause mortality was 0.7% (24/3576) in the placebo group and 0.8% (29/3581) in the romosozumab group. The incidence of nonfatal serious adverse events was 8.3% in the placebo group and 9.1% in the romosozumab group. The percentage of patients who withdrew from the study due to adverse events was 1.1% in the placebo group and 1.1% in the romosozumab group. The most common adverse reactions reported with romosozumab (greater than or equal to 5% and at a higher incidence than placebo) were arthralgia and headache. The most common adverse reaction leading to discontinuation of romosozumab was arthralgia (6 subjects [0.2%] in the placebo group and 5 subjects [0.1%] in the romosozumab group).
- In Study 2, during the 12-month double-blind treatment period, the incidence of all-cause mortality was 1.1% (22/2014) in the alendronate group and 1.5% (30/2040) in the romosozumab group. The incidence of nonfatal serious adverse events was 13.3% in the alendronate group and 11.9% in the romosozumab group. The percentage of patients who withdrew from the study due to adverse events was 1.2% in the alendronate group and 1.2% in the romosozumab group. The most common adverse reactions reported with romosozumab (greater than or equal to 5%) were arthralgia and headache.
- Table 1 outlines the most common adverse reactions occurring in greater than or equal to 2% of romosozumab treated women in at least one study.
- The adverse reactions described below are from the 12-month treatment periods of Study 1 (placebo-controlled) and Study 2 (alendronate-controllmed).
Major Adverse Cardiac Events (MACE)
- During the 12-month double-blind treatment period of the placebo-controlled trial (Study 1), myocardial infarction occurred in 9 women (0.3%) in the romosozumab group and 8 (0.2%) women in the placebo group; stroke occurred in 8 women (0.2%) in the romosozumab group and 10 (0.3%) women in the placebo group. These events occurred in patients with and without a history of myocardial infarction or stroke. Cardiovascular death occurred in 17 women (0.5%) in the romosozumab group and 15 (0.4%) women in the placebo group. The number of women with positively adjudicated MACE was 30 (0.8%) in the romosozumab group and 29 (0.8%) in the placebo group, yielding a hazard ratio of 1.03 (95% confidence interval [0.62, 1.72]) for romosozumab compared to placebo.
- During the 12-month double-blind treatment period of the active-controlled trial (Study 2), myocardial infarction occurred in 16 women (0.8%) in the romosozumab group and 5 (0.2%) women in the alendronate group; stroke occurred in 13 women (0.6%) in the romosozumab group and 7 (0.3%) women in the alendronate group. These events occurred in patients with and without a history of myocardial infarction or stroke. Cardiovascular death occurred in 17 women (0.8%) in the romosozumab group and 12 (0.6%) women in the alendronate group. The number of women with positively adjudicated MACE was 41 (2.0%) in the romosozumab group and 22 (1.1%) in the alendronate group, yielding a hazard ratio of 1.87 (95% confidence interval [1.11, 3.14]) for romosozumab compared to alendronate.
Hypersensitivity Reactions
- Across both trials, hypersensitivity reactions were reported in 364 (6.5%) women in the romosozumab group and 365 (6.5%) women in the control group. Reported reactions included angioedema (3 women [< 0.1%] in the romosozumab group vs. 3 [< 0.1%] women in the control group), erythema multiforme (1 woman [< 0.1%] in the romosozumab group vs. no woman in the control group), dermatitis (32 women [0.6%] in the romosozumab group vs. 42 women [0.8%] in the control group), rash (60 women [1.1%] in the romosozumab group vs. 53 women [0.9%] in the control group), and urticaria (23 women [0.4%] in the romosozumab group vs. 27 women [0.5%] in the control group). Although angioedema, dermatitis and urticaria were not reported at a higher incidence with romosozumab than control, there were cases of angioedema, dermatitis and urticaria that were determined to be related to romosozumab use.
Hypocalcemia
- Across both trials, adverse events of hypocalcemia occurred in 2 romosozumab-treated women and in 1 woman in the control group. Decreases in albumin-adjusted serum calcium to below the lower limit of the reference range (8.3 mg/dL) were reported in 14 (0.2%) women in the romosozumab group and 10 (0.2%) women in the control group. No patient receiving romosozumab developed serum calcium less than 7.5 mg/dL. The nadir in albumin-adjusted serum calcium occurred by month 1 after romosozumab dosing in patients with normal renal function.
Injection Site Reactions
- Across both trials, injection site reactions occurred in 278 (4.9%) women in the romosozumab group and 157 (2.8%) women in the control group. The most common injection site reactions were pain (94 [1.7%] women in the romosozumab group; 70 [1.3%] in the control group) and erythema (80 [1.4%] women in the romosozumab group and 14 [0.3%] women in the control group). Injection site reactions resulted in discontinuation of treatment in 7 (0.1%) romosozumab-treated patients and 3 (< 0.1%) patients in the control group.
Osteonecrosis of the Jaw
- Across both trials, osteonecrosis of the jaw occurred in one patient during treatment with romosozumab.
Atypical Subtrochanteric and Diaphysial Fractures
- Across both trials, atypical femoral fracture occurred in one patient during treatment with romosozumab.
## Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other romosozumab products may be misleading.
- The immunogenicity of romosozumab was evaluated using an immunoassay for the detection of anti-romosozumab-aqqg antibodies. An in vitro biological assay was performed to detect neutralizing antibodies for those subjects whose sera tested positive for anti-romosozumab-aqqg antibodies.
- Among 5914 postmenopausal women treated with romosozumab 210 mg monthly, 18.1% of subjects developed antibodies to romosozumab-aqqg. Of the subjects who developed antibodies to romosozumab-aqqg, 4.7% had antibodies that were classified as neutralizing. Development of antibodies to romosozumab-aqqg was associated with lower serum romosozumab-aqqg concentrations. Antibodies to romosozumab-aqqg were generally not associated with changes in the efficacy or safety of romosozumab.
## Postmarketing Experience
There is limited information regarding Romosozumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Romosozumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Romosozumab is not indicated for use in women of reproductive potential. In animal reproduction studies, weekly administration of romosozumab-aqqg to pregnant rats during the period of organogenesis at exposures greater than 32 times the clinical exposure produced skeletal abnormalities in the offspring. Administration of romosozumab-aqqg to rats prior to mating and through to the end of lactation produced minimal to slight decreases in femoral bone mineral density and/or cortical circumferences in the offspring at 1.5 to 56 times the expected exposure in humans.
Animal Data
- Reproductive and developmental effects of romosozumab-aqqg were assessed in the rat in a preliminary and definitive embryo-fetal development study, a combined fertility and embryo-development study, and a pre- and postnatal development study.
- Skeletal malformations including syndactyly and polydactyly occurred in 1 out of 75 litters across all rat reproductive toxicity studies, in the litter of a dam given weekly subcutaneous romosozumab-aqqg doses of 300 mg/kg (equivalent to at least 32 times the clinical exposure observed in humans following a monthly subcutaneous dose of 210 mg, based on area under the concentration-time curve [AUC] comparison).
- In the offspring of female rats given weekly romosozumab-aqqg doses from 6 weeks before cohabitation through mating and lactation, femoral periosteal and endocortical circumferences were slightly decreased at 10, 60, and 300 mg/kg (equivalent to 1.5, 19, and 56 times the clinical exposure following a monthly subcutaneous dose of 210 mg, based on AUC comparison). Cortical thickness was increased at 300 mg/kg (equivalent to 56 times expected clinical exposure). Femoral metaphysical bone mineral density was slightly decreased at 60 and 300 mg/kg (equivalent to 19 and 56 times expected clinical exposure).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Romosozumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Romosozumab during labor and delivery.
### Nursing Mothers
- Romosozumab is not indicated for use in women of reproductive potential. In animal studies where pregnant rats were given weekly doses of romosozumab-aqqg from 6 weeks before cohabitation through mating and lactation at 10, 60, or 300 mg/kg (equivalent to 1.5, 19 or 56 times the clinical exposure following a monthly subcutaneous dose of 210 mg, based on AUC comparison), romosozumab-aqqg was dose-dependently present in the serum of offspring on postnatal day 21 at 0.01 to 2.4 times maternal exposure due to gestational and/or lactational exposure.
### Pediatric Use
- Safety and effectiveness of romosozumab have not been established in pediatric patients.
### Geriatic Use
- Of the 6544 postmenopausal women with osteoporosis in the clinical studies of romosozumab, 5234 (80%) were age 65 years and over and 2390 (37%) were age 75 years and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
- Romosozumab is indicated for postmenopausal women.
### Race
There is no FDA guidance on the use of Romosozumab with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is required in patients with renal impairment.
- Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2 by MDRD equation) or receiving dialysis are at greater risk of developing hypocalcemia. Monitor calcium concentrations and adequately supplement calcium and vitamin D in patients who have severe renal impairment or are receiving dialysis.
### Hepatic Impairment
There is no FDA guidance on the use of Romosozumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Romosozumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Romosozumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Two separate syringes (and two separate subcutaneous injections) are needed to administer the total dose of 210 mg of romosozumab. Inject two 105 mg/1.17 mL prefilled syringes, one after the other.
- Romosozumab should be administered by a healthcare provider.
- The recommended dose of romosozumab is 210 mg administered subcutaneously in the abdomen, thigh or upper arm. Administer romosozumab once every month.
- The treatment duration for romosozumab is 12 monthly doses.
- Patients should be adequately supplemented with calcium and vitamin D during treatment with romosozumab.
- If the romosozumab dose is missed, administer as soon as it can be rescheduled. Thereafter, romosozumab can be scheduled every month from the date of the last dose.
Step 1. Prior to Administration:
- Remove two syringes from the carton.
- Visually inspect romosozumab for particles and discoloration prior to administration. Romosozumab is a clear to opalescent, colorless to light yellow solution. Do not use if the solution is cloudy or discolored or contains particles.
- Do not use the syringe if:
any part appears cracked or broken
the gray needle cap is missing or not securely attached
the expiration date printed on the label has passed
- any part appears cracked or broken
- the gray needle cap is missing or not securely attached
- the expiration date printed on the label has passed
- Always hold the prefilled syringe by the syringe barrel to remove the syringe from the tray. See Figure A.
Do not grasp the plunger rod.
Do not grasp the gray needle cap.
Do not remove the gray needle cap until you are ready to inject.
- Do not grasp the plunger rod.
- Do not grasp the gray needle cap.
- Do not remove the gray needle cap until you are ready to inject.
- Allow romosozumab to sit at room temperature for at least 30 minutes before injecting. Do not warm in any other way.
Step 2: Select the Injection Site and Prepare the Syringe
- Prepare and clean two injection sites, one for each of the two injections. See Figure B.
- The recommended subcutaneous injection sites include:
The thigh
Abdomen, except for a two-inch area right around the navel
Outer area of upper arm
- The thigh
- Abdomen, except for a two-inch area right around the navel
- Outer area of upper arm
- Clean the injection sites with alcohol wipes. Let the skin dry.
Choose a different site each time you give an injection. If you want to use the same injection site, make sure it is not the same spot on the injection site you used for a previous injection.
Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.
- Choose a different site each time you give an injection. If you want to use the same injection site, make sure it is not the same spot on the injection site you used for a previous injection.
- Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.
- Choose the first syringe. Pull the gray needle cap straight off and away from your body when you are ready to inject. See Figure C.
- Do not put the gray needle cap back onto the syringe.
Step 3: Inject romosozumab
- Insert needle and inject all the liquid subcutaneously. Do not administer into muscle or blood vessel. See Figure D.
- When done, gently lift the syringe off of the skin.
Step 4: Syringe and Needle Cap Disposal
- Immediately dispose of the syringe and needle cap in the nearest sharps container.
Important: Repeat all steps with the second syringe to inject the full dose.
### Monitoring
- Monitor for signs and symptoms of myocardial infarction and stroke and instruct patients to seek prompt medical attention if symptoms occur.
- Monitor patients for signs and symptoms of hypocalcemia. Patients should be adequately supplemented with calcium and vitamin D while on romosozumab.
- Monitor calcium concentrations and adequately supplement calcium and vitamin D in patients who have severe renal impairment or are receiving dialysis.
# IV Compatibility
There is limited information regarding the compatibility of Romosozumab and IV administrations.
# Overdosage
There is limited information regarding Romosozumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Romosozumab inhibits the action of sclerostin, a regulatory factor in bone metabolism. Romosozumab increases bone formation and, to a lesser extent, decreases bone resorption. Animal studies showed that romosozumab-aqqg stimulates new bone formation on trabecular and cortical bone surfaces by stimulating osteoblastic activity resulting in increases in trabecular and cortical bone mass and improvements in bone structure and strength.
## Structure
There is limited information regarding Romosozumab Structure in the drug label.
## Pharmacodynamics
- In postmenopausal women with osteoporosis, romosozumab increased the bone formation marker procollagen type 1 N-telopeptide (P1NP) with a peak increase from baseline of approximately 145% compared to placebo 2 weeks after initiating treatment, followed by a return to concentrations seen with placebo at month 9 and a decline from baseline to approximately 15% below the concentration change seen with placebo at month 12.
- Romosozumab decreased the bone resorption marker type 1 collagen C-telopeptide (CTX) with a maximal reduction from baseline of approximately 55% compared to placebo 2 weeks after initiating treatment. CTX remained below concentrations seen with placebo and was approximately 25% below the concentration change seen with placebo at month 12.
- After discontinuation of romosozumab, P1NP levels returned to baseline within 12 months; CTX increased above baseline levels within 3 months and returned toward baseline levels by month 12.
## Pharmacokinetics
- Administration of a single dose of 210 mg romosozumab in healthy volunteers resulted in a mean (standard deviation [SD]) maximum romosozumab-aqqg serum concentration (Cmax) of 22.2 (5.8) mcg/mL and a mean (SD) AUC of 389 (127) mcg*day/mL. Steady-state concentrations were achieved by month 3 following the monthly administration of 210 mg to postmenopausal women. The mean trough serum romosozumab-aqqg concentrations at months 3, 6, 9, and 12 ranged from 8 to 13 mcg/mL.
- Romosozumab-aqqg exhibited nonlinear pharmacokinetics with exposure increasing greater than dose proportionally (e.g., 550-fold increase in mean AUCinf for the 100-fold increase in subcutaneous doses ranging from 0.1 to 10 mg/kg [0.03 to 3.3 times the approved recommended dosage for a 70 kg woman).
Absorption
- The median time to maximum romosozumab-aqqg concentration (Tmax) is 5 days (range: 2 to 7 days).
Distribution
- The estimated volume of distribution at steady-state is approximately 3.92 L.
Elimination
- Romosozumab-aqqg exhibited nonlinear pharmacokinetics with the clearance of romosozumab-aqqg decreasing as the dose increased. The estimated mean systemic clearance (CL/F) of romosozumab-aqqg was 0.38 mL/hr/kg, following a single subcutaneous administration of 3 mg/kg (the approved recommended dosage for a 70 kg woman). The mean effective t1/2 was 12.8 days after 3 doses of 3 mg/kg (the approved recommended dosage for a 70 kg woman) every 4 weeks.
Metabolism
- The metabolic pathway of romosozumab-aqqg has not been characterized. As a humanized IgG2 monoclonal antibody, romosozumab-aqqg is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
Anti-Product Antibody Formation Affecting Pharmacokinetics
- Development of anti-romosozumab-aqqg antibodies was associated with reduced serum romosozumab-aqqg concentrations. The presence of anti-romosozumab-aqqg antibodies led to decreased mean romosozumab-aqqg concentrations up to 22%. The presence of neutralizing antibodies led to decreased mean romosozumab-aqqg concentrations up to 63%.
Specific Populations
- No clinically significant differences in the pharmacokinetics of romosozumab-aqqg were observed based on age (20-89 years), sex, race, disease state (low bone mass or osteoporosis), prior exposure to alendronate, or renal impairment including end-stage renal disease (ESRD) requiring dialysis. The effect of ESRD not requiring dialysis on the pharmacokinetics of romosozumab-aqqg is unknown.
Body Weight
- The exposure of romosozumab-aqqg decreases with increasing body weight.
## Nonclinical Toxicology
Carcinogenicity
- In a rat carcinogenicity study, once-weekly romosozumab-aqqg doses of 3, 10 or 50 mg/kg were administered by subcutaneous injection to Sprague-Dawley rats from 8 weeks up to 98 weeks of age, resulting in systemic exposures that were up to 19 times the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison). Romosozumab-aqqg caused a dose-dependent increase in bone mass with trabecular and cortical bone thickening at all doses. There were no effects of romosozumab-aqqg on mortality and romosozumab-aqqg did not cause significant increases in tumor incidence in male or female rats.
Mutagenicity
- Mutagenesis has not been evaluated, as monoclonal antibodies are not expected to alter DNA or chromosomes.
Impairment of Fertility
- No effects on fertility were observed in male and female rats given subcutaneous romosozumab-aqqg doses up to 300 mg/kg (up to 56 times the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab, based on AUC comparison). No effects were noted in reproductive organs in rats and cynomolgus monkeys dosed subcutaneously for 6 months with weekly doses up to 100 mg/kg (exposures up to 38 and 93 times, respectively, the systemic exposure observed in humans administered monthly subcutaneous doses of 210 mg based on AUC comparison).
- No adverse effects were noted in rats and monkeys after 26 once-weekly subcutaneous romosozumab-aqqg doses up to 100 mg/kg, equivalent to systemic exposures of 38 and 93 times, respectively, the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison).
- Bone safety studies of up to 12-month duration were conducted in ovariectomized rats and monkeys with once-weekly romosozumab-aqqg doses yielding exposures ranging from 1 to 22 times the systemic exposure in humans given monthly doses of 210 mg, based on AUC comparison. Romosozumab-aqqg increased bone mass and improved cancellous bone microarchitecture and cortical bone geometry by increasing bone formation on periosteal, endocortical, and trabecular surfaces, and decreasing bone resorption on trabecular and endocortical surfaces. The increases in bone mass were significantly correlated with increases in bone strength. In rats and monkeys, bone quality was maintained at all skeletal sites at doses ranging from 1 to 22 times human exposure, and slightly improved in vertebrae at 19 to 22 times human exposure. There was no evidence of mineralization defects, osteoid accumulation, or woven bone formation.
# Clinical Studies
Study 1 (NCT01575834) was a randomized, double-blind, placebo-controlled study of postmenopausal women aged 55 to 90 years (mean age of 71 years) with bone mineral density (BMD) T-score less than or equal to −2.5 at the total hip or femoral neck. Women were randomized to receive subcutaneous injections of either romosozumab (N = 3589) or placebo (N = 3591) for 12 months. At baseline, 18% of women had a vertebral fracture. After the 12-month treatment period, women in both arms transitioned to open-label anti-resorptive therapy (denosumab) for 12 months while remaining blinded to their initial treatment. Women received 500 to 1000 mg calcium and 600 to 800 international units vitamin D supplementation daily. The coprimary efficacy endpoints were new vertebral fracture at month 12 and month 24.
Effect on Fractures
- Romosozumab significantly reduced the incidence of new vertebral fractures through month 12 compared to placebo. In addition, the significant reduction in fracture risk persisted through the second year in women who received romosozumab during the first year and transitioned to denosumab compared to those who transitioned from placebo to denosumab (see Table 2).
- Romosozumab significantly reduced the incidence of clinical fracture (a composite endpoint of symptomatic vertebral fracture and nonvertebral fracture) at 12 months. However, 88% of these clinical fractures were nonvertebral fractures and the incidence of nonvertebral fractures was not statistically significantly different when comparing romosozumab-treated women to placebo-treated women at month 12 or month 24.
Effect on BMD
- Romosozumab significantly increased BMD at the lumbar spine, total hip, and femoral neck compared with placebo at month 12. The treatment differences in BMD were 12.7% at the lumbar spine, 5.8% at the total hip, and 5.2% at the femoral neck.
- Following the transition from romosozumab to denosumab at month 12, BMD continued to increase through month 24. In patients who transitioned from placebo to denosumab, BMD also increased with denosumab use. The differences in BMD achieved at month 12 between romosozumab and placebo patients were overall maintained at month 24, when comparing patients who transitioned from romosozumab to denosumab to those who transitioned from placebo to denosumab. There was no evidence of differences in effects on BMD at the lumbar spine or total hip across subgroups defined by baseline age, baseline BMD, or geographic region.
- After romosozumab discontinuation, BMD returns to approximately baseline levels within 12 months in the absence of follow-on antiresorptive therapy.
Bone Histology and Histomorphometry
- A total of 154 transiliac crest bone biopsy specimens were obtained from 139 postmenopausal women with osteoporosis at month 2, month 12, and/or month 24. All of these biopsies were adequate for qualitative histology and 138 (90%) were adequate for full quantitative histomorphometry assessment. Qualitative histology assessments from women treated with romosozumab showed normal bone architecture and quality at all time points. There was no evidence of woven bone, mineralization defects, or marrow fibrosis.
- Histomorphometry assessments on biopsies at months 2 and 12 compared the effect of romosozumab with placebo (15 specimens at month 2 and 39 specimens at month 12 in the romosozumab group, 14 specimens at month 2 and 31 specimens at month 12 in the placebo group). At month 2 in women treated with romosozumab, histomorphometric indices of bone formation at trabecular and endocortical surfaces were increased. These effects on bone formation were accompanied by a decrease in indices of bone resorption. At month 12, both bone formation and resorption indices were decreased with romosozumab, while bone volume, and trabecular and cortical thickness were increased.
Study 2 (NCT01631214) was a randomized, double-blind, alendronate-controlled study of postmenopausal women aged 55 to 90 years (mean age of 74 years) with BMD T-score less than or equal to −2.5 at the total hip or femoral neck and either one moderate or severe vertebral fracture or two mild vertebral fractures, or BMD T-score less than or equal to -2.0 at the total hip or femoral neck and either two moderate or severe vertebral fractures or a history of a proximal femur fracture. Women were randomized (1:1) to receive either monthly subcutaneous injections of romosozumab (N = 2046) or oral alendronate 70 mg weekly (N = 2047) for 12 months, with 500 to 1000 mg calcium and 600 to 800 international units vitamin D supplementation daily. After the 12-month treatment period, women in both arms transitioned to open-label alendronate 70 mg weekly while remaining blinded to their initial treatment.
- This was an event driven trial. The coprimary efficacy endpoints were the incidence of morphometric vertebral fracture at 24 months and time to the first clinical fracture through the primary analysis period, which ended when at least 330 subjects had a clinical fracture and all subjects had completed the 24-month visit. Clinical fracture was a composite endpoint of nonvertebral fracture and symptomatic vertebral fracture.
Effect on Fractures
- Romosozumab significantly reduced the incidence of new vertebral fracture at 24 months (see Table 3).
- Romosozumab significantly reduced the risk of clinical fracture through the end of the primary analysis period (see Table 4). This was an event-driven trial and the duration of follow-up varied across subjects. The median duration of subject follow-up for the primary analysis period was 33 months. Subjects with nonvertebral fracture comprised 83% of the subjects with clinical fracture during the primary analysis period.
- Romosozumab followed by alendronate also significantly reduced the risk of nonvertebral fracture through the primary analysis period (with a median follow-up of 33 months), with a hazard ratio of 0.81 (95% CI: 0.66, 0.99; p = 0.04) compared to alendronate alone.
Effect on Bone Mineral Density (BMD)
- Romosozumab significantly increased BMD at the lumbar spine, total hip, and femoral neck compared with alendronate at month 12. The treatment differences in BMD were 8.7% at the lumbar spine, 3.3% at the total hip, and 3.2% at the femoral neck.
- Twelve months of treatment with romosozumab followed by 12 months of treatment with alendronate significantly increased BMD compared with alendronate alone. The BMD increase with romosozumab over alendronate observed at month 12 was maintained at month 24. The treatment differences in BMD at month 24 were 8.1% at the lumbar spine, 3.8% at the total hip, and 3.8% at the femoral neck.
- There was no evidence of differences in effects on BMD at the lumbar spine or total hip across subgroups defined by baseline age, baseline BMD, or geographic region.
# How Supplied
- Romosozumab (romosozumab-aqqg) injection is a clear to opalescent, colorless to light yellow solution for subcutaneous injection supplied in a single-use prefilled syringe.
- Each single-use prefilled syringe contains 105 mg of romosozumab in a deliverable volume of 1.17 mL. To deliver a full dose, inject two 105 mg/1.17 mL romosozumab prefilled syringes, one after the other for a total dose of 210 mg.
## Storage
- Refrigerate romosozumab at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.
- If removed from the refrigerator, romosozumab can be kept at room temperature up to 25°C (77°F) in the original carton and must be used within 30 days. If not used within 30 days, discard romosozumab.
- Do not expose romosozumab to temperatures above 25°C (77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).
Major Adverse Cardiac Events
- Advise patients to seek immediate medical attention if they experience signs or symptoms of a myocardial infarction or stroke.
Hypersensitivity Reactions
- Advise patients to seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction including angioedema, erythema multiforme, dermatitis, rash, and urticaria.
Calcium and Vitamin D Supplements to Prevent Hypocalcemia
- Advise patients to take calcium and vitamin D supplements daily to reduce the risk of hypocalcemia. Advise patients to seek immediate medical attention for symptoms of hypocalcemia.
Osteonecrosis of the Jaw
- Advise patients to practice good oral hygiene during treatment with romosozumab and tell their dentist that they are receiving romosozumab before having dental work.
Atypical Femoral Fracture
- Advise patients to report signs and symptoms that could be consistent with impending atypical femoral fracture including new or unusual thigh, hip, or groin pain.
## Medication Guide
# Precautions with Alcohol
Alcohol-Romosozumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Evenity
# Look-Alike Drug Names
There is limited information regarding Romosozumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Evenity | |
31071f32e4142c0a5c82ed103035dc6fad0332bb | wikidoc | Excoriation | Excoriation
An excoriation is an erosion or destruction of the skin by mechanical means, which appears in the form of a scratch or abrasion of the skin. It is commonly seen in other skin disorders causing itching/pruritus: dry skin, dermatitis, atopic dermatitis, scabies, etc. The condition is characteristic of a symptom of other illnesses like liver failure where pruritus is caused by increases of bilirubin.
The term can be associated with neurotic excoriations. Neurotic excoriations are considered psychiatric in etiology. A patient with neurotic excoriations should try to avoid picking and scratching their skin. Because of this, another diagnosis should be made if the lesions are found on areas where the hands do not make contact. It doesn't exclude the possibility, but makes it less likely. The disorder is typically found among females more than males. Damage is common on the face, neck, back, and extremities, and damage to the skin is generally caused by rubbing, scratching, and picking. Severe itching from other causes may mimic this disorder.
Diagnosis is often made by exclusion and is identified and isolated by bandaging areas affected unless any improvement to the affected area or significant change in behavior is witnessed.
Treatment may include periodic bandaging, psychiatric guidance with life adjustments, lotions with or without menthol and phenol (hopefully to take the place of scratching). Antidepressants may work in patients with neurotic excoriations. Other medications like bedtime antihistamines, antipruritic, sometimes pimozide, or topical corticosteroids are used if there is another reason for the scratching. These are reserved for other conditions and further work up should be pursued.
de:Exkoriation
nl:Excoriatie | Excoriation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
An excoriation is an erosion or destruction of the skin by mechanical means, which appears in the form of a scratch or abrasion of the skin. It is commonly seen in other skin disorders causing itching/pruritus: dry skin, dermatitis, atopic dermatitis, scabies, etc. The condition is characteristic of a symptom of other illnesses like liver failure where pruritus is caused by increases of bilirubin.
The term can be associated with neurotic excoriations. Neurotic excoriations are considered psychiatric in etiology. A patient with neurotic excoriations should try to avoid picking and scratching their skin. Because of this, another diagnosis should be made if the lesions are found on areas where the hands do not make contact. It doesn't exclude the possibility, but makes it less likely. The disorder is typically found among females more than males. Damage is common on the face, neck, back, and extremities, and damage to the skin is generally caused by rubbing, scratching, and picking. Severe itching from other causes may mimic this disorder.
Diagnosis is often made by exclusion and is identified and isolated by bandaging areas affected unless any improvement to the affected area or significant change in behavior is witnessed.
Treatment may include periodic bandaging, psychiatric guidance with life adjustments, lotions with or without menthol and phenol (hopefully to take the place of scratching). Antidepressants may work in patients with neurotic excoriations. Other medications like bedtime antihistamines, antipruritic, sometimes pimozide, or topical corticosteroids are used if there is another reason for the scratching. These are reserved for other conditions and further work up should be pursued.
de:Exkoriation
nl:Excoriatie
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Excoriation | |
4f990909b796e7fe929f0c50655ce66d83ae8de9 | wikidoc | Exfoliation | Exfoliation
Exfoliation has several meanings:
- Exfoliation (botany) describes the loss of leaves (or, in some cases, pieces of bark) from a plant.
- Exfoliation (cosmetology), is a cosmetic technique aimed at removing dead skin cells from the face and body.
- Exfoliation (geology) is a weathering process.
- Exfoliation (material science) is the process responsible for breaking up particle aggregates. | Exfoliation
Exfoliation has several meanings:
- Exfoliation (botany) describes the loss of leaves (or, in some cases, pieces of bark) from a plant.
- Exfoliation (cosmetology), is a cosmetic technique aimed at removing dead skin cells from the face and body.
- Exfoliation (geology) is a weathering process.
- Exfoliation (material science) is the process responsible for breaking up particle aggregates.
Template:Disambig
Template:WS | https://www.wikidoc.org/index.php/Exfoliation | |
670964e0a3f46d289c5cce7e05247b0ffc3ff7c1 | wikidoc | Exotic atom | Exotic atom
An exotic atom is a normal atom in which one or more sub-atomic particles have been replaced by other particles of the same charge. For example, electrons may be replaced by other negatively charged particles such as muons or pions, or the positively charged proton which is the nucleus of the hydrogen-1 atom may be replaced by other positively charged particles, or both. Because these substitute particles are either unstable, interact with the nucleus, or both, exotic atoms have a short half-life.
# Muonic atoms
In a muonic atom, an electron is replaced by a muon, which, like the electron, is a lepton. Since leptons are only sensitive to weak, electromagnetic and gravitational forces, muonic atoms are governed to very high precision by the electromagnetic interaction. There are no complications due to strong forces between the lepton and the nucleus.
Since a muon is more massive than an electron, the Bohr orbits are closer to the nucleus in a muonic atom than in an ordinary atom, and corrections due to quantum electrodynamics are more important. Study of muonic atoms' energy levels as well as transition rates from excited states to the ground state therefore provide experimental tests of quantum electrodynamics.
Muon-catalyzed fusion is a technical application of muonic atoms.
# Hadronic atoms
A hadronic atom is an atom in which one or more of the orbital electrons has been replaced by a hadron. Possible hadrons include mesons such as the pion or kaon, yielding a mesonic atom, antiprotons, yielding a antiprotonic atom, and the Template:SubatomicParticle particle, yielding a Template:SubatomicParticle or sigmaonic atom.
Unlike leptons, hadrons can interact via the strong force, so the energy levels of hadronic atoms are influenced by nuclear forces between the nucleus and the hadron. Since the strong force is a short-range interaction, these effects are strongest if the atomic orbital involved is close to the nucleus, when the energy levels involved may broaden or disappear because of the absorption of the hadron by the nucleus. Hadronic atoms, such as pionic hydrogen and kaonic hydrogen, thus provide interesting experimental probes of the theory of strong interactions, quantum chromodynamics.
# Onium
An onium (plural: onia) is the bound state of a particle and its antiparticle. The classic onium is positronium, which consists of an electron and a positron bound together as a long-lived metastable state. Positronium has been studied since the 1950s to understand bound states in quantum field theory. A recent development called non-relativistic quantum electrodynamics (NRQED) used this system as a proving ground.
Pionium, a bound state of two oppositely-charged pions, is interesting for exploring the strong interaction. This should also be true of protonium. The true analogs of positronium in the theory of strong interactions, however, are not exotic atoms but certain mesons, the quarkonium states, which are made of a heavy quark such as the charm or bottom quark and its antiquark. (Top quarks are so heavy that they decay through the weak force before they can form bound states.) Exploration of these states through non-relativistic quantum chromodynamics (NRQCD) and lattice QCD are increasingly important tests of quantum chromodynamics.
Muonium, despite its name, is not an onium containing a muon and an antimuon, because IUPAC assigned that name to the system of an antimuon bound with an electron.
Understanding bound states of hadrons such as pionium and protonium is also important in order to clarify notions related to exotic hadrons such as mesonic molecules and pentaquark states.
# Hypernuclear atoms
Atoms may be composed of electrons orbiting a hypernucleus that includes strange particles called hyperons. Such hypernuclear atoms are generally studied for their nuclear behaviour, falling into the realm of nuclear physics rather than atomic physics.
# Quasiparticle atoms
In condensed matter systems, specifically in some semiconductors, there are states called excitons which are bound states of an electron and an electron hole. | Exotic atom
Template:TOCright
An exotic atom is a normal atom in which one or more sub-atomic particles have been replaced by other particles of the same charge. For example, electrons may be replaced by other negatively charged particles such as muons or pions, or the positively charged proton which is the nucleus of the hydrogen-1 atom may be replaced by other positively charged particles, or both.[1][2] Because these substitute particles are either unstable, interact with the nucleus, or both, exotic atoms have a short half-life.
# Muonic atoms
In a muonic atom, an electron is replaced by a muon, which, like the electron, is a lepton. Since leptons are only sensitive to weak, electromagnetic and gravitational forces, muonic atoms are governed to very high precision by the electromagnetic interaction. There are no complications due to strong forces between the lepton and the nucleus.
Since a muon is more massive than an electron, the Bohr orbits are closer to the nucleus in a muonic atom than in an ordinary atom, and corrections due to quantum electrodynamics are more important. Study of muonic atoms' energy levels as well as transition rates from excited states to the ground state therefore provide experimental tests of quantum electrodynamics.
Muon-catalyzed fusion is a technical application of muonic atoms.
# Hadronic atoms
A hadronic atom is an atom in which one or more of the orbital electrons has been replaced by a hadron.[3] Possible hadrons include mesons such as the pion or kaon, yielding a mesonic atom, antiprotons, yielding a antiprotonic atom, and the Template:SubatomicParticle particle, yielding a Template:SubatomicParticle or sigmaonic atom.[4][5][6]
Unlike leptons, hadrons can interact via the strong force, so the energy levels of hadronic atoms are influenced by nuclear forces between the nucleus and the hadron. Since the strong force is a short-range interaction, these effects are strongest if the atomic orbital involved is close to the nucleus, when the energy levels involved may broaden or disappear because of the absorption of the hadron by the nucleus.[2][5] Hadronic atoms, such as pionic hydrogen and kaonic hydrogen, thus provide interesting experimental probes of the theory of strong interactions, quantum chromodynamics.[7]
# Onium
An onium (plural: onia) is the bound state of a particle and its antiparticle. The classic onium is positronium, which consists of an electron and a positron bound together as a long-lived metastable state. Positronium has been studied since the 1950s to understand bound states in quantum field theory. A recent development called non-relativistic quantum electrodynamics (NRQED) used this system as a proving ground.
Pionium, a bound state of two oppositely-charged pions, is interesting for exploring the strong interaction. This should also be true of protonium. The true analogs of positronium in the theory of strong interactions, however, are not exotic atoms but certain mesons, the quarkonium states, which are made of a heavy quark such as the charm or bottom quark and its antiquark. (Top quarks are so heavy that they decay through the weak force before they can form bound states.) Exploration of these states through non-relativistic quantum chromodynamics (NRQCD) and lattice QCD are increasingly important tests of quantum chromodynamics.
Muonium, despite its name, is not an onium containing a muon and an antimuon, because IUPAC assigned that name to the system of an antimuon bound with an electron.
Understanding bound states of hadrons such as pionium and protonium is also important in order to clarify notions related to exotic hadrons such as mesonic molecules and pentaquark states.
# Hypernuclear atoms
Atoms may be composed of electrons orbiting a hypernucleus that includes strange particles called hyperons. Such hypernuclear atoms are generally studied for their nuclear behaviour, falling into the realm of nuclear physics rather than atomic physics.
# Quasiparticle atoms
In condensed matter systems, specifically in some semiconductors, there are states called excitons which are bound states of an electron and an electron hole. | https://www.wikidoc.org/index.php/Exotic_atom | |
bce4edcd9866af6cbdf51af5f7794720bacfd687 | wikidoc | Eye circles | Eye circles
# Overview
Dark circles or Eye circles are dark blemishes around the eyes. Also known as "bags under the eyes," there are many etiologies to cause this symptom. For instance, by lack of sleep, by deficiency of vitamin K, by heredity and by bruising.
# Causes
## Common Causes
### Heredity
Like varicose veins, dark circles under the eyes are usually an inherited trait. The skin under the eye is very thin. When blood passes through the large veins close to the surface of the skin it can produce a bluish tint. The more transparent the skin -- also an inherited trait -- the darker the circles appear.
In people with a deep-set bone structure, shadowing contributes to the dark color under the eyes.
### Allergies, asthma, and eczema
Any condition that causes the eyes to itch can contribute to darker circles due to rubbing or scratching the skin around them. Hay fever sufferers particularly will notice under-eye "smudges" during the height of the allergy season. Some food allergies can also cause the area under the eyes to appear darker.
### Medications
Any medications that cause blood vessels to dilate can cause circles under the eyes to darken. Because the skin under the eyes is very delicate, any increased blood flow shows through the skin.
### Anemia
The lack of nutrients in the diet, or the lack of a balanced diet, can contribute to the discoloration of the area under the eyes. It is believed that lack of mineral iron can cause dark circles as well. Iron deficiency is the most common type of anemia and this condition is a sign that not enough oxygen is getting to the body tissues.
The skin can also become more pale during pregnancy and menstruation (due to lack of iron), which again allow the underlying veins under the eyes to become more visible.
### Fatigue
A lack of sleep or excessive tiredness can cause paleness of the skin, which again allows the blood underneath the skin to become more visible and appear more blue or darker.
Some skin care experts say that fatigue has nothing to do with the dark circles, but it has to do with when one lies down. Gravity can cause fluid to collect in the lower eye lid.
### Age
Dark circles are likely to become more noticeable and permanent with age. Excess folds of skin under the eyes will also make dark circles more pronounced.
### Medical conditions
Another cause may be bad blood circulation. Cardio exercise increases blood circulation and may help the dark circles to disappear.
The area directly located under the eyes are closely related to kidneys and liver, so the appearance of dark circles may indicate problems or weakness in the kidney or liver activity.
Dark eye circles could be a sign of excessive loss of water from the body (dehydration).
## Causes by Organ System
## Causes in Alphabetical Order
# Cures
Although to date, there has been no end-all to curing or reducing dark circles, there are many home-made ingredients that can help make the dark circles less visible. For example it is said that putting teabags under the eyes, drinking plenty of fluids and a lot of rest can suffice. Make-up can be used to change the coloration of any exposed skin.
Vasoconstrictors
The Preparation H version with phenylephrine HCl 0.25% will constrict the capillaries resulting in the temporary reduction of the appearance of dark circles.
The cream has less petrolatum than the ointment which is important to avoid the greasy appearance.
Other vasoconstrictors such as tetrahydrozoline hydrochloride as found in Visine may offer similar temporary results. Use should be limited in order to avoid a rebound effect. | Eye circles
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dark circles or Eye circles are dark blemishes around the eyes. Also known as "bags under the eyes," there are many etiologies to cause this symptom.[1] For instance, by lack of sleep, by deficiency of vitamin K, by heredity and by bruising.
# Causes
## Common Causes
### Heredity
Like varicose veins, dark circles under the eyes are usually an inherited trait. The skin under the eye is very thin. When blood passes through the large veins close to the surface of the skin it can produce a bluish tint. The more transparent the skin -- also an inherited trait -- the darker the circles appear.
In people with a deep-set bone structure, shadowing contributes to the dark color under the eyes.
### Allergies, asthma, and eczema
Any condition that causes the eyes to itch can contribute to darker circles due to rubbing or scratching the skin around them. Hay fever sufferers particularly will notice under-eye "smudges" during the height of the allergy season. Some food allergies can also cause the area under the eyes to appear darker.
### Medications
Any medications that cause blood vessels to dilate can cause circles under the eyes to darken. Because the skin under the eyes is very delicate, any increased blood flow shows through the skin.
### Anemia
The lack of nutrients in the diet, or the lack of a balanced diet, can contribute to the discoloration of the area under the eyes. It is believed that lack of mineral iron can cause dark circles as well. Iron deficiency is the most common type of anemia and this condition is a sign that not enough oxygen is getting to the body tissues.
The skin can also become more pale during pregnancy and menstruation (due to lack of iron), which again allow the underlying veins under the eyes to become more visible.
### Fatigue
A lack of sleep or excessive tiredness can cause paleness of the skin, which again allows the blood underneath the skin to become more visible and appear more blue or darker.
Some skin care experts say that fatigue has nothing to do with the dark circles, but it has to do with when one lies down. Gravity can cause fluid to collect in the lower eye lid.
### Age
Dark circles are likely to become more noticeable and permanent with age. Excess folds of skin under the eyes will also make dark circles more pronounced.
### Medical conditions
Another cause may be bad blood circulation. Cardio exercise increases blood circulation and may help the dark circles to disappear.
The area directly located under the eyes are closely related to kidneys and liver, so the appearance of dark circles may indicate problems or weakness in the kidney or liver activity.
Dark eye circles could be a sign of excessive loss of water from the body (dehydration).
## Causes by Organ System
## Causes in Alphabetical Order
# Cures
Although to date, there has been no end-all to curing or reducing dark circles, there are many home-made ingredients that can help make the dark circles less visible. For example it is said that putting teabags under the eyes, drinking plenty of fluids and a lot of rest can suffice. Make-up can be used to change the coloration of any exposed skin.
Vasoconstrictors
The Preparation H version with phenylephrine HCl 0.25% will constrict the capillaries resulting in the temporary reduction of the appearance of dark circles.
The cream has less petrolatum than the ointment which is important to avoid the greasy appearance.
Other vasoconstrictors such as tetrahydrozoline hydrochloride as found in Visine may offer similar temporary results. Use should be limited in order to avoid a rebound effect. | https://www.wikidoc.org/index.php/Eye_bag | |
ba87d47dca30b3c1d2131c799e7097f8b5eef79d | wikidoc | Eye surgery | Eye surgery
# Overview
Eye surgery, also known as ophthalmic surgery or ocular surgery, is surgery performed on the eye or its adnexa, typically by an ophthalmologist. Although most eye surgery can be performed by an experienced general ophthalmologist, more complex procedures are usually done by one who is fellowship trained.
# Preparation and precautions
The eye is a delicate organ, requiring extreme care before, during and after a surgical procedure. An expert ophthalmologist must identify the need for specific procedure and be responsible for conducting the procedure safely. Many university programs allow patients to specify if they want to be operated upon by the consultant or the resident / fellow.
Proper anesthesia is a must for any eye surgery. Local anesthesia is most commonly used. Retrobulbar and peribulbar techniques for infiltrating the local area surrounding the eye muscle cone are used to immobilize the extraocular muscles and eliminate pain sensation. Topical anesthesia using lidocaine topical gel is preferred for quick procedures. In topical anesthesia, patient cooperation is a must for a smooth procedure. General anesthesia is recommended for children, traumatic eye injuries, major orbitotomies and for apprehensive patients. Cardiovascular monitoring is preferable in local anesthesia and is mandatory in general anesthesia. Proper sterile precautions are taken to prepare the area for surgery, including use of antiseptics like povidone-iodine. Sterile drapes, gowns and gloves are a must. A plastic sheet with a receptacle helps collect the fluids during phacoemulsification. An eye speculum is inserted to keep the eyes wide open. For anxious patients, supplementation with a facial nerve block using lidocaine and bupivacaine is recommended.
# Laser eye surgery
Although the terms Laser Eye Surgery and Refractive surgery are commonly used as if they were interchangeable, this is not the case. Lasers may be used to treat nonrefractive conditions (e.g. to seal a retinal tear), while radial keratotomy is an example of refractive surgery without the use of a laser.
# Cataract surgery
A cataract is an opacification or cloudiness of the eye's crystalline lens due to aging, disease, or trauma that typically prevents light from forming a clear image on the retina. If visual loss is significant, surgical removal of the lens may be warranted, with lost optical power usually replaced with a plastic intraocular lens (IOL). Due to the high prevalence of cataracts, cataract extraction is the most common eye surgery.
# Glaucoma surgery
Glaucoma is a group of diseases affecting the optic nerve that results in vision loss and is frequently characterized by raised intraocular pressure (IOP). There are many types of glaucoma surgery, and variations or combinations of those types, that facilitate the escape of excess aqueous humor from the eye to lower intraocular pressure, and a few that lower IOP by decreasing the production of aqueous.
### Canaloplasty
Canaloplasty is an advanced, nonpenetrating procedure designed to enhance drainage through the eye’s natural drainage system to provide sustained reduction of IOP. Canaloplasty utilizes microcatheter technology in a simple and minimally invasive procedure.
To perform a canaloplasty, an Ophthalmologist creates a tiny incision to gain access to a canal in the eye. A microcatheter circumnavigates the canal around the iris, enlarging the main drainage channel and its smaller collector channels through the injection of a sterile, gel-like material called viscoelastic. The catheter is then removed and a suture is placed within the canal and tightened. By opening up the canal, the pressure inside the eye can be reduced.
# Refractive surgery
- Refractive surgery aims to correct errors of refraction in the eye, reducing or eliminating the need for corrective lenses
Keratomilleusis is method of reshaping the cornea surface to change its optical power. A disc of cornea is shaved off, quickly frozen, lathe-ground, then returned to its original power.
Automated lamellar keratoplasty (ALK)
Laser assisted in-situ keratomileusis (LASIK)
IntraLASIK
Laser assisted sub-epithelial keratomileusis (LASEK), aka Epi-LASIK
Photorefractive keratectomy (PRK)
Laser thermal keratoplasty (LTK)
Conductive keratoplasty (CK) uses radio frequency waves to shrink corneal collagen. It is used to treat mild to moderate hyperopia.
Limbal relaxing incisions (LRI)
Astigmatic keratotomy (AK), aka Arcuate keratotomy or Transverse keratotomy
Radial keratotomy (RK)
Hexagonal keratotomy (HK)
Epikeratophakia is the removal of the corneal epithelium and replacement with a lathe cut corneal button.
Intracorneal rings (ICRs), or corneal ring segments (Intacs)
Implantable contact lenses
- Keratomilleusis is method of reshaping the cornea surface to change its optical power. A disc of cornea is shaved off, quickly frozen, lathe-ground, then returned to its original power.
- Automated lamellar keratoplasty (ALK)
- Laser assisted in-situ keratomileusis (LASIK)
IntraLASIK
- IntraLASIK
- Laser assisted sub-epithelial keratomileusis (LASEK), aka Epi-LASIK
- Photorefractive keratectomy (PRK)
- Laser thermal keratoplasty (LTK)
- Conductive keratoplasty (CK) uses radio frequency waves to shrink corneal collagen. It is used to treat mild to moderate hyperopia.
- Limbal relaxing incisions (LRI)
- Astigmatic keratotomy (AK), aka Arcuate keratotomy or Transverse keratotomy
- Radial keratotomy (RK)
- Hexagonal keratotomy (HK)
- Epikeratophakia is the removal of the corneal epithelium and replacement with a lathe cut corneal button.
- Intracorneal rings (ICRs), or corneal ring segments (Intacs)
- Implantable contact lenses
- Presbyopia reversal
Anterior ciliary sclerotomy (ACS)
Laser reversal of presbyopia (LRP)
Scleral expansion bands
- Anterior ciliary sclerotomy (ACS)
Laser reversal of presbyopia (LRP)
- Laser reversal of presbyopia (LRP)
- Scleral expansion bands
# Corneal surgery
- Corneal surgery includes most refractive surgery as well as the following:
Corneal transplant surgery, is used to remove a cloudy/diseased cornea and replace it with a clear donor cornea.
Penetrating keratoplasty (PK)
Boston Keratoprosthesis(KPro)
Phototherapeutic keratectomy (PTK)
Pterygium excision
Corneal tattooing
- Corneal transplant surgery, is used to remove a cloudy/diseased cornea and replace it with a clear donor cornea.
Penetrating keratoplasty (PK)
Boston Keratoprosthesis(KPro)
- Penetrating keratoplasty (PK)
- Boston Keratoprosthesis(KPro)
- Phototherapeutic keratectomy (PTK)
- Pterygium excision
- Corneal tattooing
# Vitreo-retinal surgery
- Vitreo-retinal surgery includes the following
Vitrectomy
Anterior vitrectomy is the removal of the front portion of vitreous tissue. It is used for preventing or treating vitreous loss during cataract or corneal surgery, or to remove misplaced vitreous in conditions such as aphakia pupillary block glaucoma.
Pars plana vitrectomy (PPV), or trans pars plana vitrectomy (TPPV), is a procedure to remove vitreous opacities and membranes through a pars plana incision. It is frequently combined with other intraocular procedures for the treatment of giant retinal tears, tractional retinal detachments, and posterior vitreous detachments .
Pan retinal photocoagulation (PRP) is a type of photocoagulation therapy used in the treatment of diabetic retinopathy.
Retinal detachment repair
Ignipuncture is an obsolete procedure that involves cauterization of the retina with a very hot pointed instrument.
A scleral buckle is used in the repair of a retinal detachment to indent or "buckle" the sclera inward, usually by sewing a piece of preserved sclera or silicone rubber to its surface.
Laser photocoagulation, or photocoagulation therapy, is the use of a laser to seal a retinal tear.
Pneumatic retinopexy
Retinal cryopexy, or retinal cryotherapy, is a procedure that uses intense cold to induce a chorioretinal scar and to destroy retinal or choroidal tissue.
Macular hole repair
Partial lamellar sclerouvectomy
Partial lamellar sclerocyclochoroidectomy
Partial lamellar sclerochoroidectomy
Posterior sclerotomy is an opening made into the vitreous through the sclera, as for detached retina or the removal of a foreign body .
Radial optic neurotomy
macular translocation surgery
through 360 degree retinotomy
through scleral imbrication technique
- Vitrectomy
Anterior vitrectomy is the removal of the front portion of vitreous tissue. It is used for preventing or treating vitreous loss during cataract or corneal surgery, or to remove misplaced vitreous in conditions such as aphakia pupillary block glaucoma.
Pars plana vitrectomy (PPV), or trans pars plana vitrectomy (TPPV), is a procedure to remove vitreous opacities and membranes through a pars plana incision. It is frequently combined with other intraocular procedures for the treatment of giant retinal tears, tractional retinal detachments, and posterior vitreous detachments .
- Anterior vitrectomy is the removal of the front portion of vitreous tissue. It is used for preventing or treating vitreous loss during cataract or corneal surgery, or to remove misplaced vitreous in conditions such as aphakia pupillary block glaucoma.
- Pars plana vitrectomy (PPV), or trans pars plana vitrectomy (TPPV), is a procedure to remove vitreous opacities and membranes through a pars plana incision. It is frequently combined with other intraocular procedures for the treatment of giant retinal tears, tractional retinal detachments, and posterior vitreous detachments .
- Pan retinal photocoagulation (PRP) is a type of photocoagulation therapy used in the treatment of diabetic retinopathy.
- Retinal detachment repair
Ignipuncture is an obsolete procedure that involves cauterization of the retina with a very hot pointed instrument.
A scleral buckle is used in the repair of a retinal detachment to indent or "buckle" the sclera inward, usually by sewing a piece of preserved sclera or silicone rubber to its surface.
Laser photocoagulation, or photocoagulation therapy, is the use of a laser to seal a retinal tear.
Pneumatic retinopexy
Retinal cryopexy, or retinal cryotherapy, is a procedure that uses intense cold to induce a chorioretinal scar and to destroy retinal or choroidal tissue.
- Ignipuncture is an obsolete procedure that involves cauterization of the retina with a very hot pointed instrument.
- A scleral buckle is used in the repair of a retinal detachment to indent or "buckle" the sclera inward, usually by sewing a piece of preserved sclera or silicone rubber to its surface.
- Laser photocoagulation, or photocoagulation therapy, is the use of a laser to seal a retinal tear.
- Pneumatic retinopexy
- Retinal cryopexy, or retinal cryotherapy, is a procedure that uses intense cold to induce a chorioretinal scar and to destroy retinal or choroidal tissue.
- Macular hole repair
- Partial lamellar sclerouvectomy
Partial lamellar sclerocyclochoroidectomy
Partial lamellar sclerochoroidectomy
- Partial lamellar sclerocyclochoroidectomy
- Partial lamellar sclerochoroidectomy
- Posterior sclerotomy is an opening made into the vitreous through the sclera, as for detached retina or the removal of a foreign body .
- Radial optic neurotomy
- macular translocation surgery
through 360 degree retinotomy
through scleral imbrication technique
- through 360 degree retinotomy
- through scleral imbrication technique
# Eye muscle surgery
With approximately 1.2 million procedures each year, extraocular muscle surgery is the third most common eye surgery in the United States
- Eye muscle surgery typically corrects strabismus and includes the following :
Loosening / weakening procedures
Recession involves moving the insertion of a muscle posteriorly towards its origin.
Myectomy
Myotomy
Tenectomy
Tenotomy
Tightening / strengthening procedures
Resection
Tucking
Advancement is the movement of an eye muscle from its original place of attachment on the eyeball to a more forward position.
Transposition / repositioning procedures
Adjustable suture surgery is a method of reattaching an extraocular muscle by means of a stitch that can be shortened or lengthened within the first post-operative day, to obtain better ocular alignment .
- Loosening / weakening procedures
Recession involves moving the insertion of a muscle posteriorly towards its origin.
Myectomy
Myotomy
Tenectomy
Tenotomy
- Recession involves moving the insertion of a muscle posteriorly towards its origin.
- Myectomy
- Myotomy
- Tenectomy
- Tenotomy
- Tightening / strengthening procedures
Resection
Tucking
Advancement is the movement of an eye muscle from its original place of attachment on the eyeball to a more forward position.
- Resection
- Tucking
- Advancement is the movement of an eye muscle from its original place of attachment on the eyeball to a more forward position.
- Transposition / repositioning procedures
- Adjustable suture surgery is a method of reattaching an extraocular muscle by means of a stitch that can be shortened or lengthened within the first post-operative day, to obtain better ocular alignment .
# Oculoplastic surgery
- Oculoplastic surgery, or oculoplastics, is the subspecialty of ophthalmology that deals with the reconstruction of the eye and associated structures. Oculoplastic surgeons perform procedures such as the repair of droopy eyelids (blepharoplasty), repair of tear duct obstructions, orbital fracture repairs, removal of tumors in and around the eyes, and facial rejuvenation procedures including laser skin resurfacing, eye lifts, brow lifts, and even facelifts. Common procedures are:
## Eyelid surgery
- Blepharoplasty (Eyelift)
Blepharoplasty is plastic surgery of the eyelids to remove excessive skin or subcutaneous fat.
Asian blepharoplasty
Ptosis repair for droopy eyelid
Ectropion repair
Entropion repair
Canthal resection
A canthectomy is the surgical removal of tissue at the junction of the upper and lower eyelids.
Cantholysis is the surgical division of the canthus.
Canthopexy
A canthoplasty is plastic surgery at the canthus.
A canthorrhaphy is suturing of the outer canthus to shorten the palpebral fissure.
A canthotomy is the surgical division of the canthus, usually the outer canthus.
A lateral canthotomy is the surgical division of the outer canthus.
Epicanthoplasty
Tarsorrhaphy is a procedure in which the eyelids are partially sewn together to narrow the opening (i.e. palpebral fissure).
- Blepharoplasty (Eyelift)
Blepharoplasty is plastic surgery of the eyelids to remove excessive skin or subcutaneous fat.
Asian blepharoplasty
- Blepharoplasty is plastic surgery of the eyelids to remove excessive skin or subcutaneous fat.
Asian blepharoplasty
- Asian blepharoplasty
- Ptosis repair for droopy eyelid
- Ectropion repair
- Entropion repair
- Canthal resection
- A canthectomy is the surgical removal of tissue at the junction of the upper and lower eyelids.
- Cantholysis is the surgical division of the canthus.
- Canthopexy
- A canthoplasty is plastic surgery at the canthus.
- A canthorrhaphy is suturing of the outer canthus to shorten the palpebral fissure.
- A canthotomy is the surgical division of the canthus, usually the outer canthus.
A lateral canthotomy is the surgical division of the outer canthus.
- A lateral canthotomy is the surgical division of the outer canthus.
- Epicanthoplasty
- Tarsorrhaphy is a procedure in which the eyelids are partially sewn together to narrow the opening (i.e. palpebral fissure).
## Surgery involving the lacrimal apparatus
- A dacryocystorhinostomy (DCR) or dacryocystorhinotomy is a procedure to restore the flow of tears into the nose from the lacrimal sac when the nasolacrimal duct does not function.
Canaliculodacryocystostomy is a surgical correction for a congenitally blocked tear duct in which the closed segment is excised and the open end is joined to the lacrimal sac.
Canaliculotomy involves slitting of the lacrimal punctum and canaliculus for the relief of epiphora
A dacryoadenectomy is the surgical removal of a lacrimal gland.
A dacryocystectomy is the surgical removal of a part of the lacrimal sac.
A dacryocystostomy is an incision into the lacrimal sac, usually to promote drainage.
A dacryocystotomy is an incision into the lacrimal sac.
- A dacryocystorhinostomy (DCR) or dacryocystorhinotomy is a procedure to restore the flow of tears into the nose from the lacrimal sac when the nasolacrimal duct does not function.
- Canaliculodacryocystostomy is a surgical correction for a congenitally blocked tear duct in which the closed segment is excised and the open end is joined to the lacrimal sac.
- Canaliculotomy involves slitting of the lacrimal punctum and canaliculus for the relief of epiphora
- A dacryoadenectomy is the surgical removal of a lacrimal gland.
- A dacryocystectomy is the surgical removal of a part of the lacrimal sac.
- A dacryocystostomy is an incision into the lacrimal sac, usually to promote drainage.
- A dacryocystotomy is an incision into the lacrimal sac.
## Eye removal
- An enucleation is the removal of the eye leaving the eye muscles and remaining orbital contents intact.
An evisceration is the removal of the eye's contents, leaving the scleral shell intact. Usually performed to reduce pain in a blind eye.
An exenteration is the removal of the entire orbital contents, including the eye, extraocular muscles, fat, and connective tissues; usually for malignant orbital tumors.
- An enucleation is the removal of the eye leaving the eye muscles and remaining orbital contents intact.
- An evisceration is the removal of the eye's contents, leaving the scleral shell intact. Usually performed to reduce pain in a blind eye.
- An exenteration is the removal of the entire orbital contents, including the eye, extraocular muscles, fat, and connective tissues; usually for malignant orbital tumors.
## Orbital surgery
- Orbital reconstruction / Ocular prosthetics (False Eyes)
- Orbital decompression for Grave's Disease
## Other oculoplastic surgery
- Botox injections
- Ultrapeel Microdermabrasion
- Endoscopic forehead and browlift
- Face lift (Rhytidectomy)
- Liposuction of the face and neck
- Browplasty
# Other surgery
Many of these described procedures are historical and are not recommended due to a risk of complications. Particularly, these include operations done on ciliary body in an attempt to control glaucoma, since highly safer surgeries for glaucoma, including lasers, non-penetrating surgery, guarded filtration surgery and seton valve implants have been invented.
- A ciliarotomy is a surgical division of the ciliary zone in the treatment of glaucoma.
- A ciliectomy is 1) the surgical removal of part of the ciliary body, or 2) the surgical removal of part of a margin of an eyelid containing the roots of the eyelashes.
- A ciliotomy is a surgical section of the ciliary nerves.
- A conjunctivoanstrostomy is an opening made form the inferior conjuctival cul-de-sac into the maxillary sinus for the treatment of epiphora.
- Conjuctivoplasty is plastic surgery of the conjunctiva.
- A conjunctivorhinostomy is a surgical correction of the total obstruction of a lacrimal canaliculus by which the conjuctiva is anastomosed with the nasal cavity to improve tear flow.
- A corectomedialysis, or coretomedialysis, is an excision of a small portion of the iris at its junction with the ciliary body to form an artificial pupil.
- A corectomy, or coretomy, is any surgical cutting operation on the iris at the pupil.
- A corelysis is a surgical detachment of adhesions of the iris to the capsule of the crystalline lens or cornea.
- A coremorphosis is the surgical formation of an artificial pupil.
- A coreplasty, or coreoplasty, is plastic surgery of the iris, usually for the formation of an artificial pupil.
- A coreoplasy, or laser pupillomydriasis, is any procedure that changes the size or shape of the pupil.
- A cyclectomy is an excision of portion of the ciliary body.
- A cyclotomy, or cyclicotomy, is a surgical incision of the ciliary body, usually for the relief of glaucoma.
- A cycloanemization is a surgical obliteration of the long ciliary arteries in the treatment of glaucoma.
- An iridectomesodialsys is the formation of an artificial pupil by detaching and excising a portion of the iris at its periphery.
- An iridodialysis, sometimes known as a coredialysis, is a localized separation or tearing away of the iris from its attachment to the ciliary body.
- An iridencleisis, or corenclisis, is a surgical procedure for glaucoma in which a portion of the iris is incised and incarcerated in a limbal incision. (Subdivided into basal iridencleisis and total iridencleisis.)
- An iridesis is a surgical procedure in which a portion of the iris is brought through and incarcerated in a corneal incision in order to reposition the pupil.
- An iridocorneosclerectomy is the surgical removal of a portion of the iris, the cornea, and the sclera.
- An iridocyclectomy is the surgical removal of the iris and the ciliary body.
- An iridocystectomy is the surgical removal of a portion of the iris to form an artificial pupil.
- An iridosclerectomy is the surgical removal of a portion of the sclera and a portion of the iris in the region of the limbus for the treatment of glaucoma.
- An iridosclerotomy is the surgical puncture of the sclera and the margin of the iris for the treatment of glaucoma.
- A rhinommectomy is the surgical removal of a portion of the internal canthus.
- A trepanotrabeculectomy is used in the treatment of chronic open and chronic closed angle glaucoma. | Eye surgery
# Overview
Eye surgery, also known as ophthalmic surgery or ocular surgery, is surgery performed on the eye or its adnexa, typically by an ophthalmologist.[1] Although most eye surgery can be performed by an experienced general ophthalmologist, more complex procedures are usually done by one who is fellowship trained.
# Preparation and precautions
The eye is a delicate organ, requiring extreme care before, during and after a surgical procedure. An expert ophthalmologist must identify the need for specific procedure and be responsible for conducting the procedure safely. Many university programs allow patients to specify if they want to be operated upon by the consultant or the resident / fellow.
Proper anesthesia is a must for any eye surgery. Local anesthesia is most commonly used. Retrobulbar and peribulbar techniques for infiltrating the local area surrounding the eye muscle cone are used to immobilize the extraocular muscles and eliminate pain sensation. Topical anesthesia using lidocaine topical gel is preferred for quick procedures. In topical anesthesia, patient cooperation is a must for a smooth procedure. General anesthesia is recommended for children, traumatic eye injuries, major orbitotomies and for apprehensive patients. Cardiovascular monitoring is preferable in local anesthesia and is mandatory in general anesthesia. Proper sterile precautions are taken to prepare the area for surgery, including use of antiseptics like povidone-iodine. Sterile drapes, gowns and gloves are a must. A plastic sheet with a receptacle helps collect the fluids during phacoemulsification. An eye speculum is inserted to keep the eyes wide open. For anxious patients, supplementation with a facial nerve block using lidocaine and bupivacaine is recommended.
# Laser eye surgery
Although the terms Laser Eye Surgery and Refractive surgery are commonly used as if they were interchangeable, this is not the case. Lasers may be used to treat nonrefractive conditions (e.g. to seal a retinal tear), while radial keratotomy is an example of refractive surgery without the use of a laser.
# Cataract surgery
A cataract is an opacification or cloudiness of the eye's crystalline lens due to aging, disease, or trauma that typically prevents light from forming a clear image on the retina. If visual loss is significant, surgical removal of the lens may be warranted, with lost optical power usually replaced with a plastic intraocular lens (IOL). Due to the high prevalence of cataracts, cataract extraction is the most common eye surgery.[2]
# Glaucoma surgery
Glaucoma is a group of diseases affecting the optic nerve that results in vision loss and is frequently characterized by raised intraocular pressure (IOP). There are many types of glaucoma surgery, and variations or combinations of those types, that facilitate the escape of excess aqueous humor from the eye to lower intraocular pressure, and a few that lower IOP by decreasing the production of aqueous.
### Canaloplasty
Canaloplasty is an advanced, nonpenetrating procedure designed to enhance drainage through the eye’s natural drainage system to provide sustained reduction of IOP. Canaloplasty utilizes microcatheter technology in a simple and minimally invasive procedure.
To perform a canaloplasty, an Ophthalmologist creates a tiny incision to gain access to a canal in the eye. A microcatheter circumnavigates the canal around the iris, enlarging the main drainage channel and its smaller collector channels through the injection of a sterile, gel-like material called viscoelastic. The catheter is then removed and a suture is placed within the canal and tightened. By opening up the canal, the pressure inside the eye can be reduced.
# Refractive surgery
- Refractive surgery aims to correct errors of refraction in the eye, reducing or eliminating the need for corrective lenses
Keratomilleusis is method of reshaping the cornea surface to change its optical power. A disc of cornea is shaved off, quickly frozen, lathe-ground, then returned to its original power.
Automated lamellar keratoplasty (ALK)
Laser assisted in-situ keratomileusis (LASIK)[3]
IntraLASIK
Laser assisted sub-epithelial keratomileusis (LASEK), aka Epi-LASIK
Photorefractive keratectomy (PRK)[4]
Laser thermal keratoplasty (LTK)
Conductive keratoplasty (CK) uses radio frequency waves to shrink corneal collagen. It is used to treat mild to moderate hyperopia.[3]
Limbal relaxing incisions (LRI)
Astigmatic keratotomy (AK), aka Arcuate keratotomy or Transverse keratotomy
Radial keratotomy (RK)
Hexagonal keratotomy (HK)
Epikeratophakia is the removal of the corneal epithelium and replacement with a lathe cut corneal button.[5]
Intracorneal rings (ICRs), or corneal ring segments (Intacs) [6]
Implantable contact lenses
- Keratomilleusis is method of reshaping the cornea surface to change its optical power. A disc of cornea is shaved off, quickly frozen, lathe-ground, then returned to its original power.
- Automated lamellar keratoplasty (ALK)
- Laser assisted in-situ keratomileusis (LASIK)[3]
IntraLASIK
- IntraLASIK
- Laser assisted sub-epithelial keratomileusis (LASEK), aka Epi-LASIK
- Photorefractive keratectomy (PRK)[4]
- Laser thermal keratoplasty (LTK)
- Conductive keratoplasty (CK) uses radio frequency waves to shrink corneal collagen. It is used to treat mild to moderate hyperopia.[3]
- Limbal relaxing incisions (LRI)
- Astigmatic keratotomy (AK), aka Arcuate keratotomy or Transverse keratotomy
- Radial keratotomy (RK)
- Hexagonal keratotomy (HK)
- Epikeratophakia is the removal of the corneal epithelium and replacement with a lathe cut corneal button.[5]
- Intracorneal rings (ICRs), or corneal ring segments (Intacs) [6]
- Implantable contact lenses
- Presbyopia reversal
Anterior ciliary sclerotomy (ACS)
Laser reversal of presbyopia (LRP)
Scleral expansion bands
- Anterior ciliary sclerotomy (ACS)
Laser reversal of presbyopia (LRP)
- Laser reversal of presbyopia (LRP)
- Scleral expansion bands
# Corneal surgery
- Corneal surgery includes most refractive surgery as well as the following:
Corneal transplant surgery, is used to remove a cloudy/diseased cornea and replace it with a clear donor cornea.[5]
Penetrating keratoplasty (PK)
Boston Keratoprosthesis(KPro)
Phototherapeutic keratectomy (PTK)[7]
Pterygium excision[8]
Corneal tattooing
- Corneal transplant surgery, is used to remove a cloudy/diseased cornea and replace it with a clear donor cornea.[5]
Penetrating keratoplasty (PK)
Boston Keratoprosthesis(KPro)
- Penetrating keratoplasty (PK)
- Boston Keratoprosthesis(KPro)
- Phototherapeutic keratectomy (PTK)[7]
- Pterygium excision[8]
- Corneal tattooing
# Vitreo-retinal surgery
- Vitreo-retinal surgery includes the following
Vitrectomy[9]
Anterior vitrectomy is the removal of the front portion of vitreous tissue. It is used for preventing or treating vitreous loss during cataract or corneal surgery, or to remove misplaced vitreous in conditions such as aphakia pupillary block glaucoma.
Pars plana vitrectomy (PPV), or trans pars plana vitrectomy (TPPV), is a procedure to remove vitreous opacities and membranes through a pars plana incision. It is frequently combined with other intraocular procedures for the treatment of giant retinal tears, tractional retinal detachments, and posterior vitreous detachments [1].
Pan retinal photocoagulation (PRP) is a type of photocoagulation therapy used in the treatment of diabetic retinopathy.[10]
Retinal detachment repair
Ignipuncture is an obsolete procedure that involves cauterization of the retina with a very hot pointed instrument.[11]
A scleral buckle is used in the repair of a retinal detachment to indent or "buckle" the sclera inward, usually by sewing a piece of preserved sclera or silicone rubber to its surface.[12]
Laser photocoagulation, or photocoagulation therapy, is the use of a laser to seal a retinal tear.[10]
Pneumatic retinopexy
Retinal cryopexy, or retinal cryotherapy, is a procedure that uses intense cold to induce a chorioretinal scar and to destroy retinal or choroidal tissue.[13]
Macular hole repair
Partial lamellar sclerouvectomy[14]
Partial lamellar sclerocyclochoroidectomy
Partial lamellar sclerochoroidectomy
Posterior sclerotomy is an opening made into the vitreous through the sclera, as for detached retina or the removal of a foreign body [2].
Radial optic neurotomy
macular translocation surgery
through 360 degree retinotomy
through scleral imbrication technique
- Vitrectomy[9]
Anterior vitrectomy is the removal of the front portion of vitreous tissue. It is used for preventing or treating vitreous loss during cataract or corneal surgery, or to remove misplaced vitreous in conditions such as aphakia pupillary block glaucoma.
Pars plana vitrectomy (PPV), or trans pars plana vitrectomy (TPPV), is a procedure to remove vitreous opacities and membranes through a pars plana incision. It is frequently combined with other intraocular procedures for the treatment of giant retinal tears, tractional retinal detachments, and posterior vitreous detachments [1].
- Anterior vitrectomy is the removal of the front portion of vitreous tissue. It is used for preventing or treating vitreous loss during cataract or corneal surgery, or to remove misplaced vitreous in conditions such as aphakia pupillary block glaucoma.
- Pars plana vitrectomy (PPV), or trans pars plana vitrectomy (TPPV), is a procedure to remove vitreous opacities and membranes through a pars plana incision. It is frequently combined with other intraocular procedures for the treatment of giant retinal tears, tractional retinal detachments, and posterior vitreous detachments [1].
- Pan retinal photocoagulation (PRP) is a type of photocoagulation therapy used in the treatment of diabetic retinopathy.[10]
- Retinal detachment repair
Ignipuncture is an obsolete procedure that involves cauterization of the retina with a very hot pointed instrument.[11]
A scleral buckle is used in the repair of a retinal detachment to indent or "buckle" the sclera inward, usually by sewing a piece of preserved sclera or silicone rubber to its surface.[12]
Laser photocoagulation, or photocoagulation therapy, is the use of a laser to seal a retinal tear.[10]
Pneumatic retinopexy
Retinal cryopexy, or retinal cryotherapy, is a procedure that uses intense cold to induce a chorioretinal scar and to destroy retinal or choroidal tissue.[13]
- Ignipuncture is an obsolete procedure that involves cauterization of the retina with a very hot pointed instrument.[11]
- A scleral buckle is used in the repair of a retinal detachment to indent or "buckle" the sclera inward, usually by sewing a piece of preserved sclera or silicone rubber to its surface.[12]
- Laser photocoagulation, or photocoagulation therapy, is the use of a laser to seal a retinal tear.[10]
- Pneumatic retinopexy
- Retinal cryopexy, or retinal cryotherapy, is a procedure that uses intense cold to induce a chorioretinal scar and to destroy retinal or choroidal tissue.[13]
- Macular hole repair
- Partial lamellar sclerouvectomy[14]
Partial lamellar sclerocyclochoroidectomy
Partial lamellar sclerochoroidectomy
- Partial lamellar sclerocyclochoroidectomy
- Partial lamellar sclerochoroidectomy
- Posterior sclerotomy is an opening made into the vitreous through the sclera, as for detached retina or the removal of a foreign body [2].
- Radial optic neurotomy
- macular translocation surgery
through 360 degree retinotomy
through scleral imbrication technique
- through 360 degree retinotomy
- through scleral imbrication technique
# Eye muscle surgery
With approximately 1.2 million procedures each year, extraocular muscle surgery is the third most common eye surgery in the United States
[3].
- Eye muscle surgery typically corrects strabismus and includes the following[15] [4]:
Loosening / weakening procedures
Recession involves moving the insertion of a muscle posteriorly towards its origin.
Myectomy
Myotomy
Tenectomy
Tenotomy
Tightening / strengthening procedures
Resection
Tucking
Advancement is the movement of an eye muscle from its original place of attachment on the eyeball to a more forward position.
Transposition / repositioning procedures
Adjustable suture surgery is a method of reattaching an extraocular muscle by means of a stitch that can be shortened or lengthened within the first post-operative day, to obtain better ocular alignment [5].
- Loosening / weakening procedures
Recession involves moving the insertion of a muscle posteriorly towards its origin.
Myectomy
Myotomy
Tenectomy
Tenotomy
- Recession involves moving the insertion of a muscle posteriorly towards its origin.
- Myectomy
- Myotomy
- Tenectomy
- Tenotomy
- Tightening / strengthening procedures
Resection
Tucking
Advancement is the movement of an eye muscle from its original place of attachment on the eyeball to a more forward position.
- Resection
- Tucking
- Advancement is the movement of an eye muscle from its original place of attachment on the eyeball to a more forward position.
- Transposition / repositioning procedures
- Adjustable suture surgery is a method of reattaching an extraocular muscle by means of a stitch that can be shortened or lengthened within the first post-operative day, to obtain better ocular alignment [5].
# Oculoplastic surgery
- Oculoplastic surgery, or oculoplastics, is the subspecialty of ophthalmology that deals with the reconstruction of the eye and associated structures. Oculoplastic surgeons perform procedures such as the repair of droopy eyelids (blepharoplasty)[6], repair of tear duct obstructions, orbital fracture repairs, removal of tumors in and around the eyes, and facial rejuvenation procedures including laser skin resurfacing, eye lifts, brow lifts, and even facelifts. Common procedures are:
## Eyelid surgery [7]
- Blepharoplasty (Eyelift)
Blepharoplasty is plastic surgery of the eyelids to remove excessive skin or subcutaneous fat.[16]
Asian blepharoplasty
Ptosis repair for droopy eyelid
Ectropion repair[8]
Entropion repair
Canthal resection
A canthectomy is the surgical removal of tissue at the junction of the upper and lower eyelids.[17]
Cantholysis is the surgical division of the canthus.[17]
Canthopexy
A canthoplasty is plastic surgery at the canthus.[17]
A canthorrhaphy is suturing of the outer canthus to shorten the palpebral fissure.[17]
A canthotomy is the surgical division of the canthus, usually the outer canthus.[17]
A lateral canthotomy is the surgical division of the outer canthus.
Epicanthoplasty
Tarsorrhaphy is a procedure in which the eyelids are partially sewn together to narrow the opening (i.e. palpebral fissure).
- Blepharoplasty (Eyelift)
Blepharoplasty is plastic surgery of the eyelids to remove excessive skin or subcutaneous fat.[16]
Asian blepharoplasty
- Blepharoplasty is plastic surgery of the eyelids to remove excessive skin or subcutaneous fat.[16]
Asian blepharoplasty
- Asian blepharoplasty
- Ptosis repair for droopy eyelid
- Ectropion repair[8]
- Entropion repair
- Canthal resection
- A canthectomy is the surgical removal of tissue at the junction of the upper and lower eyelids.[17]
- Cantholysis is the surgical division of the canthus.[17]
- Canthopexy
- A canthoplasty is plastic surgery at the canthus.[17]
- A canthorrhaphy is suturing of the outer canthus to shorten the palpebral fissure.[17]
- A canthotomy is the surgical division of the canthus, usually the outer canthus.[17]
A lateral canthotomy is the surgical division of the outer canthus.
- A lateral canthotomy is the surgical division of the outer canthus.
- Epicanthoplasty
- Tarsorrhaphy is a procedure in which the eyelids are partially sewn together to narrow the opening (i.e. palpebral fissure).
## Surgery involving the lacrimal apparatus
- A dacryocystorhinostomy (DCR) or dacryocystorhinotomy is a procedure to restore the flow of tears into the nose from the lacrimal sac when the nasolacrimal duct does not function.[17][18]
Canaliculodacryocystostomy is a surgical correction for a congenitally blocked tear duct in which the closed segment is excised and the open end is joined to the lacrimal sac.[17][19]
Canaliculotomy involves slitting of the lacrimal punctum and canaliculus for the relief of epiphora[17]
A dacryoadenectomy is the surgical removal of a lacrimal gland.[17]
A dacryocystectomy is the surgical removal of a part of the lacrimal sac.[17]
A dacryocystostomy is an incision into the lacrimal sac, usually to promote drainage.[17]
A dacryocystotomy is an incision into the lacrimal sac.[17]
- A dacryocystorhinostomy (DCR) or dacryocystorhinotomy is a procedure to restore the flow of tears into the nose from the lacrimal sac when the nasolacrimal duct does not function.[17][18]
- Canaliculodacryocystostomy is a surgical correction for a congenitally blocked tear duct in which the closed segment is excised and the open end is joined to the lacrimal sac.[17][19]
- Canaliculotomy involves slitting of the lacrimal punctum and canaliculus for the relief of epiphora[17]
- A dacryoadenectomy is the surgical removal of a lacrimal gland.[17]
- A dacryocystectomy is the surgical removal of a part of the lacrimal sac.[17]
- A dacryocystostomy is an incision into the lacrimal sac, usually to promote drainage.[17]
- A dacryocystotomy is an incision into the lacrimal sac.[17]
## Eye removal
- An enucleation is the removal of the eye leaving the eye muscles and remaining orbital contents intact.[20]
An evisceration is the removal of the eye's contents, leaving the scleral shell intact. Usually performed to reduce pain in a blind eye.[21]
An exenteration is the removal of the entire orbital contents, including the eye, extraocular muscles, fat, and connective tissues; usually for malignant orbital tumors.[22]
- An enucleation is the removal of the eye leaving the eye muscles and remaining orbital contents intact.[20]
- An evisceration is the removal of the eye's contents, leaving the scleral shell intact. Usually performed to reduce pain in a blind eye.[21]
- An exenteration is the removal of the entire orbital contents, including the eye, extraocular muscles, fat, and connective tissues; usually for malignant orbital tumors.[22]
## Orbital surgery
- Orbital reconstruction / Ocular prosthetics (False Eyes)
- Orbital decompression for Grave's Disease
## Other oculoplastic surgery
- Botox injections
- Ultrapeel Microdermabrasion
- Endoscopic forehead and browlift
- Face lift (Rhytidectomy)
- Liposuction of the face and neck
- Browplasty [9]
# Other surgery
Many of these described procedures are historical and are not recommended due to a risk of complications. Particularly, these include operations done on ciliary body in an attempt to control glaucoma, since highly safer surgeries for glaucoma, including lasers, non-penetrating surgery, guarded filtration surgery and seton valve implants have been invented.
- A ciliarotomy is a surgical division of the ciliary zone in the treatment of glaucoma.[17]
- A ciliectomy is 1) the surgical removal of part of the ciliary body, or 2) the surgical removal of part of a margin of an eyelid containing the roots of the eyelashes.[17]
- A ciliotomy is a surgical section of the ciliary nerves.[17]
- A conjunctivoanstrostomy is an opening made form the inferior conjuctival cul-de-sac into the maxillary sinus for the treatment of epiphora.[17]
- Conjuctivoplasty is plastic surgery of the conjunctiva.[17]
- A conjunctivorhinostomy is a surgical correction of the total obstruction of a lacrimal canaliculus by which the conjuctiva is anastomosed with the nasal cavity to improve tear flow.[17]
- A corectomedialysis, or coretomedialysis, is an excision of a small portion of the iris at its junction with the ciliary body to form an artificial pupil.[17]
- A corectomy, or coretomy, is any surgical cutting operation on the iris at the pupil.[17]
- A corelysis is a surgical detachment of adhesions of the iris to the capsule of the crystalline lens or cornea.[17]
- A coremorphosis is the surgical formation of an artificial pupil.[17]
- A coreplasty, or coreoplasty, is plastic surgery of the iris, usually for the formation of an artificial pupil.[17]
- A coreoplasy, or laser pupillomydriasis, is any procedure that changes the size or shape of the pupil.[21]
- A cyclectomy is an excision of portion of the ciliary body.[17]
- A cyclotomy, or cyclicotomy, is a surgical incision of the ciliary body, usually for the relief of glaucoma.[17]
- A cycloanemization is a surgical obliteration of the long ciliary arteries in the treatment of glaucoma.[17]
- An iridectomesodialsys is the formation of an artificial pupil by detaching and excising a portion of the iris at its periphery.[17]
- An iridodialysis, sometimes known as a coredialysis, is a localized separation or tearing away of the iris from its attachment to the ciliary body.[17][21]
- An iridencleisis, or corenclisis, is a surgical procedure for glaucoma in which a portion of the iris is incised and incarcerated in a limbal incision.[17] (Subdivided into basal iridencleisis and total iridencleisis.[23])
- An iridesis is a surgical procedure in which a portion of the iris is brought through and incarcerated in a corneal incision in order to reposition the pupil.[17][10]
- An iridocorneosclerectomy is the surgical removal of a portion of the iris, the cornea, and the sclera.[17]
- An iridocyclectomy is the surgical removal of the iris and the ciliary body.[17]
- An iridocystectomy is the surgical removal of a portion of the iris to form an artificial pupil.[17]
- An iridosclerectomy is the surgical removal of a portion of the sclera and a portion of the iris in the region of the limbus for the treatment of glaucoma.[17]
- An iridosclerotomy is the surgical puncture of the sclera and the margin of the iris for the treatment of glaucoma.[17]
- A rhinommectomy is the surgical removal of a portion of the internal canthus.[17]
- A trepanotrabeculectomy is used in the treatment of chronic open and chronic closed angle glaucoma.[23] | https://www.wikidoc.org/index.php/Eye_surgery | |
46669758d6b1a09dd8bf775c609afd95b133aed9 | wikidoc | FG syndrome | FG syndrome
Synonyms and keywords: Opitz-Kaveggia syndrome; Keller syndrome; FGS; FGS1; mental retardation, large head, imperforate anus; congenital hypotonia, and partial agenesis of the corpus callosum; OKS
# Overview
FG syndrome is a rare genetic syndrome linked to the X chromosome and causing physical anomalies and developmental delays.
# Historical Perspective
First reported by Opitz and Kaveggia in 1974, the name of the syndrome comes from the initials of the surnames of two sisters, who had five sons with the syndrome. The first study of the syndrome, published in 1974, established that it was linked to inheritance of the X chromosome.
A 2008 study concluded that Kim Peek, who was the basis for the Dustin Hoffman character in the movie Rain Man, probably had FG syndrome.
# Pathophysiology
## Genetics
- Researchers have identified five regions of the X chromosome that are linked to FG syndrome in affected families. In one of these regions, a mutation in a particular gene called MED12 has been found to cause the disorder. Researchers are investigating genes in other regions of the X chromosome that may also be associated with FG syndrome.
- The MED12 gene provides instructions for making a protein that helps regulate gene activity. Specifically, the MED12 protein forms part of a large complex (a group of proteins that work together) that turns genes on and off. The MED12 protein is thought to play an essential role in development both before and after birth.
- Researchers have identified one mutation in the MED12 gene in several people with FG syndrome. Although the mutation alters the structure of the MED12 protein, it is unclear how this change leads to intellectual disability, behavioral changes, and the physical features associated with this condition.
# Epidemiology and Demographics
The prevalence of FG syndrome is unknown, although several hundred cases have been reported worldwide. Researchers suspect that FG syndrome may be over diagnosed because many of its signs and symptoms are also seen with other disorders.
# Natural History, Complications and Prognosis
About a third of reported cases of individuals with FG syndrome die in infancy, usually due to respiratory infection; premature death is rare after infancy.
# Diagnosis
## Symptoms
- Mental retardation usually severe;
- Hyperactive behavior, often with an outgoing personality;
- Severe constipation
- Seizures
## Physical Examination
### Appearance of the Patient
- Short stature
### Head
- Macrocephaly
- Prominent forehead
### Eyes
- Hypertelorism
- Down-slanting palpebral fissures
### Throat
- Droopy, "open-mouthed" expression, a thin upper lip, a full or pouting lower lip due to hypotonia
### Abdomen
- Inguinal hernia
### Extremities
- Broad thumbs and great toes
### Neurologic
- Severe hypotonia
### Others
- Imperforate anus may be present
- Undescended testes (cryptorchidism)
## Laboratory Findings
### MRI
Partial or complete loss of corpus callosum | FG syndrome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kalsang Dolma, M.B.B.S.[2]
Synonyms and keywords: Opitz-Kaveggia syndrome; Keller syndrome; FGS; FGS1; mental retardation, large head, imperforate anus; congenital hypotonia, and partial agenesis of the corpus callosum; OKS
# Overview
FG syndrome is a rare genetic syndrome linked to the X chromosome and causing physical anomalies and developmental delays.
# Historical Perspective
First reported by Opitz and Kaveggia in 1974, the name of the syndrome comes from the initials of the surnames of two sisters, who had five sons with the syndrome. The first study of the syndrome, published in 1974, established that it was linked to inheritance of the X chromosome.
A 2008 study concluded that Kim Peek, who was the basis for the Dustin Hoffman character in the movie Rain Man, probably had FG syndrome.
# Pathophysiology
## Genetics
- Researchers have identified five regions of the X chromosome that are linked to FG syndrome in affected families. In one of these regions, a mutation in a particular gene called MED12 has been found to cause the disorder. Researchers are investigating genes in other regions of the X chromosome that may also be associated with FG syndrome.
- The MED12 gene provides instructions for making a protein that helps regulate gene activity. Specifically, the MED12 protein forms part of a large complex (a group of proteins that work together) that turns genes on and off. The MED12 protein is thought to play an essential role in development both before and after birth.
- Researchers have identified one mutation in the MED12 gene in several people with FG syndrome. Although the mutation alters the structure of the MED12 protein, it is unclear how this change leads to intellectual disability, behavioral changes, and the physical features associated with this condition.
# Epidemiology and Demographics
The prevalence of FG syndrome is unknown, although several hundred cases have been reported worldwide. Researchers suspect that FG syndrome may be over diagnosed because many of its signs and symptoms are also seen with other disorders.
# Natural History, Complications and Prognosis
About a third of reported cases of individuals with FG syndrome die in infancy, usually due to respiratory infection; premature death is rare after infancy.
# Diagnosis
## Symptoms
- Mental retardation usually severe;
- Hyperactive behavior, often with an outgoing personality;
- Severe constipation
- Seizures
## Physical Examination
### Appearance of the Patient
- Short stature
### Head
- Macrocephaly
- Prominent forehead
### Eyes
- Hypertelorism
- Down-slanting palpebral fissures
### Throat
- Droopy, "open-mouthed" expression, a thin upper lip, a full or pouting lower lip due to hypotonia
### Abdomen
- Inguinal hernia
### Extremities
- Broad thumbs and great toes
### Neurologic
- Severe hypotonia
### Others
- Imperforate anus may be present
- Undescended testes (cryptorchidism)
## Laboratory Findings
### MRI
Partial or complete loss of corpus callosum | https://www.wikidoc.org/index.php/FGS | |
e16d4ae2bf959b14869912e44941a2d905bc106c | wikidoc | FLNC (gene) | FLNC (gene)
Filamin-C (FLN-C) also known as actin-binding-like protein (ABPL) or filamin-2 (FLN2) is a protein that in humans is encoded by the FLNC gene. Filamin-C is mainly expressed in cardiac and skeletal muscles, and functions at Z-discs and in subsarcolemmal regions.
# Structure
Filamin-C is a 290.8 kDa protein composed of 2725 amino acids. Filamin-C, like the ubiquitously-expressed isoform Filamin-A, have an N-terminal filamentous actin-binding domain, followed by a lengthy C-terminal self-association domain containing a series of immunoglobulin-like domains, and a membrane glycoprotein-binding domain. Filamin-C interacts with γ-sarcoglycan and δ-sarcoglycan at the sarcolemma; myotilin and FATZ/calsarcin/myozenin at Z-lines, as well as LL5β. Filamin-C has also been shown to interact with INPPL1, KCND2, and MAP2K4.
# Function
The family of Filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. However, the precise function of the Filamin-C isoform is still under investigation. As Filamin-C is localized mainly to striated muscle, its functions are likely specific to the specialized sarcomeric cytoskeleton present in muscle. As Filamin-C is found at both subsarcolemmal regions and at Z-lines, one plausible function of Filamin-C would be to act as a mode of communication between the membrane and the sarcomere. In skeletal muscle, Filamin-C is found at sites of core formation in skeletal myopathies, and alterations in subcellular localization of Filamin-C have been exhibited in limb-girdle muscular dystrophy and Duchenne muscular dystrophy.
# Clinical significance
Mutations in Filamin C have been associated with human hypertrophic cardiomyopathy, restrictive cardiomyopathy and a higher incidence of sudden cardiac death. Expression of mutant protein in rat cardiac cells demonstrated that mutant Filamin C forms aggregates, which may provide a mechanistic link to the observed cardiac dysfunction. Deficiency of this protein has been associated with muscle weakness. | FLNC (gene)
Filamin-C (FLN-C) also known as actin-binding-like protein (ABPL) or filamin-2 (FLN2) is a protein that in humans is encoded by the FLNC gene.[1][2][3] Filamin-C is mainly expressed in cardiac and skeletal muscles, and functions at Z-discs and in subsarcolemmal regions.
# Structure
Filamin-C is a 290.8 kDa protein composed of 2725 amino acids.[4][5] Filamin-C, like the ubiquitously-expressed isoform Filamin-A, have an N-terminal filamentous actin-binding domain, followed by a lengthy C-terminal self-association domain containing a series of immunoglobulin-like domains, and a membrane glycoprotein-binding domain.[6] Filamin-C interacts with γ-sarcoglycan and δ-sarcoglycan at the sarcolemma;[7][7][8][8] myotilin and FATZ/calsarcin/myozenin at Z-lines,[9][10][11][12] as well as LL5β.[13] Filamin-C has also been shown to interact with INPPL1,[14] KCND2,[15] and MAP2K4.[16]
# Function
The family of Filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. However, the precise function of the Filamin-C isoform is still under investigation. As Filamin-C is localized mainly to striated muscle, its functions are likely specific to the specialized sarcomeric cytoskeleton present in muscle. As Filamin-C is found at both subsarcolemmal regions and at Z-lines, one plausible function of Filamin-C would be to act as a mode of communication between the membrane and the sarcomere. In skeletal muscle, Filamin-C is found at sites of core formation in skeletal myopathies,[17] and alterations in subcellular localization of Filamin-C have been exhibited in limb-girdle muscular dystrophy and Duchenne muscular dystrophy.[18]
# Clinical significance
Mutations in Filamin C have been associated with human hypertrophic cardiomyopathy, restrictive cardiomyopathy[19] and a higher incidence of sudden cardiac death.[20] Expression of mutant protein in rat cardiac cells demonstrated that mutant Filamin C forms aggregates, which may provide a mechanistic link to the observed cardiac dysfunction.[20] Deficiency of this protein has been associated with muscle weakness.[21] | https://www.wikidoc.org/index.php/FLNC_(gene) | |
7e37630bac5b5457c7157aefe43837ca89907ace | wikidoc | Factor VIII | Factor VIII
Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the F8 gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder. Factor VIII is produced in liver sinusoidal cells and endothelial cells outside the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to another molecule called von Willebrand factor, until an injury that damages blood vessels occurs. In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active protein (sometimes written as coagulation factor VIIIa) interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.
Factor VIII participates in blood coagulation; it is a cofactor for factor IXa which, in the presence of Ca2+ and phospholipids, forms a complex that converts factor X to the activated form Xa. The factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity.
People with high levels of factor VIII are at increased risk for deep vein thrombosis and pulmonary embolism. Copper is a required cofactor for factor VIII and copper deficiency is known to increase the activity of factor VIII.
There is a formulation as a medication that is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.
# Genetics
Factor VIII was first characterized in 1984 by scientists at Genentech. The gene for factor VIII is located on the X chromosome (Xq28). The gene for factor VIII presents an interesting primary structure, as another gene is embedded in one of its introns.
# Structure
Factor VIII protein consists of six domains: A1-A2-B-A3-C1-C2, and is homologous to factor V.
The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin. The C domains belong to the phospholipid-binding discoidin domain family, and the C2 domain mediate membrane binding.
Activation of factor VIII to factor VIIIa is done by cleavage and release of the B domain. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor VIIIa.
# Physiology
FVIII is a glycoprotein procofactor. Although the primary site of release in humans is ambiguous, it is synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium, and the sinusoidal cells of the liver. Hemophilia A has been corrected by liver transplantation. Transplanting hepatocytes was ineffective, but liver endothelial cells were effective.
In the blood, it mainly circulates in a stable
noncovalent complex with von Willebrand factor. Upon activation by thrombin (factor IIa), it dissociates from the complex to interact with factor IXa in the coagulation cascade. It is a cofactor to factor IXa in the activation of factor X, which, in turn, with its cofactor factor Va, activates more thrombin. Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using factor XIII) into a blood clot.
No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most prominently by activated protein C and factor IXa) and quickly cleared from the blood stream.
Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances.
# Medical use
FVIII concentrated from donated blood plasma, or alternatively recombinant FVIIa can be given to hemophiliacs to restore hemostasis.
Antibody formation to factor VIII can also be a major concern for patients receiving therapy against bleeding; the incidence of these inhibitors is dependent of various factors, including the factor VIII product itself.
# Contamination scandal
In the 1980s, some pharmaceutical companies such as Baxter International and Bayer sparked controversy by continuing to sell contaminated factor VIII after new heat-treated versions were available. Under FDA pressure, unheated product was pulled from US markets, but was sold to Asian, Latin American, and some European countries. The product was tainted with HIV, a concern that had been discussed by Bayer and the U.S. Food and Drug Administration (FDA).
In the early 1990s, pharmaceutical companies began to produce recombinant synthesized factor products, which now prevent nearly all forms of disease transmission during replacement therapy. | Factor VIII
Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the F8 gene.[1][2] Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder.[3] Factor VIII is produced in liver sinusoidal cells and endothelial cells outside the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to another molecule called von Willebrand factor, until an injury that damages blood vessels occurs.[4] In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active protein (sometimes written as coagulation factor VIIIa) interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.[4]
Factor VIII participates in blood coagulation; it is a cofactor for factor IXa which, in the presence of Ca2+ and phospholipids, forms a complex that converts factor X to the activated form Xa. The factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity.[5]
People with high levels of factor VIII are at increased risk for deep vein thrombosis and pulmonary embolism.[6] Copper is a required cofactor for factor VIII and copper deficiency is known to increase the activity of factor VIII.[7]
There is a formulation as a medication that is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[8]
# Genetics
Factor VIII was first characterized in 1984 by scientists at Genentech.[9] The gene for factor VIII is located on the X chromosome (Xq28). The gene for factor VIII presents an interesting primary structure, as another gene is embedded in one of its introns.[10]
# Structure
Factor VIII protein consists of six domains: A1-A2-B-A3-C1-C2, and is homologous to factor V.
The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin.[11] The C domains belong to the phospholipid-binding discoidin domain family, and the C2 domain mediate membrane binding.[12]
Activation of factor VIII to factor VIIIa is done by cleavage and release of the B domain. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor VIIIa.[13]
# Physiology
FVIII is a glycoprotein procofactor. Although the primary site of release in humans is ambiguous, it is synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium, and the sinusoidal cells of the liver.[14] Hemophilia A has been corrected by liver transplantation.[15] Transplanting hepatocytes was ineffective, but liver endothelial cells were effective.[15]
In the blood, it mainly circulates in a stable
noncovalent complex with von Willebrand factor. Upon activation by thrombin (factor IIa), it dissociates from the complex to interact with factor IXa in the coagulation cascade. It is a cofactor to factor IXa in the activation of factor X, which, in turn, with its cofactor factor Va, activates more thrombin. Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using factor XIII) into a blood clot.
No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most prominently by activated protein C and factor IXa) and quickly cleared from the blood stream.
Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances.[16][17]
# Medical use
FVIII concentrated from donated blood plasma, or alternatively recombinant FVIIa can be given to hemophiliacs to restore hemostasis.
Antibody formation to factor VIII can also be a major concern for patients receiving therapy against bleeding; the incidence of these inhibitors is dependent of various factors, including the factor VIII product itself.[18]
# Contamination scandal
In the 1980s, some pharmaceutical companies such as Baxter International and Bayer sparked controversy by continuing to sell contaminated factor VIII after new heat-treated versions were available.[19] Under FDA pressure, unheated product was pulled from US markets, but was sold to Asian, Latin American, and some European countries. The product was tainted with HIV, a concern that had been discussed by Bayer and the U.S. Food and Drug Administration (FDA).[19]
In the early 1990s, pharmaceutical companies began to produce recombinant synthesized factor products, which now prevent nearly all forms of disease transmission during replacement therapy. | https://www.wikidoc.org/index.php/FVIII | |
b21febd030e4eb2433b4ed21a70ed23700a9704f | wikidoc | False alarm | False alarm
A false alarm, also called a nuisance alarm, is the phony report of an emergency, causing unnecessary panic and/or bringing resources (such as fire engines) to a place where they are not needed. Over time, repeated false alarms in a certain area may cause occupants to start to ignore all alarms, knowing that each time it will likely be a fake. The concept of this can be traced at least as far back as Aesop's story of The Boy Who Cried Wolf, where many episodes of a boy falsely yelling "wolf" caused the townspeople to ignore his cries when a real wolf came. In addition, false alarms have the potential of diverting emergency responders away from legitimate emergencies, which could ultimately lead to loss of life.
In industrial alarm management, a false alarm could refer either to an alarm with little information content that can usually safely be eliminated, or one that could be valid but is triggered by a faulty instrument. Both types are problematic because of the "cry wolf" effect described above.
The term "false alarm" is actually a misnomer, and is regularly replaced by the term "nuisance alarm." When a sensor operates, it is hardly false, and it is usually a true indication of the present state of the sensor. A more appropriate term is nuisance, indicating that the alarm activation is inconvenient, annoying, or vexatious. A prime example of this difference is burglar alarms being set off by spiders. (A spider crawling on a web in front of the motion detector appears very large to the motion detector.)
One tragic example of the consequences of continued false alarms was at Boland Hall at Seton Hall University on January 19, 2000. Months of false alarms caused many students to start ignoring the fire alarms. However, when an actual fire broke out, three students who ignored the alarms died, and many others suffered injuries.
Likewise, after too many audible car alarms are found false, most people no longer pay attention to see whether someone is stealing a vehicle, so even certain experienced thieves may confess that these alarms would not deter them from stealing vehicles.
# Other uses
In (signal) detection theory, a false alarm occurs where a non-target event exceeds the detection criterion and is identified as a target (see Constant false alarm rate).
False alarms could also refer to situations where one becomes startled about something that is later determined to be untrue. | False alarm
A false alarm, also called a nuisance alarm, is the phony report of an emergency, causing unnecessary panic and/or bringing resources (such as fire engines) to a place where they are not needed. Over time, repeated false alarms in a certain area may cause occupants to start to ignore all alarms, knowing that each time it will likely be a fake. The concept of this can be traced at least as far back as Aesop's story of The Boy Who Cried Wolf, where many episodes of a boy falsely yelling "wolf" caused the townspeople to ignore his cries when a real wolf came. In addition, false alarms have the potential of diverting emergency responders away from legitimate emergencies, which could ultimately lead to loss of life.
In industrial alarm management, a false alarm could refer either to an alarm with little information content that can usually safely be eliminated, or one that could be valid but is triggered by a faulty instrument. Both types are problematic because of the "cry wolf" effect described above.
The term "false alarm" is actually a misnomer, and is regularly replaced by the term "nuisance alarm." When a sensor operates, it is hardly false, and it is usually a true indication of the present state of the sensor. A more appropriate term is nuisance, indicating that the alarm activation is inconvenient, annoying, or vexatious. A prime example of this difference is burglar alarms being set off by spiders. (A spider crawling on a web in front of the motion detector appears very large to the motion detector.) [1]
One tragic example of the consequences of continued false alarms was at Boland Hall at Seton Hall University on January 19, 2000. Months of false alarms caused many students to start ignoring the fire alarms. However, when an actual fire broke out, three students who ignored the alarms died, and many others suffered injuries.
Likewise, after too many audible car alarms are found false, most people no longer pay attention to see whether someone is stealing a vehicle, so even certain experienced thieves may confess that these alarms would not deter them from stealing vehicles.
# Other uses
In (signal) detection theory, a false alarm occurs where a non-target event exceeds the detection criterion and is identified as a target (see Constant false alarm rate).
False alarms could also refer to situations where one becomes startled about something that is later determined to be untrue. | https://www.wikidoc.org/index.php/False_alarm | |
2b325e843143bb09ed3bfe541fe6e1e671a4af4f | wikidoc | Famciclovir | Famciclovir
# Disclaimer
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# Overview
Famciclovir is a nucleoside analogue DNA polymerase inhibitor that is FDA approved for the {{{indicationType}}} of herpes labialis (cold sores), genital herpes, herpes zoster (shingles) in immunocompetent adult patients and recurrent orolabial or genital herpes in HIV-infected adult patients. Common adverse reactions include headache and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Famciclovir, USP is indicated for the treatment of recurrent herpes labialis.
- The recommended dosage of famciclovir for the treatment of recurrent herpes labialis is 1500 mg as a single dose. Therapy should be initiated at the first sign or symptom of herpes labialis (e.g., tingling, itching, burning, pain, or lesion).
- Recurrent episodes: Famciclovir, USP is indicated for the treatment of recurrent episodes of genital herpes. The efficacy of famciclovir, USP when initiated more than 6 hours after onset of symptoms or lesions has not been established. The recommended dosage of famciclovir for the treatment of recurrent episodes of genital herpes is 1000 mg twice daily for 1 day. Therapy should be initiated at the first sign or symptom of a recurrent episode (e.g., tingling, itching, burning, pain, or lesion).
- Suppressive therapy: Famciclovir, USP is indicated for chronic suppressive therapy of recurrent episodes of genital herpes. The efficacy and safety of famciclovir, USP for the suppression of recurrent genital herpes beyond 1 year have not been established. The recommended dosage of famciclovir for chronic suppressive therapy of recurrent episodes of genital herpes is 250 mg twice daily.
- Herpes zoster (shingles): Famciclovir, USP is indicated for the treatment of herpes zoster. The efficacy of famciclovir, USP when initiated more than 72 hours after onset of rash has not been established. The recommended dosage of famciclovir for the treatment of herpes zoster is 500 mg every 8 hours for 7 days. Therapy should be initiated as soon as herpes zoster is diagnosed.
- Recurrent orolabial or genital herpes: Famciclovir, USP is indicated for the treatment of recurrent episodes of orolabial or genital herpes in HIV-infected adults. The efficacy of famciclovir, USP when initiated more than 48 hours after onset of symptoms or lesions has not been established.
The recommended dosage of famciclovir for the treatment of recurrent orolabial or genital herpes in HIV-infected patients is 500 mg twice daily for 7 days. Therapy should be initiated at the first sign or symptom of a recurrent episode (e.g., tingling, itching, burning, pain, or lesion).
- Dosage recommendations for adult patients with renal impairment are provided in Table 1
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: CDC/NIH/IDSA
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Category B
- Dosing Information
- Famciclovir 500 mg orally twice daily for 5 to 14 days.
- Developed by: CDC/NIH/IDSA
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Category C
- Dosing Information
- Famciclovir 500 mg orally twice daily for 5 to 14 days.
- Developed by: CDC/NIH/IDSA
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Category C
- Dosing Information
- Famciclovir 500 mg orally 3 times daily (AII) for 7 to 10 days; longer durations may be required if lesions are slow to resolve.
- Developed by: CDC/NIH/IDSA
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Category B
- Dosing Information
- Famciclovir 500 mg orally twice daily for 5 to 14 days (AI).
- Developed by: CDC/NIH/IDSA
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Category C
- Dosing Information
- Famciclovir 500 mg orally 3 times daily for 5 to 7 days .
### Non–Guideline-Supported Use
- Dosing Information
- 16-week course of oral famciclovir500-milligram (mg) dose 3 times a day,
- Dosing Information
- Oral famciclovir 500 milligrams 3 times a day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Famciclovir in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Famciclovir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Famciclovir in pediatric patients.
# Contraindications
- Famciclovir tablets are contraindicated in patients with known hypersensitivity to the product, its components, or Denavir® (penciclovir cream).
# Warnings
### Precautions
- Acute renal failure: Cases of acute renal failure have been reported in patients with underlying ] who have received inappropriately high doses of famciclovir for their level of renal function. Dosage reduction is recommended when administering famciclovir tablets to patients with renal impairment.
# Adverse Reactions
## Clinical Trials Experience
- Acute renal failure is discussed in greater detail in other sections of the label.
- The most common adverse events reported in at least 1 indication by >10% of adult patients treated with famciclovir are headache and nausea.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Immunocompetent patients: The safety of famciclovir has been evaluated in active- and placebo-controlled clinical studies involving 816 famciclovir treated patients with herpes zoster (famciclovir , 250 mg three times daily to 750 mg three times daily); 163 famciclovir treated patients with recurrent genital herpes ( famciclovir, 1000 mg twice daily); 1,197 patients with recurrent genital herpes treated with famciclovir as suppressive therapy (125 mg once daily to 250 mg three times daily) of which 570 patients received famciclovir (open-labeled and/or double-blind) for at least 10 months; and 447 famciclovir treated patients with herpes labialis ( famciclovir, 1500 mg once daily or 750 mg twice daily). Table 2 lists selected adverse events.
- Table 3 selected laboratory abnormalities in genital herpes suppression trials
- HIV-infected patients: In HIV-infected patients, the most frequently reported adverse events for famciclovir (500 mg twice daily; n=150) and acyclovir (400 mg, 5x/day; n=143), respectively, were headache (17% vs. 15%), nausea (11% vs. 13%), diarrhea (7% vs. 11%), vomiting (5% vs. 4%), fatigue (4% vs. 2%), and abdominal pain (3% vs. 6%).
## Postmarketing Experience
The adverse events listed below have been reported during postapproval use of famciclovir tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
Palpitations
Abnormal liver function tests, cholestatic jaundice
Thrombocytopenia
Dizziness, somnolence, confusion (including delirium, disorientation, and confusional state occurring predominantly in the elderly), hallucinations
Urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema (e.g., face, eyelid, periorbital, and pharyngeal edema), leukocytoclastic vasculitis
# Drug Interactions
- Potential for famciclovir to Affect Other Drugs
- The steady-state pharmacokinetics of digoxin were not altered by concomitant administration of multiple doses of famciclovir (500 mg three times daily). No clinically significant effect on the pharmacokinetics of zidovudine, its metabolite zidovudine glucuronide, or emtricitabine was observed following a single oral dose of 500 mg famciclovir coadministered with zidovudine or emtricitabine.
- An in vitro study using human liver microsomes suggests that famciclovir is not an inhibitor of CYP3A4 enzymes.
- Potential for Other Drugs to Affect Penciclovir
- No clinically significant alterations in penciclovir pharmacokinetics were observed following single-dose administration of 500 mg famciclovir after pretreatment with multiple doses of allopurinol, cimetidine, theophylline, zidovudine, promethazine, when given shortly after an antacid (magnesium and aluminum hydroxide), or concomitantly with emtricitabine. No clinically significant effect on penciclovir pharmacokinetics was observed following multiple-dose (three times daily) administration of famciclovir (500 mg) with multiple doses of digoxin.
- Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may result in increased plasma concentrations of penciclovir.
- The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme and/or inhibiting this enzyme could potentially occur. Clinical interaction studies of famciclovir with cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir. Raloxifene, a potent aldehyde oxidase inhibitor in vitro, could decrease the formation of penciclovir. However, a clinical drug-drug interaction study to determine the magnitude of interaction between penciclovir and raloxifene has not been conducted.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- After oral administration, famciclovir (prodrug) is converted to penciclovir (active drug). There are no adequate and well-controlled studies of famciclovir or penciclovir use in pregnant women. No adverse effects on embryofetal development were observed in animal reproduction studies using famciclovir and penciclovir at doses higher than the maximum recommended human dose (MRHD) and human exposure. Because animal reproduction studies are not always predictive of human response, famciclovir should be used during pregnancy only if needed.
- In animal reproduction studies, pregnant rats and rabbits received oral famciclovir at doses (up to 1000 mg/kg/day) that provided 2.7 to 10.8 times (rats) and 1.4 to 5.4 times (rabbits) the human systemic exposure based on AUC. No adverse effects were observed on embryo-fetal development. In other studies, pregnant rats and rabbits received intravenous famciclovir at doses (360 mg/kg/day) 1.5 to 6 times (rats) and (120 mg/kg/day) 1.1 to 4.5 times (rabbits) or penciclovir at doses (80 mg/kg/day) 0.3 to 1.3 times (rats) and (60 mg/kg/day) 0.5 to 2.1 times (rabbits) the MRHD based on body surface area comparisons. No adverse effects were observed on embryo-fetal development.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Famciclovir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Famciclovir during labor and delivery.
### Nursing Mothers
- It is not known whether famciclovir (prodrug) or penciclovir (active drug) are excreted in human milk. Following oral administration of famciclovir to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma. There are no data on the safety of famciclovir in infants. Famciclovir should not be used in nursing mothers unless the potential benefits are considered to outweigh the potential risks associated with treatment.
### Pediatric Use
- The efficacy of famciclovir tablets has not been established in pediatric patients. The pharmacokinetic profile and safety of famciclovir (experimental granules mixed with OraSweet® or tablets) were studied in 2 open-label studies.
- Study 1 was a single-dose pharmacokinetic and safety study in infants 1 month to <1 year of age who had an active herpes simplex virus (HSV) infection or who were at risk for HSV infection. Eighteen subjects were enrolled and received a single dose of famciclovir experimental granules mixed with OraSweet based on the patient’s body weight (doses ranged from 25 mg to 175 mg). These doses were selected to provide penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. The efficacy and safety of famciclovir have not been established as suppressive therapy in infants following neonatal HSV infections. In addition, the efficacy cannot be extrapolated from adults to infants because there is no similar disease in adults. Therefore, famciclovir is not recommended in infants.
- Study 2 was an open-label, single-dose pharmacokinetic, multiple-dose safety study of famciclovir experimental granules mixed with OraSweet in children 1 to <12 years of age with clinically suspected HSV or varicella zoster virus (VZV) infection. Fifty-one subjects were enrolled in the pharmacokinetic part of the study and received a single body weight adjusted dose of famciclovir (doses ranged from 125 mg to 500 mg). These doses were selected to provide penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. Based on the pharmacokinetic data observed with these doses in children, a new weight-based dosing algorithm was designed and used in the multiple-dose safety part of the study. Pharmacokinetic data were not obtained with the revised weight-based dosing algorithm.
- A total of 100 patients were enrolled in the multiple-dose safety part of the study; 47 subjects with active or latent HSV infection and 53 subjects with chickenpox. Patients with active or latent HSV infection received famciclovir twice a day for 7 days. The daily dose of famciclovir ranged from 150 mg to 500 mg twice daily depending on the patient’s body weight. Patients with chickenpox received famciclovir three times daily for 7 days. The daily dose of famciclovir ranged from 150 mg to 500 mg three times daily depending on the patient’s body weight. The clinical adverse events and laboratory test abnormalities observed in this study were similar to these seen in adults. The available data are insufficient to support the use of famciclovir for the treatment of children 1 to <12 years of age with chickenpox or infections due to HSV for the following reasons:
- Chickenpox: The efficacy of famciclovir for the treatment of chickenpox has not been established in either pediatric or adult patients. Famciclovir is approved for the treatment of herpes zoster in adult patients. However, extrapolation of efficacy data from adults with herpes zoster to children with chickenpox would not be appropriate. Although chickenpox and herpes zoster are caused by the same virus, the diseases are different.
- Genital herpes: Clinical information on genital herpes in children is limited. Therefore, efficacy data from adults cannot be extrapolated to this population. Further, famciclovir has not been studied in children 1 to <12 years of age with recurrent genital herpes. None of the children in Study 2 had genital herpes.
- Herpes labialis: There are no pharmacokinetic and safety data in children 1 to <12 years of age to support a famciclovir dose that provides penciclovir systemic exposures comparable to the penciclovir systemic exposures in adults after a single dose administration of 1500 mg. Moreover, no efficacy data have been obtained in children 1 to <12 years of age with recurrent herpes labialis.
- Information from a pediatric study in patients aged 12 years to less than 18 years of age with recurrent herpes labialis is approved for Novartis Pharmaceutical Corporation's Famvir® Tablets. However, due to Novartis Pharmaceutical Corporation’s marketing exclusivity rights, a description of those studies is not approved for this famciclovir tablet product.
### Geriatic Use
- Of 816 patients with herpes zoster in clinical studies who were treated with famciclovir, 248 (30.4%) were ≥65 years of age and 103 (13%) were ≥75 years of age. No overall differences were observed in the incidence or types of adverse events between younger and older patients. Of 610 patients with recurrent herpes simplex (type 1 or type 2) in clinical studies who were treated with famciclovir, 26 (4.3%) were >65 years of age and 7 (1.1%) were >75 years of age. Clinical studies of famciclovir in patients with recurrent genital herpes did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects.
- No famciclovir dosage adjustment based on age is recommended unless renal function is impaired. In general, appropriate caution should be exercised in the administration and monitoring of famciclovir in elderly patients reflecting the greater frequency of decreased renal function and concomitant use of other drugs.
### Gender
There is no FDA guidance on the use of Famciclovir with respect to specific gender populations.
### Race
- In a randomized, double-blind, placebo-controlled trial conducted in 304 immunocompetent black and African American adults with recurrent genital herpes there was no difference in median time to healing between patients receiving famciclovir or placebo. In general, the adverse reaction profile was similar to that observed in other famciclovir clinical trials for adult patients. The relevance of these study results to other indications in black and African American patients is unknown.
### Renal Impairment
- Apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal function. After the administration of a single 500 mg famciclovir oral dose (n=27) to healthy volunteers and to volunteers with varying degrees of renal impairment (CLCR ranged from 6.4 to 138.8 mL/min), the following results were obtained (Table 4):
- Table 4 Pharmacokinetic Parameters of Penciclovir in Subjects with Different Degrees of Renal Impairment
- In a multiple-dose study of famciclovir conducted in subjects with varying degrees of renal impairment (n=18), the pharmacokinetics of penciclovir were comparable to those after single doses.
- A dosage adjustment is recommended for patients with renal impairment.
### Hepatic Impairment
- Mild or moderate hepatic impairment (chronic hepatitis , chronic ethanol abuse , or primary biliary cirrhosis ) had no effect on the extent of availability (AUC) of penciclovir following a single dose of 500 mg famciclovir. However, there was a 44% decrease in penciclovir mean maximum plasma concentration (Cmax) and the time to maximum plasma concentration (tmax) was increased by 0.75 hours in patients with hepatic impairment compared to normal volunteers. No dosage adjustment is recommended for patients with mild or moderate hepatic impairment. The pharmacokinetics of penciclovir has not been evaluated in patients with severe hepatic impairment. Conversion of famciclovir to the active metabolite penciclovir may be impaired in these patients resulting in a lower penciclovir plasma concentrations, and thus possibly a decrease of efficacy of famciclovir.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Famciclovir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Famciclovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Famciclovir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Famciclovir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Appropriate symptomatic and supportive therapy should be given. Penciclovir is removed by hemodialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Famciclovir in the drug label.
# Pharmacology
## Mechanism of Action
- Famciclovir is a prodrug of penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2 or VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2-and 7 hours in VZV-infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown.
- Antiviral activity: In cell culture studies, penciclovir is inhibitory to the following herpes viruses: HSV-1, HSV-2 and VZV. The antiviral activity of penciclovir against wild type strains grown on human foreskin fibroblasts was assessed with a plaque reduction assay and staining with crystal violet 3 days postinfection for HSV and 10 days postinfection for VZV. The median EC50 values of penciclovir against laboratory and clinical isolates of HSV-1, HSV-2, and VZV were 2 μM (range 1.2 to 2.4 μM, n = 7), 2.6 μM (range 1.6 to 11 μM, n = 6), and 34 μM (range 6.7 to 71 μM, n = 6), respectively.
## Structure
- The active ingredient in famciclovir tablets is famciclovir, USP an orally administered prodrug of the antiviral agent penciclovir. Chemically, famciclovir is known as 2--1,3-propanediol diacetate. Its molecular formula is C14H19N5O4; its molecular weight is 321.3. It is a synthetic acyclic guanine derivative and has the following structure:
- Famciclovir, USP is a white to pale yellow solid. It is freely soluble in acetone and methanol, and sparingly soluble in ethanol and isopropanol. At 25°C famciclovir, USP is freely soluble (>25% w/v) in water initially, but rapidly precipitates as the sparingly soluble (2% to 3% w/v) monohydrate. Famciclovir, USP is not hygroscopic below 85% relative humidity. Partition coefficients are: octanol/water (pH 4.8) P=1.09 and octanol/phosphate buffer (pH 7.4) P=2.08.
- Famciclovir tablets contain 125 mg, 250 mg, or 500 mg of famciclovir, USP together with the following inactive ingredients: hydroxypropyl cellulose, hypromellose, anhydrous lactose, magnesium stearate, polyethylene glycols, sodium starch glycolate and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Famciclovir in the drug label.
## Pharmacokinetics
- Famciclovir is the diacetyl 6-deoxy analog of the active antiviral compound penciclovir. Following oral administration famciclovir undergoes rapid and extensive metabolism to penciclovir and little or no famciclovir is detected in plasma or urine. Penciclovir is predominantly eliminated unchanged by the kidney. Therefore, the dose of famciclovir needs to be adjusted in patients with different degrees of renal impairment.
- Pharmacokinetics in adults:
- Absorption and Bioavailability: The absolute bioavailability of penciclovir is 77 ± 8% as determined following the administration of a 500 mg famciclovir oral dose and a 400 mg penciclovir intravenous dose to 12 healthy male subjects.
- Penciclovir concentrations increased in proportion to dose over a famciclovir dose range of 125 mg to 1000 mg administered as a single dose. Table 5 shows the mean pharmacokinetic parameters of penciclovir after single administration of famciclovir to healthy male volunteers.
- Following oral single-dose administration of 500 mg famciclovir to 7 patients with herpes zoster, the AUC (mean ± SD), Cmax, and tmax were 12.1±1.7 mcg hr/mL, 4.0±0.7 mcg/mL, and 0.7±0.2 hours, respectively. The AUC of penciclovir was approximately 35% greater in patients with herpes zoster as compared to healthy volunteers. Some of this difference may be due to differences in renal function between the 2 groups.
- There is no accumulation of penciclovir after the administration of 500 mg famciclovir three times daily for 7 days.
- Penciclovir Cmax decreased approximately 50% and tmax was delayed by 1.5 hours when a capsule formulation of famciclovir was administered with food (nutritional content was approximately 910 Kcal and 26% fat). There was no effect on the extent of availability (AUC) of penciclovir. There was an 18% decrease in Cmax and a delay in tmax of about 1 hour when famciclovir was given 2 hours after a meal as compared to its administration 2 hours before a meal. Because there was no effect on the extent of systemic availability of penciclovir, famciclovir can be taken without regard to meals.
- Distribution: The volume of distribution (Vdβ) was 1.08±0.17 L/kg in 12 healthy male subjects following a single intravenous dose of penciclovir at 400 mg administered as a 1-hour intravenous infusion. Penciclovir is <20% bound to plasma proteins over the concentration range of 0.1 to 20 mcg/mL. The blood/plasma ratio of penciclovir is approximately 1.
- Metabolism: Following oral administration, famciclovir is deacetylated and oxidized to form penciclovir. Metabolites that are inactive include 6-deoxy penciclovir, monoacetylated penciclovir, and 6-deoxy monoacetylated penciclovir (5%, <0.5% and <0.5% of the dose in the urine, respectively). Little or no famciclovir is detected in plasma or urine. An in vitro study using human liver microsomes demonstrated that cytochrome P450 does not play an important role in famciclovir metabolism. The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir in vivo.
- Elimination: Approximately 94% of administered radioactivity was recovered in urine over 24 hours (83% of the dose was excreted in the first 6 hours) after the administration of 5 mg/kg radiolabeled penciclovir as a 1-hour infusion to 3 healthy male volunteers. Penciclovir accounted for 91% of the radioactivity excreted in the urine.
- Following the oral administration of a single 500 mg dose of radiolabeled famciclovir to 3 healthy male volunteers, 73% and 27% of administered radioactivity were recovered in urine and feces over 72 hours, respectively. Penciclovir accounted for 82% and 6-deoxy penciclovir accounted for 7% of the radioactivity excreted in the urine. Approximately 60% of the administered radiolabeled dose was collected in urine in the first 6 hours.
- After intravenous administration of penciclovir in 48 healthy male volunteers, mean ± SD total plasma clearance of penciclovir was 36.6±6.3 L/hr (0.48±0.09 L/hr/kg). Penciclovir renal clearance accounted for 74.5±8.8% of total plasma clearance.
- Renal clearance of penciclovir following the oral administration of a single 500 mg dose of famciclovir to 109 healthy male volunteers was 27.7±7.6 L/hr. Active tubular secretion contributes to the renal elimination of penciclovir.
- The plasma elimination half-life of penciclovir was 2.0±0.3 hours after intravenous administration of penciclovir to 48 healthy male volunteers and 2.3±0.4 hours after oral administration of 500 mg famciclovir to 124 healthy male volunteers. The half-life in 17 patients with herpes zoster was 2.8±1.0 hours and 2.7±1.0 hours after single and repeated doses, respectively.
- Special populations:
- Geriatric patients: Based on cross study comparison, penciclovir AUC was 40% higher and penciclovir renal clearance was 22% lower in elderly subjects (n=18, age 65 to 79 years) as compared with younger subjects Some of this difference may be due to differences in renal function between the 2 groups. No famciclovir dosage adjustment based on age is recommended unless renal function is impaired.
- Patients with renal impairment: In subjects with varying degrees of renal impairment, apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal function, after both single and repeated dosing. A dosage adjustment is recommended for patients with renal impairment.
- Patients with hepatic impairment: Mild or moderate hepatic impairment had no effect on the extent of availability (AUC) of penciclovir. No dosage adjustment is recommended for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of penciclovir has not been evaluated.
- HIV-infected patients: Following oral administration of a single dose of 500 mg famciclovir to HIV-positive patients, the pharmacokinetic parameters of penciclovir were comparable to those observed in healthy subjects.
- Gender: The pharmacokinetics of penciclovir were evaluated in 18 healthy male and 18 healthy female volunteers after single-dose oral administration of 500 mg famciclovir. AUC of penciclovir was 9.3±1.9 mcg hr/mL and 11.1±2.1 mcg hr/mL in males and females, respectively. Penciclovir renal clearance was 28.5±8.9 L/hr and 21.8±4.3 L/hr, respectively.
- These differences were attributed to differences in renal function between the 2 groups. No famciclovir dosage adjustment based on gender is recommended.
- Race: A retrospective evaluation was performed to compare the pharmacokinetic parameters obtained in black and Caucasian subjects after single and repeat once-daily, twice-daily, or three times-daily administration of famciclovir 500 mg. Data from a study in healthy volunteers (single dose), a study in subjects with varying degrees of renal impairment (single and repeat dose) and a study in subjects with hepatic impairment (single dose) did not indicate any significant differences in the pharmacokinetics of penciclovir between black and Caucasian subjects.
- Mechanism of action: Famciclovir is a prodrug of penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2 or VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2-and 7 hours in VZV-infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown.
- Antiviral activity: In cell culture studies, penciclovir is inhibitory to the following herpes viruses: HSV-1, HSV-2 and VZV. The antiviral activity of penciclovir against wild type strains grown on human foreskin fibroblasts was assessed with a plaque reduction assay and staining with crystal violet 3 days postinfection for HSV and 10 days postinfection for VZV. The median EC50 values of penciclovir against laboratory and clinical isolates of HSV-1, HSV-2, and VZV were 2 μM (range 1.2 to 2.4 μM, n = 7), 2.6 μM (range 1.6 to 11 μM, n = 6), and 34 μM (range 6.7 to 71 μM, n = 6), respectively.
- Resistance: Penciclovir-resistant mutants of HSV and VZV can result from mutations in the viral thymidine kinase (TK) and DNA polymerase genes. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). The median EC50 values observed in a plaque reduction assay with penciclovir resistant HSV-1, HSV-2, and VZV were 69 μM(range 14 to 115 μM, n = 6), 46 μM (range 4 to >395 μM, n = 9), and 92 μM (range 51 to 148 μM, n = 4), respectively. The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.
- Cross-resistance: Cross-resistance has been observed among HSV DNA polymerase inhibitors. The most commonly encountered acyclovir resistant mutants that are TK negative are also resistant to penciclovir.
## Nonclinical Toxicology
- Carcinogenesis: Two-year dietary carcinogenicity studies with famciclovir were conducted in rats and mice. An increase in the incidence of mammary adenocarcinoma (a common tumor in animals of this strain) was seen in female rats receiving the high dose of 600 mg/kg/day (1.1 to 4.5x the human systemic exposure at the recommended total daily oral dose ranging between 500 mg and 2000 mg, based on area under the plasma concentration curve comparisons for penciclovir). No increases in tumor incidence were reported in male rats treated at doses up to 240 mg/kg/day (0.7 to 2.7x the human AUC), or in male and female mice at doses up to 600 mg/kg/day (0.3 to 1.2x the human AUC).
- Mutagenesis: Famciclovir and penciclovir (the active metabolite of famciclovir) were tested for genotoxic potential in a battery of in vitro and in vivo assays. Famciclovir and penciclovir were negative in in vitro tests for gene mutations in bacteria (S. typhimurium and E. coli) and unscheduled DNA synthesis in mammalian HeLa 83 cells (at doses up to 10,000 and 5,000 mcg/plate, respectively). Famciclovir was also negative in the L5178Y mouse lymphoma assay (5000 mcg/mL), the in vivo mouse micronucleus test (4800 mg/kg), and rat dominant lethal study (5000 mg/kg). Famciclovir induced increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage (1200 mcg/mL). Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations, with and without metabolic activation (1000 mcg/mL). In human lymphocytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation (250 mcg/mL). Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when administered intravenously at doses highly toxic to bone marrow (500 mg/kg), but not when administered orally.
- Impairment of fertility: Testicular toxicity was observed in rats, mice, and dogs following repeated administration of famciclovir or penciclovir. Testicular changes included atrophy of the seminiferous tubules, reduction in sperm count, and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of toxicity to male reproduction was related to dose and duration of exposure. In male rats, decreased fertility was observed after 10 weeks of dosing at 500 mg/kg/day (1.4 to 5.7x the human AUC). The no observable effect level for sperm and testicular toxicity in rats following chronic administration (26 weeks) was 50 mg/kg/day (0.15 to 0.6x the human systemic exposure based on AUC comparisons). Testicular toxicity was observed following chronic administration to mice (104 weeks) and dogs (26 weeks) at doses of 600 mg/kg/day (0.3 to 1.2x the human AUC) and 150 mg/kg/day (1.3 to 5.1x the human AUC), respectively.
- Famciclovir had no effect on general reproductive performance or fertility in female rats at doses up to 1000 mg/kg/day (2.7 to 10.8x the human AUC).
- Two placebo-controlled studies in a total of 130 otherwise healthy men with a normal sperm profile over an 8-week baseline period and recurrent genital herpes receiving oral famciclovir (250 mg twice daily) (n=66) or placebo (n=64) therapy for 18 weeks showed no evidence of significant effects on sperm count, motility or morphology during treatment or during an 8-week follow-up.
# Clinical Studies
- A randomized, double-blind, placebo-controlled trial was conducted in 701 immunocompetent adults with recurrent herpes labialis. Patients self-initiated therapy within 1 hour of first onset of signs or symptoms of a recurrent herpes labialis episode with famciclovir 1500 mg as a single dose (n=227), famciclovir 750 mg twice daily (n=220) or placebo (n=254) for 1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule stage) was 4.4 days in the famciclovir 1500 mg single-dose group (n=152) as compared to 6.2 days in the placebo group (n=168). The median difference in time to healing between the placebo and famciclovir 1500 mg treated groups was 1.3 days (95% CI: 0.6 – 2.0). No differences in proportion of patients with aborted lesions (not progressing beyond the papule stage) were observed between patients receiving famciclovir or placebo: 33% for famciclovir 1500 mg single dose and 34% for placebo. The median time to loss of pain and tenderness was 1.7 days in famciclovir 1500 mg single dose-treated patients vs. 2.9 days in placebo-treated patients.
- Recurrent episodes: A randomized, double-blind, placebo-controlled trial was conducted in 329 immunocompetent adults with recurrent genital herpes. Patients self-initiated therapy within 6 hours of the first sign or symptom of a recurrent genital herpes episode with either famciclovir 1000 mg twice daily (n=163) or placebo (n=166) for 1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule stage) was 4.3 days in famciclovir-treated patients (n=125) as compared to 6.1 days in placebo-treated patients (n=145). The median difference in time to healing between the placebo and famciclovir-treated groups was 1.2 days (95% CI: 0.5 to 2.0). Twenty-three percent of famciclovir-treated patients had aborted lesions (no lesion development beyond erythema) vs. 13% in placebo-treated patients. The median time to loss of all symptoms (e.g., tingling, itching, burning, pain, or tenderness) was 3.3 days in famciclovir-treated patients vs. 5.4 days in placebo-treated patients.
- A randomized (2:1), double-blind, placebo-controlled trial was conducted in 304 immunocompetent black and African American adults with recurrent genital herpes. Patients self-initiated therapy within 6 hours of the first sign or symptom of a recurrent genital herpes episode with either famciclovir 1000 mg twice daily (n=206) or placebo (n=98) for 1 day. The median time to healing among patients with non-aborted lesions was 5.4 days in famciclovir-treated patients (n=152) as compared to 4.8 days in placebo-treated patients (n=78). The median difference in time to healing between the placebo and famciclovir-treated groups was -0.26 days (95% CI: -0.98 to 0.40).
- Suppressive therapy: Two randomized, double-blind, placebo-controlled, 12-month trials were conducted in 934 immunocompetent adults with a history of 6 or more recurrences of genital herpes episodes per year. Comparisons included famciclovir 125 mg three times daily, 250 mg twice daily, 250 mg three times daily, and placebo. At 12 months, 60% to 65% of patients were still receiving famciclovir and 25% were receiving placebo treatment. Recurrence rates at 6 and 12 months in patients treated with the 250 mg twice daily dose are shown in Table 6.
- Table 6 : Recurrence Rates at 6 and 12 Months in Adults with Recurrent Genital Herpes on Suppressive Therapy
- Famciclovir-treated patients had approximately 1/5 the median number of recurrences as compared to placebo-treated patients. Higher doses of famciclovir were not associated with an increase in efficacy.
- A randomized, double-blind trial compared famciclovir 500 mg twice daily for 7 days (n=150) with oral acyclovir 400 mg 5 times daily for 7 days (n=143) in HIV-infected patients with recurrent orolabial or genital herpes treated within 48 hours of lesion onset. Approximately 40% of patients had a CD4+ count below 200 cells/mm3, 54% of patients had anogenital lesions and 35% had orolabial lesions. Famciclovir therapy was comparable to oral acyclovir in reducing new lesion formation and in time to complete healing.
- Two randomized, double-blind trials, 1 placebo-controlled and 1 active-controlled, were conducted in 964 immunocompetent adults with uncomplicated herpes zoster. Treatment was initiated within 72 hours of first lesion appearance and was continued for 7 days.
- In the placebo-controlled trial, 419 patients were treated with either famciclovir 500 mg three times daily (n=138), famciclovir 750 mg three times daily (n=135) or placebo (n=146). The median time to full crusting was 5 days among famciclovir 500 mg-treated patients as compared to 7 days in placebo-treated patients. The times to full crusting, loss of vesicles, loss of ulcers, and loss of crusts were shorter for famciclovir 500 mg-treated patients than for placebo-treated patients in the overall study population. The effects of famciclovir were greater when therapy was initiated within 48 hours of rash onset; it was also more profound in patients 50 years of age or older. Among the 65.2% of patients with at least 1 positive viral culture, famciclovir treated patients had a shorter median duration of viral shedding than placebo-treated patients (1 day and 2 days, respectively).
- There were no overall differences in the duration of pain before rash healing between famciclovir-and placebo-treated groups. In addition, there was no difference in the incidence of pain after rash healing (postherpetic neuralgia) between the treatment groups. In the 186 patients (44.4% of total study population) who developed postherpetic neuralgia, the median duration of postherpetic neuralgia was shorter in patients treated with famciclovir 500 mg than in those treated with placebo (63 days and 119 days, respectively). No additional efficacy was demonstrated with higher dose of famciclovir.
- In the active-controlled trial, 545 patients were treated with 1 of 3 doses of famciclovir three times daily or with acyclovir 800 mg five times daily. Times to full lesion crusting and times to loss of acute pain were comparable for all groups and there were no statistically significant differences in the time to loss of postherpetic neuralgia between famciclovir and acyclovir-treated groups.
# How Supplied
- Famciclovir tablets are supplied as film-coated tablets as follows: 125 mg in bottles of 30; 250 mg in bottles of 30; 500 mg in bottles of 30
- Famciclovir 125 mg tablet: White to off white, round film-coated, biconvex, engraved with "ML 67" on one side and plain on the other side.
- 125 mg 30's ......................................NDC 33342-024-07
- Famciclovir 250 mg tablet: White to off white, round film-coated, biconvex, engraved with "ML 70" on one side and plain on the other side.
- 250 mg 30's ......................................NDC 33342-025-07
- Famciclovir 500 mg tablet: White to off white, oval film-coated, biconvex, engraved with "ML 72" on one side and plain on the other side.
- 500 mg 30's .....................................NDC33342-026-07
- Store at 20° - 25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F).
## Storage
There is limited information regarding Famciclovir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- There is no evidence that famciclovir will affect the ability of a patient to drive or to use machines. However, patients who experience dizziness, somnolence, confusion or other central nervous system disturbances while taking famciclovir tablets should refrain from driving or operating machinery.
- Because famciclovir tablets contains lactose (Famciclovir 125 mg, 250 mg and 500 mg tablets contain lactose 25.97 mg, 51.95 mg and 103.90 mg, respectively), patients with rare hereditary problems of galactose intolerance, a severe lactase deficiency or glucose-galactose malabsorption should be advised to discuss with their healthcare provider before taking famciclovir tablets.
- Herpes Labialis (Cold Sores)
- Patients should be advised to initiate treatment at the earliest sign or symptom of a recurrence of cold sores (e.g., tingling, itching, burning, pain, or lesion). Patients should be instructed that treatment for cold sores should not exceed 1 dose. Patients should be informed that famciclovir tablets are not a cure for cold sores.
- Genital Herpes
- Patients should be informed that famciclovir tablets are not a cure for genital herpes. There are no data evaluating whether famciclovir tablets will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices.
- If episodic therapy for recurrent genital herpes is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.
- There are no data on safety or effectiveness of chronic suppressive therapy of longer than 1-year duration.
- Herpes Zoster (Shingles)
- There are no data on treatment initiated more than 72 hours after onset of zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.
- Read this Patient Information before you start taking famciclovir tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.
- What is famciclovir tablet?
- Famciclovir tablet is a prescription antiviral medicine used to:
treat outbreaks of cold sores (fever blisters) in healthy adults
treat outbreaks of genital herpes in healthy adults
decrease the number of outbreaks of genital herpes in healthy adults treat outbreaks of herpes simplex lesions in or around the mouth, genitals, and anal area in people infected with HIV
treat shingles (herpes zoster) in adults with normal immune system
- treat outbreaks of cold sores (fever blisters) in healthy adults
- treat outbreaks of genital herpes in healthy adults
- decrease the number of outbreaks of genital herpes in healthy adults treat outbreaks of herpes simplex lesions in or around the mouth, genitals, and anal area in people infected with HIV
- treat shingles (herpes zoster) in adults with normal immune system
- It is not known if famciclovir tablets are safe and effective in children younger than 18 years of age.
- Famciclovir tablets are not a cure for herpes. It is not known if famciclovir tablets can stop the spread of herpes to others. If you are sexually active, you can pass herpes to your partner even if you are taking famciclovir tablets. Herpes can be transmitted even if you do not have active symptoms. You should continue to practice safer sex to lower the chances of spreading genital herpes to others. Do not have sexual contact with your partner during an outbreak of genital herpes or if you have any symptoms of genital herpes. Use a condom made of latex or polyurethane when you have a sexual contact. Ask your healthcare provider for more information about safer sex practices.
- Who should not take famciclovir tablets?
- Do not take famciclovir tablets if you are allergic to any of its ingredients or to Denavir® (penciclovir cream).
- What should I tell my healthcare provider before taking famciclovir tablets?
- Before you start taking famciclovir tablets, tell your healthcare provider if you:
have kidney or liver problems
have a rare genetic problem with galactose intolerance, a severe lactase deficiency or you do not absorb glucose-galactose (malabsorption)
are pregnant or planning to become pregnant. It is not known if famciclovir tablets will harm your unborn baby
are breastfeeding or plan to breastfeed
- have kidney or liver problems
- have a rare genetic problem with galactose intolerance, a severe lactase deficiency or you do not absorb glucose-galactose (malabsorption)
- are pregnant or planning to become pregnant. It is not known if famciclovir tablets will harm your unborn baby
- are breastfeeding or plan to breastfeed
- Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take:
any other medicines and products you use to treat herpes outbreaks
probenecid (Probalan)
- any other medicines and products you use to treat herpes outbreaks
- probenecid (Probalan)
- Know the medicines you take. Keep a list of them with you to show to your healthcare provider and pharmacist every time you get a new medicine.
- How should I take famciclovir tablets?
- Take famciclovir tablets exactly as prescribed
- Your healthcare provider will tell you how many famciclovir tablets to take and when to take them. Your dose of famciclovir tablets and how often you take it may be different depending on your condition
- Famciclovir tablets can be taken with or without food
- It is important for you to finish all of the medicine as prescribed, even if you begin to feel better
- Your symptoms may continue even after you finish all of your famciclovir tablets. This does not mean that you need more medicine, since you have already finished a full course of famciclovir tablets and it will continue to work in your body. Talk to your healthcare provider if you have any questions about your condition and your treatment
- What are the possible side effects of famciclovir tablets?
- The most common side effects of famciclovir tablets include:
headache
nausea
- headache
- nausea
- Talk to your healthcare provider if you have any side effect that bothers you or that does not go away.
- These are not all the possible side effects of famciclovir tablets. Ask your healthcare provider or pharmacist for more information.
- Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- How should I store famciclovir tablets?
- Store famciclovir tablets at room temperature between 59°F and 86°F (15°C to 30°C).
- Keep famciclovir tablets and all medicines out of reach from children.
- General information about famciclovir tablets
- Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use famciclovir tablets for a condition for which it was not prescribed. Do not give famciclovir tablets to other people, even if they have the same symptoms you have. It may harm them.
- This leaflet summarizes the most important information about famciclovir tablets. If you would like more information, talk with your healthcare provider. Your healthcare provider or pharmacist can give you information about famciclovir tablets that is written for health professionals. For more information, call 1-888-943-3210.
- What are the ingredients in famciclovir tablets?
- Active ingredient: famciclovir
- Inactive ingredients: hydroxypropyl cellulose, hypromellose, anhydrous lactose, magnesium stearate, polyethylene glycols, sodium starch glycolate and titanium dioxide
# Precautions with Alcohol
- Alcohol-Famciclovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FAMCICLOVIR®
# Look-Alike Drug Names
There is limited information regarding Famciclovir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Famciclovir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Famciclovir is a nucleoside analogue DNA polymerase inhibitor that is FDA approved for the {{{indicationType}}} of herpes labialis (cold sores), genital herpes, herpes zoster (shingles) in immunocompetent adult patients and recurrent orolabial or genital herpes in HIV-infected adult patients. Common adverse reactions include headache and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Famciclovir, USP is indicated for the treatment of recurrent herpes labialis.
- The recommended dosage of famciclovir for the treatment of recurrent herpes labialis is 1500 mg as a single dose. Therapy should be initiated at the first sign or symptom of herpes labialis (e.g., tingling, itching, burning, pain, or lesion).
- Recurrent episodes: Famciclovir, USP is indicated for the treatment of recurrent episodes of genital herpes. The efficacy of famciclovir, USP when initiated more than 6 hours after onset of symptoms or lesions has not been established. The recommended dosage of famciclovir for the treatment of recurrent episodes of genital herpes is 1000 mg twice daily for 1 day. Therapy should be initiated at the first sign or symptom of a recurrent episode (e.g., tingling, itching, burning, pain, or lesion).
- Suppressive therapy: Famciclovir, USP is indicated for chronic suppressive therapy of recurrent episodes of genital herpes. The efficacy and safety of famciclovir, USP for the suppression of recurrent genital herpes beyond 1 year have not been established. The recommended dosage of famciclovir for chronic suppressive therapy of recurrent episodes of genital herpes is 250 mg twice daily.
- Herpes zoster (shingles): Famciclovir, USP is indicated for the treatment of herpes zoster. The efficacy of famciclovir, USP when initiated more than 72 hours after onset of rash has not been established. The recommended dosage of famciclovir for the treatment of herpes zoster is 500 mg every 8 hours for 7 days. Therapy should be initiated as soon as herpes zoster is diagnosed.
- Recurrent orolabial or genital herpes: Famciclovir, USP is indicated for the treatment of recurrent episodes of orolabial or genital herpes in HIV-infected adults. The efficacy of famciclovir, USP when initiated more than 48 hours after onset of symptoms or lesions has not been established.
The recommended dosage of famciclovir for the treatment of recurrent orolabial or genital herpes in HIV-infected patients is 500 mg twice daily for 7 days. Therapy should be initiated at the first sign or symptom of a recurrent episode (e.g., tingling, itching, burning, pain, or lesion).
- Dosage recommendations for adult patients with renal impairment are provided in Table 1
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: CDC/NIH/IDSA
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Category B
- Dosing Information
- Famciclovir 500 mg orally twice daily for 5 to 14 days.
- Developed by: CDC/NIH/IDSA
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Category C
- Dosing Information
- Famciclovir 500 mg orally twice daily for 5 to 14 days.
- Developed by: CDC/NIH/IDSA
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Category C
- Dosing Information
- Famciclovir 500 mg orally 3 times daily (AII) for 7 to 10 days; longer durations may be required if lesions are slow to resolve.
- Developed by: CDC/NIH/IDSA
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Category B
- Dosing Information
- Famciclovir 500 mg orally twice daily for 5 to 14 days (AI).
- Developed by: CDC/NIH/IDSA
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Category C
- Dosing Information
- Famciclovir 500 mg orally 3 times daily for 5 to 7 days .
### Non–Guideline-Supported Use
- Dosing Information
- 16-week course of oral famciclovir500-milligram (mg) dose 3 times a day,
- Dosing Information
- Oral famciclovir 500 milligrams 3 times a day.[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Famciclovir in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Famciclovir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Famciclovir in pediatric patients.
# Contraindications
- Famciclovir tablets are contraindicated in patients with known hypersensitivity to the product, its components, or Denavir® (penciclovir cream).
# Warnings
### Precautions
- Acute renal failure: Cases of acute renal failure have been reported in patients with underlying [[[renal disease]] who have received inappropriately high doses of famciclovir for their level of renal function. Dosage reduction is recommended when administering famciclovir tablets to patients with renal impairment.
# Adverse Reactions
## Clinical Trials Experience
- Acute renal failure is discussed in greater detail in other sections of the label.
- The most common adverse events reported in at least 1 indication by >10% of adult patients treated with famciclovir are headache and nausea.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Immunocompetent patients: The safety of famciclovir has been evaluated in active- and placebo-controlled clinical studies involving 816 famciclovir treated patients with herpes zoster (famciclovir , 250 mg three times daily to 750 mg three times daily); 163 famciclovir treated patients with recurrent genital herpes ( famciclovir, 1000 mg twice daily); 1,197 patients with recurrent genital herpes treated with famciclovir as suppressive therapy (125 mg once daily to 250 mg three times daily) of which 570 patients received famciclovir (open-labeled and/or double-blind) for at least 10 months; and 447 famciclovir treated patients with herpes labialis ( famciclovir, 1500 mg once daily or 750 mg twice daily). Table 2 lists selected adverse events.
- Table 3 selected laboratory abnormalities in genital herpes suppression trials
- HIV-infected patients: In HIV-infected patients, the most frequently reported adverse events for famciclovir (500 mg twice daily; n=150) and acyclovir (400 mg, 5x/day; n=143), respectively, were headache (17% vs. 15%), nausea (11% vs. 13%), diarrhea (7% vs. 11%), vomiting (5% vs. 4%), fatigue (4% vs. 2%), and abdominal pain (3% vs. 6%).
## Postmarketing Experience
The adverse events listed below have been reported during postapproval use of famciclovir tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
Palpitations
Abnormal liver function tests, cholestatic jaundice
Thrombocytopenia
Dizziness, somnolence, confusion (including delirium, disorientation, and confusional state occurring predominantly in the elderly), hallucinations
Urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema (e.g., face, eyelid, periorbital, and pharyngeal edema), leukocytoclastic vasculitis
# Drug Interactions
- Potential for famciclovir to Affect Other Drugs
- The steady-state pharmacokinetics of digoxin were not altered by concomitant administration of multiple doses of famciclovir (500 mg three times daily). No clinically significant effect on the pharmacokinetics of zidovudine, its metabolite zidovudine glucuronide, or emtricitabine was observed following a single oral dose of 500 mg famciclovir coadministered with zidovudine or emtricitabine.
- An in vitro study using human liver microsomes suggests that famciclovir is not an inhibitor of CYP3A4 enzymes.
- Potential for Other Drugs to Affect Penciclovir
- No clinically significant alterations in penciclovir pharmacokinetics were observed following single-dose administration of 500 mg famciclovir after pretreatment with multiple doses of allopurinol, cimetidine, theophylline, zidovudine, promethazine, when given shortly after an antacid (magnesium and aluminum hydroxide), or concomitantly with emtricitabine. No clinically significant effect on penciclovir pharmacokinetics was observed following multiple-dose (three times daily) administration of famciclovir (500 mg) with multiple doses of digoxin.
- Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may result in increased plasma concentrations of penciclovir.
- The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme and/or inhibiting this enzyme could potentially occur. Clinical interaction studies of famciclovir with cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir. Raloxifene, a potent aldehyde oxidase inhibitor in vitro, could decrease the formation of penciclovir. However, a clinical drug-drug interaction study to determine the magnitude of interaction between penciclovir and raloxifene has not been conducted.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- After oral administration, famciclovir (prodrug) is converted to penciclovir (active drug). There are no adequate and well-controlled studies of famciclovir or penciclovir use in pregnant women. No adverse effects on embryofetal development were observed in animal reproduction studies using famciclovir and penciclovir at doses higher than the maximum recommended human dose (MRHD) and human exposure. Because animal reproduction studies are not always predictive of human response, famciclovir should be used during pregnancy only if needed.
- In animal reproduction studies, pregnant rats and rabbits received oral famciclovir at doses (up to 1000 mg/kg/day) that provided 2.7 to 10.8 times (rats) and 1.4 to 5.4 times (rabbits) the human systemic exposure based on AUC. No adverse effects were observed on embryo-fetal development. In other studies, pregnant rats and rabbits received intravenous famciclovir at doses (360 mg/kg/day) 1.5 to 6 times (rats) and (120 mg/kg/day) 1.1 to 4.5 times (rabbits) or penciclovir at doses (80 mg/kg/day) 0.3 to 1.3 times (rats) and (60 mg/kg/day) 0.5 to 2.1 times (rabbits) the MRHD based on body surface area comparisons. No adverse effects were observed on embryo-fetal development.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Famciclovir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Famciclovir during labor and delivery.
### Nursing Mothers
- It is not known whether famciclovir (prodrug) or penciclovir (active drug) are excreted in human milk. Following oral administration of famciclovir to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma. There are no data on the safety of famciclovir in infants. Famciclovir should not be used in nursing mothers unless the potential benefits are considered to outweigh the potential risks associated with treatment.
### Pediatric Use
- The efficacy of famciclovir tablets has not been established in pediatric patients. The pharmacokinetic profile and safety of famciclovir (experimental granules mixed with OraSweet® or tablets) were studied in 2 open-label studies.
- Study 1 was a single-dose pharmacokinetic and safety study in infants 1 month to <1 year of age who had an active herpes simplex virus (HSV) infection or who were at risk for HSV infection. Eighteen subjects were enrolled and received a single dose of famciclovir experimental granules mixed with OraSweet based on the patient’s body weight (doses ranged from 25 mg to 175 mg). These doses were selected to provide penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. The efficacy and safety of famciclovir have not been established as suppressive therapy in infants following neonatal HSV infections. In addition, the efficacy cannot be extrapolated from adults to infants because there is no similar disease in adults. Therefore, famciclovir is not recommended in infants.
- Study 2 was an open-label, single-dose pharmacokinetic, multiple-dose safety study of famciclovir experimental granules mixed with OraSweet in children 1 to <12 years of age with clinically suspected HSV or varicella zoster virus (VZV) infection. Fifty-one subjects were enrolled in the pharmacokinetic part of the study and received a single body weight adjusted dose of famciclovir (doses ranged from 125 mg to 500 mg). These doses were selected to provide penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. Based on the pharmacokinetic data observed with these doses in children, a new weight-based dosing algorithm was designed and used in the multiple-dose safety part of the study. Pharmacokinetic data were not obtained with the revised weight-based dosing algorithm.
- A total of 100 patients were enrolled in the multiple-dose safety part of the study; 47 subjects with active or latent HSV infection and 53 subjects with chickenpox. Patients with active or latent HSV infection received famciclovir twice a day for 7 days. The daily dose of famciclovir ranged from 150 mg to 500 mg twice daily depending on the patient’s body weight. Patients with chickenpox received famciclovir three times daily for 7 days. The daily dose of famciclovir ranged from 150 mg to 500 mg three times daily depending on the patient’s body weight. The clinical adverse events and laboratory test abnormalities observed in this study were similar to these seen in adults. The available data are insufficient to support the use of famciclovir for the treatment of children 1 to <12 years of age with chickenpox or infections due to HSV for the following reasons:
- Chickenpox: The efficacy of famciclovir for the treatment of chickenpox has not been established in either pediatric or adult patients. Famciclovir is approved for the treatment of herpes zoster in adult patients. However, extrapolation of efficacy data from adults with herpes zoster to children with chickenpox would not be appropriate. Although chickenpox and herpes zoster are caused by the same virus, the diseases are different.
- Genital herpes: Clinical information on genital herpes in children is limited. Therefore, efficacy data from adults cannot be extrapolated to this population. Further, famciclovir has not been studied in children 1 to <12 years of age with recurrent genital herpes. None of the children in Study 2 had genital herpes.
- Herpes labialis: There are no pharmacokinetic and safety data in children 1 to <12 years of age to support a famciclovir dose that provides penciclovir systemic exposures comparable to the penciclovir systemic exposures in adults after a single dose administration of 1500 mg. Moreover, no efficacy data have been obtained in children 1 to <12 years of age with recurrent herpes labialis.
- Information from a pediatric study in patients aged 12 years to less than 18 years of age with recurrent herpes labialis is approved for Novartis Pharmaceutical Corporation's Famvir® Tablets. However, due to Novartis Pharmaceutical Corporation’s marketing exclusivity rights, a description of those studies is not approved for this famciclovir tablet product.
### Geriatic Use
- Of 816 patients with herpes zoster in clinical studies who were treated with famciclovir, 248 (30.4%) were ≥65 years of age and 103 (13%) were ≥75 years of age. No overall differences were observed in the incidence or types of adverse events between younger and older patients. Of 610 patients with recurrent herpes simplex (type 1 or type 2) in clinical studies who were treated with famciclovir, 26 (4.3%) were >65 years of age and 7 (1.1%) were >75 years of age. Clinical studies of famciclovir in patients with recurrent genital herpes did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects.
- No famciclovir dosage adjustment based on age is recommended unless renal function is impaired. In general, appropriate caution should be exercised in the administration and monitoring of famciclovir in elderly patients reflecting the greater frequency of decreased renal function and concomitant use of other drugs.
### Gender
There is no FDA guidance on the use of Famciclovir with respect to specific gender populations.
### Race
- In a randomized, double-blind, placebo-controlled trial conducted in 304 immunocompetent black and African American adults with recurrent genital herpes there was no difference in median time to healing between patients receiving famciclovir or placebo. In general, the adverse reaction profile was similar to that observed in other famciclovir clinical trials for adult patients. The relevance of these study results to other indications in black and African American patients is unknown.
### Renal Impairment
- Apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal function. After the administration of a single 500 mg famciclovir oral dose (n=27) to healthy volunteers and to volunteers with varying degrees of renal impairment (CLCR ranged from 6.4 to 138.8 mL/min), the following results were obtained (Table 4):
- Table 4 Pharmacokinetic Parameters of Penciclovir in Subjects with Different Degrees of Renal Impairment
- In a multiple-dose study of famciclovir conducted in subjects with varying degrees of renal impairment (n=18), the pharmacokinetics of penciclovir were comparable to those after single doses.
- A dosage adjustment is recommended for patients with renal impairment.
### Hepatic Impairment
- Mild or moderate hepatic impairment (chronic hepatitis [n=6], chronic ethanol abuse [n=8], or primary biliary cirrhosis [n=1]) had no effect on the extent of availability (AUC) of penciclovir following a single dose of 500 mg famciclovir. However, there was a 44% decrease in penciclovir mean maximum plasma concentration (Cmax) and the time to maximum plasma concentration (tmax) was increased by 0.75 hours in patients with hepatic impairment compared to normal volunteers. No dosage adjustment is recommended for patients with mild or moderate hepatic impairment. The pharmacokinetics of penciclovir has not been evaluated in patients with severe hepatic impairment. Conversion of famciclovir to the active metabolite penciclovir may be impaired in these patients resulting in a lower penciclovir plasma concentrations, and thus possibly a decrease of efficacy of famciclovir.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Famciclovir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Famciclovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Famciclovir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Famciclovir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Appropriate symptomatic and supportive therapy should be given. Penciclovir is removed by hemodialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Famciclovir in the drug label.
# Pharmacology
## Mechanism of Action
- Famciclovir is a prodrug of penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2 or VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2-and 7 hours in VZV-infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown.
- Antiviral activity: In cell culture studies, penciclovir is inhibitory to the following herpes viruses: HSV-1, HSV-2 and VZV. The antiviral activity of penciclovir against wild type strains grown on human foreskin fibroblasts was assessed with a plaque reduction assay and staining with crystal violet 3 days postinfection for HSV and 10 days postinfection for VZV. The median EC50 values of penciclovir against laboratory and clinical isolates of HSV-1, HSV-2, and VZV were 2 μM (range 1.2 to 2.4 μM, n = 7), 2.6 μM (range 1.6 to 11 μM, n = 6), and 34 μM (range 6.7 to 71 μM, n = 6), respectively.
## Structure
- The active ingredient in famciclovir tablets is famciclovir, USP an orally administered prodrug of the antiviral agent penciclovir. Chemically, famciclovir is known as 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate. Its molecular formula is C14H19N5O4; its molecular weight is 321.3. It is a synthetic acyclic guanine derivative and has the following structure:
- Famciclovir, USP is a white to pale yellow solid. It is freely soluble in acetone and methanol, and sparingly soluble in ethanol and isopropanol. At 25°C famciclovir, USP is freely soluble (>25% w/v) in water initially, but rapidly precipitates as the sparingly soluble (2% to 3% w/v) monohydrate. Famciclovir, USP is not hygroscopic below 85% relative humidity. Partition coefficients are: octanol/water (pH 4.8) P=1.09 and octanol/phosphate buffer (pH 7.4) P=2.08.
- Famciclovir tablets contain 125 mg, 250 mg, or 500 mg of famciclovir, USP together with the following inactive ingredients: hydroxypropyl cellulose, hypromellose, anhydrous lactose, magnesium stearate, polyethylene glycols, sodium starch glycolate and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Famciclovir in the drug label.
## Pharmacokinetics
- Famciclovir is the diacetyl 6-deoxy analog of the active antiviral compound penciclovir. Following oral administration famciclovir undergoes rapid and extensive metabolism to penciclovir and little or no famciclovir is detected in plasma or urine. Penciclovir is predominantly eliminated unchanged by the kidney. Therefore, the dose of famciclovir needs to be adjusted in patients with different degrees of renal impairment.
- Pharmacokinetics in adults:
- Absorption and Bioavailability: The absolute bioavailability of penciclovir is 77 ± 8% as determined following the administration of a 500 mg famciclovir oral dose and a 400 mg penciclovir intravenous dose to 12 healthy male subjects.
- Penciclovir concentrations increased in proportion to dose over a famciclovir dose range of 125 mg to 1000 mg administered as a single dose. Table 5 shows the mean pharmacokinetic parameters of penciclovir after single administration of famciclovir to healthy male volunteers.
- Following oral single-dose administration of 500 mg famciclovir to 7 patients with herpes zoster, the AUC (mean ± SD), Cmax, and tmax were 12.1±1.7 mcg hr/mL, 4.0±0.7 mcg/mL, and 0.7±0.2 hours, respectively. The AUC of penciclovir was approximately 35% greater in patients with herpes zoster as compared to healthy volunteers. Some of this difference may be due to differences in renal function between the 2 groups.
- There is no accumulation of penciclovir after the administration of 500 mg famciclovir three times daily for 7 days.
- Penciclovir Cmax decreased approximately 50% and tmax was delayed by 1.5 hours when a capsule formulation of famciclovir was administered with food (nutritional content was approximately 910 Kcal and 26% fat). There was no effect on the extent of availability (AUC) of penciclovir. There was an 18% decrease in Cmax and a delay in tmax of about 1 hour when famciclovir was given 2 hours after a meal as compared to its administration 2 hours before a meal. Because there was no effect on the extent of systemic availability of penciclovir, famciclovir can be taken without regard to meals.
- Distribution: The volume of distribution (Vdβ) was 1.08±0.17 L/kg in 12 healthy male subjects following a single intravenous dose of penciclovir at 400 mg administered as a 1-hour intravenous infusion. Penciclovir is <20% bound to plasma proteins over the concentration range of 0.1 to 20 mcg/mL. The blood/plasma ratio of penciclovir is approximately 1.
- Metabolism: Following oral administration, famciclovir is deacetylated and oxidized to form penciclovir. Metabolites that are inactive include 6-deoxy penciclovir, monoacetylated penciclovir, and 6-deoxy monoacetylated penciclovir (5%, <0.5% and <0.5% of the dose in the urine, respectively). Little or no famciclovir is detected in plasma or urine. An in vitro study using human liver microsomes demonstrated that cytochrome P450 does not play an important role in famciclovir metabolism. The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir in vivo.
- Elimination: Approximately 94% of administered radioactivity was recovered in urine over 24 hours (83% of the dose was excreted in the first 6 hours) after the administration of 5 mg/kg radiolabeled penciclovir as a 1-hour infusion to 3 healthy male volunteers. Penciclovir accounted for 91% of the radioactivity excreted in the urine.
- Following the oral administration of a single 500 mg dose of radiolabeled famciclovir to 3 healthy male volunteers, 73% and 27% of administered radioactivity were recovered in urine and feces over 72 hours, respectively. Penciclovir accounted for 82% and 6-deoxy penciclovir accounted for 7% of the radioactivity excreted in the urine. Approximately 60% of the administered radiolabeled dose was collected in urine in the first 6 hours.
- After intravenous administration of penciclovir in 48 healthy male volunteers, mean ± SD total plasma clearance of penciclovir was 36.6±6.3 L/hr (0.48±0.09 L/hr/kg). Penciclovir renal clearance accounted for 74.5±8.8% of total plasma clearance.
- Renal clearance of penciclovir following the oral administration of a single 500 mg dose of famciclovir to 109 healthy male volunteers was 27.7±7.6 L/hr. Active tubular secretion contributes to the renal elimination of penciclovir.
- The plasma elimination half-life of penciclovir was 2.0±0.3 hours after intravenous administration of penciclovir to 48 healthy male volunteers and 2.3±0.4 hours after oral administration of 500 mg famciclovir to 124 healthy male volunteers. The half-life in 17 patients with herpes zoster was 2.8±1.0 hours and 2.7±1.0 hours after single and repeated doses, respectively.
- Special populations:
- Geriatric patients: Based on cross study comparison, penciclovir AUC was 40% higher and penciclovir renal clearance was 22% lower in elderly subjects (n=18, age 65 to 79 years) as compared with younger subjects Some of this difference may be due to differences in renal function between the 2 groups. No famciclovir dosage adjustment based on age is recommended unless renal function is impaired.
- Patients with renal impairment: In subjects with varying degrees of renal impairment, apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal function, after both single and repeated dosing. A dosage adjustment is recommended for patients with renal impairment.
- Patients with hepatic impairment: Mild or moderate hepatic impairment had no effect on the extent of availability (AUC) of penciclovir. No dosage adjustment is recommended for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of penciclovir has not been evaluated.
- HIV-infected patients: Following oral administration of a single dose of 500 mg famciclovir to HIV-positive patients, the pharmacokinetic parameters of penciclovir were comparable to those observed in healthy subjects.
- Gender: The pharmacokinetics of penciclovir were evaluated in 18 healthy male and 18 healthy female volunteers after single-dose oral administration of 500 mg famciclovir. AUC of penciclovir was 9.3±1.9 mcg hr/mL and 11.1±2.1 mcg hr/mL in males and females, respectively. Penciclovir renal clearance was 28.5±8.9 L/hr and 21.8±4.3 L/hr, respectively.
- These differences were attributed to differences in renal function between the 2 groups. No famciclovir dosage adjustment based on gender is recommended.
- Race: A retrospective evaluation was performed to compare the pharmacokinetic parameters obtained in black and Caucasian subjects after single and repeat once-daily, twice-daily, or three times-daily administration of famciclovir 500 mg. Data from a study in healthy volunteers (single dose), a study in subjects with varying degrees of renal impairment (single and repeat dose) and a study in subjects with hepatic impairment (single dose) did not indicate any significant differences in the pharmacokinetics of penciclovir between black and Caucasian subjects.
- Mechanism of action: Famciclovir is a prodrug of penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2 or VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2-and 7 hours in VZV-infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown.
- Antiviral activity: In cell culture studies, penciclovir is inhibitory to the following herpes viruses: HSV-1, HSV-2 and VZV. The antiviral activity of penciclovir against wild type strains grown on human foreskin fibroblasts was assessed with a plaque reduction assay and staining with crystal violet 3 days postinfection for HSV and 10 days postinfection for VZV. The median EC50 values of penciclovir against laboratory and clinical isolates of HSV-1, HSV-2, and VZV were 2 μM (range 1.2 to 2.4 μM, n = 7), 2.6 μM (range 1.6 to 11 μM, n = 6), and 34 μM (range 6.7 to 71 μM, n = 6), respectively.
- Resistance: Penciclovir-resistant mutants of HSV and VZV can result from mutations in the viral thymidine kinase (TK) and DNA polymerase genes. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). The median EC50 values observed in a plaque reduction assay with penciclovir resistant HSV-1, HSV-2, and VZV were 69 μM(range 14 to 115 μM, n = 6), 46 μM (range 4 to >395 μM, n = 9), and 92 μM (range 51 to 148 μM, n = 4), respectively. The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.
- Cross-resistance: Cross-resistance has been observed among HSV DNA polymerase inhibitors. The most commonly encountered acyclovir resistant mutants that are TK negative are also resistant to penciclovir.
## Nonclinical Toxicology
- Carcinogenesis: Two-year dietary carcinogenicity studies with famciclovir were conducted in rats and mice. An increase in the incidence of mammary adenocarcinoma (a common tumor in animals of this strain) was seen in female rats receiving the high dose of 600 mg/kg/day (1.1 to 4.5x the human systemic exposure at the recommended total daily oral dose ranging between 500 mg and 2000 mg, based on area under the plasma concentration curve comparisons [24 hr AUC] for penciclovir). No increases in tumor incidence were reported in male rats treated at doses up to 240 mg/kg/day (0.7 to 2.7x the human AUC), or in male and female mice at doses up to 600 mg/kg/day (0.3 to 1.2x the human AUC).
- Mutagenesis: Famciclovir and penciclovir (the active metabolite of famciclovir) were tested for genotoxic potential in a battery of in vitro and in vivo assays. Famciclovir and penciclovir were negative in in vitro tests for gene mutations in bacteria (S. typhimurium and E. coli) and unscheduled DNA synthesis in mammalian HeLa 83 cells (at doses up to 10,000 and 5,000 mcg/plate, respectively). Famciclovir was also negative in the L5178Y mouse lymphoma assay (5000 mcg/mL), the in vivo mouse micronucleus test (4800 mg/kg), and rat dominant lethal study (5000 mg/kg). Famciclovir induced increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage (1200 mcg/mL). Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations, with and without metabolic activation (1000 mcg/mL). In human lymphocytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation (250 mcg/mL). Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when administered intravenously at doses highly toxic to bone marrow (500 mg/kg), but not when administered orally.
- Impairment of fertility: Testicular toxicity was observed in rats, mice, and dogs following repeated administration of famciclovir or penciclovir. Testicular changes included atrophy of the seminiferous tubules, reduction in sperm count, and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of toxicity to male reproduction was related to dose and duration of exposure. In male rats, decreased fertility was observed after 10 weeks of dosing at 500 mg/kg/day (1.4 to 5.7x the human AUC). The no observable effect level for sperm and testicular toxicity in rats following chronic administration (26 weeks) was 50 mg/kg/day (0.15 to 0.6x the human systemic exposure based on AUC comparisons). Testicular toxicity was observed following chronic administration to mice (104 weeks) and dogs (26 weeks) at doses of 600 mg/kg/day (0.3 to 1.2x the human AUC) and 150 mg/kg/day (1.3 to 5.1x the human AUC), respectively.
- Famciclovir had no effect on general reproductive performance or fertility in female rats at doses up to 1000 mg/kg/day (2.7 to 10.8x the human AUC).
- Two placebo-controlled studies in a total of 130 otherwise healthy men with a normal sperm profile over an 8-week baseline period and recurrent genital herpes receiving oral famciclovir (250 mg twice daily) (n=66) or placebo (n=64) therapy for 18 weeks showed no evidence of significant effects on sperm count, motility or morphology during treatment or during an 8-week follow-up.
# Clinical Studies
- A randomized, double-blind, placebo-controlled trial was conducted in 701 immunocompetent adults with recurrent herpes labialis. Patients self-initiated therapy within 1 hour of first onset of signs or symptoms of a recurrent herpes labialis episode with famciclovir 1500 mg as a single dose (n=227), famciclovir 750 mg twice daily (n=220) or placebo (n=254) for 1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule stage) was 4.4 days in the famciclovir 1500 mg single-dose group (n=152) as compared to 6.2 days in the placebo group (n=168). The median difference in time to healing between the placebo and famciclovir 1500 mg treated groups was 1.3 days (95% CI: 0.6 – 2.0). No differences in proportion of patients with aborted lesions (not progressing beyond the papule stage) were observed between patients receiving famciclovir or placebo: 33% for famciclovir 1500 mg single dose and 34% for placebo. The median time to loss of pain and tenderness was 1.7 days in famciclovir 1500 mg single dose-treated patients vs. 2.9 days in placebo-treated patients.
- Recurrent episodes: A randomized, double-blind, placebo-controlled trial was conducted in 329 immunocompetent adults with recurrent genital herpes. Patients self-initiated therapy within 6 hours of the first sign or symptom of a recurrent genital herpes episode with either famciclovir 1000 mg twice daily (n=163) or placebo (n=166) for 1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule stage) was 4.3 days in famciclovir-treated patients (n=125) as compared to 6.1 days in placebo-treated patients (n=145). The median difference in time to healing between the placebo and famciclovir-treated groups was 1.2 days (95% CI: 0.5 to 2.0). Twenty-three percent of famciclovir-treated patients had aborted lesions (no lesion development beyond erythema) vs. 13% in placebo-treated patients. The median time to loss of all symptoms (e.g., tingling, itching, burning, pain, or tenderness) was 3.3 days in famciclovir-treated patients vs. 5.4 days in placebo-treated patients.
- A randomized (2:1), double-blind, placebo-controlled trial was conducted in 304 immunocompetent black and African American adults with recurrent genital herpes. Patients self-initiated therapy within 6 hours of the first sign or symptom of a recurrent genital herpes episode with either famciclovir 1000 mg twice daily (n=206) or placebo (n=98) for 1 day. The median time to healing among patients with non-aborted lesions was 5.4 days in famciclovir-treated patients (n=152) as compared to 4.8 days in placebo-treated patients (n=78). The median difference in time to healing between the placebo and famciclovir-treated groups was -0.26 days (95% CI: -0.98 to 0.40).
- Suppressive therapy: Two randomized, double-blind, placebo-controlled, 12-month trials were conducted in 934 immunocompetent adults with a history of 6 or more recurrences of genital herpes episodes per year. Comparisons included famciclovir 125 mg three times daily, 250 mg twice daily, 250 mg three times daily, and placebo. At 12 months, 60% to 65% of patients were still receiving famciclovir and 25% were receiving placebo treatment. Recurrence rates at 6 and 12 months in patients treated with the 250 mg twice daily dose are shown in Table 6.
- Table 6 : Recurrence Rates at 6 and 12 Months in Adults with Recurrent Genital Herpes on Suppressive Therapy
- Famciclovir-treated patients had approximately 1/5 the median number of recurrences as compared to placebo-treated patients. Higher doses of famciclovir were not associated with an increase in efficacy.
- A randomized, double-blind trial compared famciclovir 500 mg twice daily for 7 days (n=150) with oral acyclovir 400 mg 5 times daily for 7 days (n=143) in HIV-infected patients with recurrent orolabial or genital herpes treated within 48 hours of lesion onset. Approximately 40% of patients had a CD4+ count below 200 cells/mm3, 54% of patients had anogenital lesions and 35% had orolabial lesions. Famciclovir therapy was comparable to oral acyclovir in reducing new lesion formation and in time to complete healing.
- Two randomized, double-blind trials, 1 placebo-controlled and 1 active-controlled, were conducted in 964 immunocompetent adults with uncomplicated herpes zoster. Treatment was initiated within 72 hours of first lesion appearance and was continued for 7 days.
- In the placebo-controlled trial, 419 patients were treated with either famciclovir 500 mg three times daily (n=138), famciclovir 750 mg three times daily (n=135) or placebo (n=146). The median time to full crusting was 5 days among famciclovir 500 mg-treated patients as compared to 7 days in placebo-treated patients. The times to full crusting, loss of vesicles, loss of ulcers, and loss of crusts were shorter for famciclovir 500 mg-treated patients than for placebo-treated patients in the overall study population. The effects of famciclovir were greater when therapy was initiated within 48 hours of rash onset; it was also more profound in patients 50 years of age or older. Among the 65.2% of patients with at least 1 positive viral culture, famciclovir treated patients had a shorter median duration of viral shedding than placebo-treated patients (1 day and 2 days, respectively).
- There were no overall differences in the duration of pain before rash healing between famciclovir-and placebo-treated groups. In addition, there was no difference in the incidence of pain after rash healing (postherpetic neuralgia) between the treatment groups. In the 186 patients (44.4% of total study population) who developed postherpetic neuralgia, the median duration of postherpetic neuralgia was shorter in patients treated with famciclovir 500 mg than in those treated with placebo (63 days and 119 days, respectively). No additional efficacy was demonstrated with higher dose of famciclovir.
- In the active-controlled trial, 545 patients were treated with 1 of 3 doses of famciclovir three times daily or with acyclovir 800 mg five times daily. Times to full lesion crusting and times to loss of acute pain were comparable for all groups and there were no statistically significant differences in the time to loss of postherpetic neuralgia between famciclovir and acyclovir-treated groups.
# How Supplied
- Famciclovir tablets are supplied as film-coated tablets as follows: 125 mg in bottles of 30; 250 mg in bottles of 30; 500 mg in bottles of 30
- Famciclovir 125 mg tablet: White to off white, round film-coated, biconvex, engraved with "ML 67" on one side and plain on the other side.
- 125 mg 30's ......................................NDC 33342-024-07
- Famciclovir 250 mg tablet: White to off white, round film-coated, biconvex, engraved with "ML 70" on one side and plain on the other side.
- 250 mg 30's ......................................NDC 33342-025-07
- Famciclovir 500 mg tablet: White to off white, oval film-coated, biconvex, engraved with "ML 72" on one side and plain on the other side.
- 500 mg 30's .....................................NDC33342-026-07
- Store at 20° - 25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F).
## Storage
There is limited information regarding Famciclovir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- There is no evidence that famciclovir will affect the ability of a patient to drive or to use machines. However, patients who experience dizziness, somnolence, confusion or other central nervous system disturbances while taking famciclovir tablets should refrain from driving or operating machinery.
- Because famciclovir tablets contains lactose (Famciclovir 125 mg, 250 mg and 500 mg tablets contain lactose 25.97 mg, 51.95 mg and 103.90 mg, respectively), patients with rare hereditary problems of galactose intolerance, a severe lactase deficiency or glucose-galactose malabsorption should be advised to discuss with their healthcare provider before taking famciclovir tablets.
- Herpes Labialis (Cold Sores)
- Patients should be advised to initiate treatment at the earliest sign or symptom of a recurrence of cold sores (e.g., tingling, itching, burning, pain, or lesion). Patients should be instructed that treatment for cold sores should not exceed 1 dose. Patients should be informed that famciclovir tablets are not a cure for cold sores.
- Genital Herpes
- Patients should be informed that famciclovir tablets are not a cure for genital herpes. There are no data evaluating whether famciclovir tablets will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices.
- If episodic therapy for recurrent genital herpes is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.
- There are no data on safety or effectiveness of chronic suppressive therapy of longer than 1-year duration.
- Herpes Zoster (Shingles)
- There are no data on treatment initiated more than 72 hours after onset of zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.
- Read this Patient Information before you start taking famciclovir tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.
- What is famciclovir tablet?
- Famciclovir tablet is a prescription antiviral medicine used to:
treat outbreaks of cold sores (fever blisters) in healthy adults
treat outbreaks of genital herpes in healthy adults
decrease the number of outbreaks of genital herpes in healthy adults treat outbreaks of herpes simplex lesions in or around the mouth, genitals, and anal area in people infected with HIV
treat shingles (herpes zoster) in adults with normal immune system
- treat outbreaks of cold sores (fever blisters) in healthy adults
- treat outbreaks of genital herpes in healthy adults
- decrease the number of outbreaks of genital herpes in healthy adults treat outbreaks of herpes simplex lesions in or around the mouth, genitals, and anal area in people infected with HIV
- treat shingles (herpes zoster) in adults with normal immune system
- It is not known if famciclovir tablets are safe and effective in children younger than 18 years of age.
- Famciclovir tablets are not a cure for herpes. It is not known if famciclovir tablets can stop the spread of herpes to others. If you are sexually active, you can pass herpes to your partner even if you are taking famciclovir tablets. Herpes can be transmitted even if you do not have active symptoms. You should continue to practice safer sex to lower the chances of spreading genital herpes to others. Do not have sexual contact with your partner during an outbreak of genital herpes or if you have any symptoms of genital herpes. Use a condom made of latex or polyurethane when you have a sexual contact. Ask your healthcare provider for more information about safer sex practices.
- Who should not take famciclovir tablets?
- Do not take famciclovir tablets if you are allergic to any of its ingredients or to Denavir® (penciclovir cream).
- What should I tell my healthcare provider before taking famciclovir tablets?
- Before you start taking famciclovir tablets, tell your healthcare provider if you:
have kidney or liver problems
have a rare genetic problem with galactose intolerance, a severe lactase deficiency or you do not absorb glucose-galactose (malabsorption)
are pregnant or planning to become pregnant. It is not known if famciclovir tablets will harm your unborn baby
are breastfeeding or plan to breastfeed
- have kidney or liver problems
- have a rare genetic problem with galactose intolerance, a severe lactase deficiency or you do not absorb glucose-galactose (malabsorption)
- are pregnant or planning to become pregnant. It is not known if famciclovir tablets will harm your unborn baby
- are breastfeeding or plan to breastfeed
- Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take:
any other medicines and products you use to treat herpes outbreaks
probenecid (Probalan)
- any other medicines and products you use to treat herpes outbreaks
- probenecid (Probalan)
- Know the medicines you take. Keep a list of them with you to show to your healthcare provider and pharmacist every time you get a new medicine.
- How should I take famciclovir tablets?
- Take famciclovir tablets exactly as prescribed
- Your healthcare provider will tell you how many famciclovir tablets to take and when to take them. Your dose of famciclovir tablets and how often you take it may be different depending on your condition
- Famciclovir tablets can be taken with or without food
- It is important for you to finish all of the medicine as prescribed, even if you begin to feel better
- Your symptoms may continue even after you finish all of your famciclovir tablets. This does not mean that you need more medicine, since you have already finished a full course of famciclovir tablets and it will continue to work in your body. Talk to your healthcare provider if you have any questions about your condition and your treatment
- What are the possible side effects of famciclovir tablets?
- The most common side effects of famciclovir tablets include:
headache
nausea
- headache
- nausea
- Talk to your healthcare provider if you have any side effect that bothers you or that does not go away.
- These are not all the possible side effects of famciclovir tablets. Ask your healthcare provider or pharmacist for more information.
- Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- How should I store famciclovir tablets?
- Store famciclovir tablets at room temperature between 59°F and 86°F (15°C to 30°C).
- Keep famciclovir tablets and all medicines out of reach from children.
- General information about famciclovir tablets
- Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use famciclovir tablets for a condition for which it was not prescribed. Do not give famciclovir tablets to other people, even if they have the same symptoms you have. It may harm them.
- This leaflet summarizes the most important information about famciclovir tablets. If you would like more information, talk with your healthcare provider. Your healthcare provider or pharmacist can give you information about famciclovir tablets that is written for health professionals. For more information, call 1-888-943-3210.
- What are the ingredients in famciclovir tablets?
- Active ingredient: famciclovir
- Inactive ingredients: hydroxypropyl cellulose, hypromellose, anhydrous lactose, magnesium stearate, polyethylene glycols, sodium starch glycolate and titanium dioxide
# Precautions with Alcohol
- Alcohol-Famciclovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FAMCICLOVIR®[2]
# Look-Alike Drug Names
There is limited information regarding Famciclovir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Famciclovir | |
27dee10b371dff7802e261ab966dd117c93257ce | wikidoc | Retinopathy | Retinopathy
# Overview
Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Most commonly, it is a problem with the blood supply that is the cause for this condition.
Frequently, retinopathy is an ocular manifestation of systemic disease.
# Causes
The main causes of retinopathy are:
- Diabetes - diabetic retinopathy
- Arterial hypertension - hypertensive retinopathy
- Prematurity of the newborn - retinopathy of prematurity (ROP)
- Sickle cell anemia
- Direct sunlight exposure - solar retinopathy
- Medicinal products - drug-related retinopathy- Hydroxychloroquine, Interferon alfa-2b , Tamoxifen, Trifluoperazine
- Retinal vein or artery occlusion
# Prognosis
Many types of retinopathy are progressive and may result in blindness, severe vision loss, or impairment, particularly if the macula becomes affected.
# Treatment
Retinopathy is diagnosed by an optometrist or an ophthalmologist during ophthalmoscopy. Treatment depends on the cause of the disease.
# Related Chapters
- List of eye diseases and disorders
- List of systemic diseases with ocular manifestations | Retinopathy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Most commonly, it is a problem with the blood supply that is the cause for this condition.
Frequently, retinopathy is an ocular manifestation of systemic disease.
# Causes
The main causes of retinopathy are:
- Diabetes - diabetic retinopathy
- Arterial hypertension - hypertensive retinopathy
- Prematurity of the newborn - retinopathy of prematurity (ROP)
- Sickle cell anemia
- Direct sunlight exposure - solar retinopathy
- Medicinal products - drug-related retinopathy- Hydroxychloroquine, Interferon alfa-2b , Tamoxifen, Trifluoperazine
- Retinal vein or artery occlusion
# Prognosis
Many types of retinopathy are progressive and may result in blindness, severe vision loss, or impairment, particularly if the macula becomes affected.
# Treatment
Retinopathy is diagnosed by an optometrist or an ophthalmologist during ophthalmoscopy. Treatment depends on the cause of the disease.
# Related Chapters
- List of eye diseases and disorders
- List of systemic diseases with ocular manifestations | https://www.wikidoc.org/index.php/Familial_exudative_vitreoretinopathy | |
12f672a78a85a839760522cf6ed9ebfd0e25b90c | wikidoc | Fulvestrant | Fulvestrant
- Treatment for hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
- The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter.
Hepatic Impairment
- A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter.
- Fulvestrant has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C)
- Because fulvestrant is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use.
# Hepatic Impairment
- The safety and pharmacokinetics of fulvestrant were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function.
- Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended.
- Fulvestrant has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
# Use in Pregnancy
- Based on its mechanism of action and findings in animals, fulvestrant can cause fetal harm when administered to a pregnant woman.
- Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area.
- There are no adequate and well-controlled studies in pregnant women using fulvestrant. Women of childbearing potential should be advised not to become pregnant while receiving fulvestrant.
- If fulvestrant is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
Comparison of fulvestrant 500 mg and fulvestrant 250 mg
- The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared fulvestrant 500 mg with fulvestrant 250 mg. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients).
- Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the controlled clinical trial Study 1 comparing the administration of fulvestrant 500 mg intramuscularly once a month with fulvestrant 250 mg intramuscularly once a month.
- In the pooled safety population (N=1127) from clinical trials comparing fulvestrant 500 mg to fulvestrant 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in > 15% of patients receiving fulvestrant. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg fulvestrant arms.
Comparison of fulvestrant 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3)
- The most commonly reported adverse reactions in the fulvestrant and anastrozole treatment groups, regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis.
- Injection site reactions with mild transient pain and inflammation were seen with fulvestrant and occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North American Trial Study 2).
- Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of fulvestrant 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day.
Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with fulvestrant. If bleeding persists, further evaluation should be considered.
Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).
- In studies in female rats at intramuscular doses ≥ 0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥ 0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis.
- Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed. Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures.
- The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry.
- Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26.
- Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 ); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 ). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of fulvestrant on bone mineral density in children has not been studied and is not known.
- Eight patients (27%) experienced adverse reactions that were considered possibly related to fulvestrant. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to fulvestrant. No patients discontinued study treatment due to an AE and no patients died.
Pharmacokinetics
- The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis.
- In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively.
- A dose of fulvestrant 250 mg is recommended in patients with moderate hepatic impairment (Child-Pugh class B)
# Administration Technique
- The proper method of administration of fulvestrant for intramuscular use is described in the instructions that follow:
- Remove glass syringe barrel from tray and check that it is not damaged.
- Remove perforated patient record label from syringe.
- Peel open the safety needle outer packaging.
- Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap (see Figure 1).
- Twist to lock the needle to the luer connector.
- Remove needle sheath.
- Remove excess gas from the syringe (a small gas bubble may remain).
- Administer intramuscularly slowly in the buttock.
- Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered (see Figure 2).
- Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector.
- Repeat steps 1 through 10 for second syringe.
How To Use fulvestrant
For the 2 x 5 mL syringe package, the contents of both syringes must be injected to receive the 500 mg recommended dose.
- In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the growth of tamoxifen-resistant, as well as estrogen-sensitive human breast cancer (MCF-7) cell lines. In in vivo tumor studies, fulvestrant delayed the establishment of tumors from xenografts of human breast cancer MCF-7 cells in nude mice. Fulvestrant inhibited the growth of established MCF-7 xenografts and of tamoxifen-resistant breast tumor xenografts.
- Fulvestrant showed no agonist-type effects in in vivo uterotropic assays in immature or ovariectomized mice and rats. In in vivo studies in immature rats and ovariectomized monkeys, fulvestrant blocked the uterotrophic action of estradiol. In postmenopausal women, the absence of changes in plasma concentrations of FSH and LH in response to fulvestrant treatment (250 mg monthly) suggests no peripheral steroidal effects.
- Fulvestrant is a white powder with a molecular weight of 606.77. The solution for injection is a clear, colorless to yellow, viscous liquid.
- Each injection contains as inactive ingredients: 10% w/v Alcohol, USP, 10% w/v benzyl alcohol, NF, and 15% w/v benzyl benzoate, USP, as co-solvents, and made up to 100% w/v with Castor Oil, USP as a co-solvent and release rate modifier.
- The single dose and multiple dose PK parameters for the 500 mg dosing regimen with an additional dose (AD) at Day 15 are reported in Table 3. The additional dose of fulvestrant given two weeks after the initial dose allows for steady state concentrations to be reached within the first month of dosing.
# Distribution
- The apparent volume of distribution at steady state is approximately 3 to 5 L/kg.
- This suggests that distribution is largely extravascular. Fulvestrant is highly (99%) bound to plasma proteins; VLDL, LDL and HDL lipoprotein fractions appear to be the major binding components. The role of sex hormone-binding globulin, if any, could not be determined.
# Metabolism
- Biotransformation and disposition of fulvestrant in humans have been determined following intramuscular and intravenous administration of 14C-labeled fulvestrant. Metabolism of fulvestrant appears to involve combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or sulphate at the 2, 3 and 17 positions of the steroid nucleus, and oxidation of the side chain sulphoxide. Identified metabolites are either less active or exhibit similar activity to fulvestrant in antiestrogen models.
- Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution of P-450 and non-P-450 routes in vivo is unknown.
# Excretion
- Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%). Renal elimination was negligible (less than 1%).
- After an intramuscular injection of 250 mg, the clearance (Mean ± SD) was 690 ± 226 mL/min with an apparent half-life about 40 days.
# Special Populations
- In patients with breast cancer, there was no difference in fulvestrant pharmacokinetic profile related to age (range 33 to 89 years).
- Following administration of a single intravenous dose, there were no pharmacokinetic differences between men and women or between premenopausal and postmenopausal women. Similarly, there were no differences between men and postmenopausal women after intramuscular administration.
- In the advanced breast cancer treatment trials, the potential for pharmacokinetic differences due to race have been evaluated in 294 women including 87.4% Caucasian, 7.8% Black, and 4.4% Hispanic. No differences in fulvestrant plasma pharmacokinetics were observed among these groups. In a separate trial, pharmacokinetic data from postmenopausal ethnic Japanese women were similar to those obtained in non-Japanese patients.
# Drug-Drug Interactions
- There are no known drug-drug interactions. Fulvestrant does not significantly inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2C19, 2D6, and 3A4 in vitro, and studies of co-administration of fulvestrant with midazolam indicate that therapeutic doses of fulvestrant have no inhibitory effects on CYP 3A4 or alter blood levels of drug metabolized by that enzyme. Although fulvestrant is partly metabolized by CYP 3A4, a clinical study with rifampin, an inducer of CYP 3A4, showed no effect on the pharmacokinetics of fulvestrant. Also results from a healthy volunteer study with ketoconazole, a potent inhibitor of CYP3A4, indicated that ketoconazole had no effect on the pharmacokinetics of fulvestrant and dosage adjustment is not necessary in patients co-prescribed CYP 3A4 inhibitors or inducers.
- A two-year carcinogenesis study was conducted in female and male rats, at intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days and 10 mg/rat/15 days.
- These doses correspond to 0.9-, 1.5-, and 3-fold (in females) and 0.8-, 0.8-, and 2-fold (in males) the systemic exposure achieved in women receiving the recommended dose of 500 mg/month. An increased incidence of benign ovarian granulosa cell tumors and testicular Leydig cell tumors was evident, in females dosed at 10 mg/rat/15 days and males dosed at 15 mg/rat/30 days, respectively. In addition, a two year carcinogenicity study was conducted in female and male mice at orally administered doses of 0, 20, 150 and 500 mg/kg/day.
- These doses correspond to 0, 0.8, 8.4 and 18 -fold (in females) and 0, 0.8, 7.1 and 11.9 – fold (in males), the systemic exposure (AUC0-30 days) achieved in women receiving the recommended dose of 500 mg/month. There was an increased incidence of sex cord stromal tumors (both benign and malignant) in the ovary at doses of 150 and 500 mg/kg/day. Induction of such tumors is consistent with the pharmacology-related endocrine feedback alterations in gonadotropin levels caused by an antiestrogen.
- Fulvestrant was not mutagenic or clastogenic in multiple in vitro tests with and without the addition of a mammalian liver metabolic activation factor (bacterial mutation assay in strains of Salmonella typhimurium and Escherichia coli, in vitro cytogenetics study in human lymphocytes, mammalian cell mutation assay in mouse lymphoma cells and in vivo micronucleus test in rat).
- In female rats, fulvestrant administered at doses ≥ 0.01 mg/kg/day (0.6% the human recommended dose based on body surface area ), for 2 weeks prior to and for 1 week following mating, caused a reduction in fertility and embryonic survival. No adverse effects on female fertility and embryonic survival were evident in female animals dosed at 0.001 mg/kg/day (0.06% the human dose based on BSA). Restoration of female fertility to values similar to controls was evident following a 29-day withdrawal period after dosing at 2 mg/kg/day (equivalent to the human dose based on BSA). The effects of fulvestrant on the fertility of female rats appear to be consistent with its antiestrogenic activity. The potential effects of fulvestrant on the fertility of male animals were not studied but, in a 6-month toxicology study, male rats treated with intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days, or 10 mg/rat/15 days fulvestrant showed a loss of spermatozoa from the seminiferous tubules, seminiferous tubular atrophy, and degenerative changes in the epididymides. Changes in the testes and epididymides had not recovered 20 weeks after cessation of dosing. These fulvestrant doses correspond to 1.3-, 1.2- and 3.5-fold the systemic exposure achieved in women receiving the recommended dose of 500 mg/month.
- Comparison of fulvestrant 500 mg and fulvestrant 250 mg (Study 1)
- A Phase 3 randomized, double-blind, controlled clinical trial (Study 1) was completed in 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease. This trial compared the efficacy and safety of fulvestrant 500 mg (n=362) with fulvestrant 250 mg (n=374).
- Fulvestrant 500 mg was administered as two 5 mL injections each containing fulvestrant 250 mg/5mL, one in each buttock, on Days 1, 15, 29 and every 28 (+/- 3) days thereafter. Fulvestrant 250 mg was administered as two 5 mL injections (one containing fulvestrant 250 mg/5mL injection plus one placebo injection), one in each buttock, on Days 1, 15 (2 placebo injections only), 29 and every 28 (+/- 3) days thereafter.
- The median age of study participants was 61. All patients had ER+ advanced breast cancer. Approximately 30% of subjects had no measurable disease. Approximately 55% of patients had visceral disease.
- Results of Study 1 are summarized in Table 4. The efficacy of fulvestrant 500 mg was compared to that of fulvestrant 250 mg. Figure 4 shows a Kaplan-Meier plot of the Progression Free Survival (PFS) data after a minimum follow-up duration of 18 months demonstrating statistically significant superiority of fulvestrant 500 mg vs fulvestrant 250 mg. In the initial Overall Survival (OS) analysis after a minimum follow-up duration of 18 months, there was no statistically significant difference in OS between the two treatment groups. After a minimum follow-up duration of 50 months, an updated OS analysis was performed. Figure 5 shows a Kaplan-Meier plot of the updated OS data.
Comparison of fulvestrant 250 mg and Anastrozole 1 mg in Combined Data (Studies 2 and 3)
- Efficacy of fulvestrant was established by comparison to the selective aromatase inhibitor anastrozole in two randomized, controlled clinical trials (one conducted in North America, Study 2; the other predominantly in Europe, Study 3) in postmenopausal women with locally advanced or metastatic breast cancer. All patients had progressed after previous therapy with an antiestrogen or progestin for breast cancer in the adjuvant or advanced disease setting.
- The median age of study participants was 64. 81.6% of patients had ER+ and/or PgR+ tumors. Patients with ER- /PgR- or unknown tumors were required to have demonstrated a prior response to endocrine therapy. Sites of metastases occurred as follows: visceral only 18.2%; viscera – liver involvement 23.0%; lung involvement 28.1%; bone only 19.7%; soft tissue only 5.2%; skin and soft tissue 18.7%.
- In both trials, eligible patients with measurable and/or evaluable disease were randomized to receive either fulvestrant 250 mg intramuscularly once a month (28 days + 3 days) or anastrozole 1 mg orally once a day. All patients were assessed monthly for the first three months and every three months thereafter. Study 2 was a double-blind, randomized trial in 400 postmenopausal women. Study 3 was an open-label, randomized trial conducted in 451 postmenopausal women. Patients on the fulvestrant arm of Study 2 received two separate injections (2 X 2.5 mL), whereas fulvestrant patients received a single injection (1 X 5 mL) in Study 3. In both trials, patients were initially randomized to a 125 mg per month dose as well, but interim analysis showed a very low response rate, and low dose groups were dropped.
- Results of the trials, after a minimum follow-up duration of 14.6 months, are summarized in Table 5. The effectiveness of fulvestrant 250 mg was determined by comparing Objective Response Rate (ORR) and Time to Progression (TTP) results to anastrozole 1 mg, the active control. The two studies ruled out (by one-sided 97.7% confidence limit) inferiority of fulvestrant to anastrozole of 6.3% and 1.4% in terms of ORR. There was no statistically significant difference in overall survival (OS) between the two treatment groups after a follow-up duration of 28.2 months in Study 2 and 24.4 months in Study 3.
- There are no efficacy data for the use of fulvestrant in premenopausal women with advanced breast cancer (women with functioning ovaries as evidenced by menstruation and/or premenopausal LH, FSH and estradiol levels).
- NDC 0310–0720–10
- The syringes are presented in a tray with polystyrene plunger rod and safety needles for connection to the barrel.
- TO PROTECT FROM LIGHT, STORE IN THE ORIGINAL CARTON UNTIL TIME OF USE.
Women of childbearing potential should be advised not to become pregnant while receiving fulvestrant. fulvestrant can cause fetal harm when administered to a pregnant woman.
# Blood Disorders
Because fulvestrant is administered intramuscularly, it should be used with caution in patients with bleeding disorders, decreased platelet count, or in patients receiving anticoagulants (for example, warfarin)
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- Treatment for hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
- The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter.
Hepatic Impairment
- A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter.
- Fulvestrant has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C)
- Because fulvestrant is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use.
### Hepatic Impairment
- The safety and pharmacokinetics of fulvestrant were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function.
- Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended.
- Fulvestrant has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
### Use in Pregnancy
- Based on its mechanism of action and findings in animals, fulvestrant can cause fetal harm when administered to a pregnant woman.
- Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area.
- There are no adequate and well-controlled studies in pregnant women using fulvestrant. Women of childbearing potential should be advised not to become pregnant while receiving fulvestrant.
- If fulvestrant is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
Comparison of fulvestrant 500 mg and fulvestrant 250 mg
- The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared fulvestrant 500 mg with fulvestrant 250 mg. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients).
- Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the controlled clinical trial Study 1 comparing the administration of fulvestrant 500 mg intramuscularly once a month with fulvestrant 250 mg intramuscularly once a month.
- In the pooled safety population (N=1127) from clinical trials comparing fulvestrant 500 mg to fulvestrant 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in > 15% of patients receiving fulvestrant. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg fulvestrant arms.
Comparison of fulvestrant 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3)
- The most commonly reported adverse reactions in the fulvestrant and anastrozole treatment groups, regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis.
- Injection site reactions with mild transient pain and inflammation were seen with fulvestrant and occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North American Trial Study 2).
- Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of fulvestrant 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day.
Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with fulvestrant. If bleeding persists, further evaluation should be considered.
Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).
- In studies in female rats at intramuscular doses ≥ 0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥ 0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis.
- Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed. Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures.
- The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry.
- Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26.
- Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of fulvestrant on bone mineral density in children has not been studied and is not known.
- Eight patients (27%) experienced adverse reactions that were considered possibly related to fulvestrant. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to fulvestrant. No patients discontinued study treatment due to an AE and no patients died.
Pharmacokinetics
- The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis.
- In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively.
- A dose of fulvestrant 250 mg is recommended in patients with moderate hepatic impairment (Child-Pugh class B)
### Administration Technique
- The proper method of administration of fulvestrant for intramuscular use is described in the instructions that follow:
- Remove glass syringe barrel from tray and check that it is not damaged.
- Remove perforated patient record label from syringe.
- Peel open the safety needle outer packaging.
- Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap (see Figure 1).
- Twist to lock the needle to the luer connector.
- Remove needle sheath.
- Remove excess gas from the syringe (a small gas bubble may remain).
- Administer intramuscularly slowly in the buttock.
- Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered (see Figure 2).
- Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector.
- Repeat steps 1 through 10 for second syringe.
How To Use fulvestrant
For the 2 x 5 mL syringe package, the contents of both syringes must be injected to receive the 500 mg recommended dose.
- In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the growth of tamoxifen-resistant, as well as estrogen-sensitive human breast cancer (MCF-7) cell lines. In in vivo tumor studies, fulvestrant delayed the establishment of tumors from xenografts of human breast cancer MCF-7 cells in nude mice. Fulvestrant inhibited the growth of established MCF-7 xenografts and of tamoxifen-resistant breast tumor xenografts.
- Fulvestrant showed no agonist-type effects in in vivo uterotropic assays in immature or ovariectomized mice and rats. In in vivo studies in immature rats and ovariectomized monkeys, fulvestrant blocked the uterotrophic action of estradiol. In postmenopausal women, the absence of changes in plasma concentrations of FSH and LH in response to fulvestrant treatment (250 mg monthly) suggests no peripheral steroidal effects.
- Fulvestrant is a white powder with a molecular weight of 606.77. The solution for injection is a clear, colorless to yellow, viscous liquid.
- Each injection contains as inactive ingredients: 10% w/v Alcohol, USP, 10% w/v benzyl alcohol, NF, and 15% w/v benzyl benzoate, USP, as co-solvents, and made up to 100% w/v with Castor Oil, USP as a co-solvent and release rate modifier.
- The single dose and multiple dose PK parameters for the 500 mg dosing regimen with an additional dose (AD) at Day 15 are reported in Table 3. The additional dose of fulvestrant given two weeks after the initial dose allows for steady state concentrations to be reached within the first month of dosing.
### Distribution
- The apparent volume of distribution at steady state is approximately 3 to 5 L/kg.
- This suggests that distribution is largely extravascular. Fulvestrant is highly (99%) bound to plasma proteins; VLDL, LDL and HDL lipoprotein fractions appear to be the major binding components. The role of sex hormone-binding globulin, if any, could not be determined.
### Metabolism
- Biotransformation and disposition of fulvestrant in humans have been determined following intramuscular and intravenous administration of 14C-labeled fulvestrant. Metabolism of fulvestrant appears to involve combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or sulphate at the 2, 3 and 17 positions of the steroid nucleus, and oxidation of the side chain sulphoxide. Identified metabolites are either less active or exhibit similar activity to fulvestrant in antiestrogen models.
- Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution of P-450 and non-P-450 routes in vivo is unknown.
### Excretion
- Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%). Renal elimination was negligible (less than 1%).
- After an intramuscular injection of 250 mg, the clearance (Mean ± SD) was 690 ± 226 mL/min with an apparent half-life about 40 days.
### Special Populations
- In patients with breast cancer, there was no difference in fulvestrant pharmacokinetic profile related to age (range 33 to 89 years).
- Following administration of a single intravenous dose, there were no pharmacokinetic differences between men and women or between premenopausal and postmenopausal women. Similarly, there were no differences between men and postmenopausal women after intramuscular administration.
- In the advanced breast cancer treatment trials, the potential for pharmacokinetic differences due to race have been evaluated in 294 women including 87.4% Caucasian, 7.8% Black, and 4.4% Hispanic. No differences in fulvestrant plasma pharmacokinetics were observed among these groups. In a separate trial, pharmacokinetic data from postmenopausal ethnic Japanese women were similar to those obtained in non-Japanese patients.
### Drug-Drug Interactions
- There are no known drug-drug interactions. Fulvestrant does not significantly inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2C19, 2D6, and 3A4 in vitro, and studies of co-administration of fulvestrant with midazolam indicate that therapeutic doses of fulvestrant have no inhibitory effects on CYP 3A4 or alter blood levels of drug metabolized by that enzyme. Although fulvestrant is partly metabolized by CYP 3A4, a clinical study with rifampin, an inducer of CYP 3A4, showed no effect on the pharmacokinetics of fulvestrant. Also results from a healthy volunteer study with ketoconazole, a potent inhibitor of CYP3A4, indicated that ketoconazole had no effect on the pharmacokinetics of fulvestrant and dosage adjustment is not necessary in patients co-prescribed CYP 3A4 inhibitors or inducers.
- A two-year carcinogenesis study was conducted in female and male rats, at intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days and 10 mg/rat/15 days.
- These doses correspond to 0.9-, 1.5-, and 3-fold (in females) and 0.8-, 0.8-, and 2-fold (in males) the systemic exposure [AUC0-30 days] achieved in women receiving the recommended dose of 500 mg/month. An increased incidence of benign ovarian granulosa cell tumors and testicular Leydig cell tumors was evident, in females dosed at 10 mg/rat/15 days and males dosed at 15 mg/rat/30 days, respectively. In addition, a two year carcinogenicity study was conducted in female and male mice at orally administered doses of 0, 20, 150 and 500 mg/kg/day.
- These doses correspond to 0, 0.8, 8.4 and 18 -fold (in females) and 0, 0.8, 7.1 and 11.9 – fold (in males), the systemic exposure (AUC0-30 days) achieved in women receiving the recommended dose of 500 mg/month. There was an increased incidence of sex cord stromal tumors (both benign and malignant) in the ovary at doses of 150 and 500 mg/kg/day. Induction of such tumors is consistent with the pharmacology-related endocrine feedback alterations in gonadotropin levels caused by an antiestrogen.
- Fulvestrant was not mutagenic or clastogenic in multiple in vitro tests with and without the addition of a mammalian liver metabolic activation factor (bacterial mutation assay in strains of Salmonella typhimurium and Escherichia coli, in vitro cytogenetics study in human lymphocytes, mammalian cell mutation assay in mouse lymphoma cells and in vivo micronucleus test in rat).
- In female rats, fulvestrant administered at doses ≥ 0.01 mg/kg/day (0.6% the human recommended dose based on body surface area [BSA]), for 2 weeks prior to and for 1 week following mating, caused a reduction in fertility and embryonic survival. No adverse effects on female fertility and embryonic survival were evident in female animals dosed at 0.001 mg/kg/day (0.06% the human dose based on BSA). Restoration of female fertility to values similar to controls was evident following a 29-day withdrawal period after dosing at 2 mg/kg/day (equivalent to the human dose based on BSA). The effects of fulvestrant on the fertility of female rats appear to be consistent with its antiestrogenic activity. The potential effects of fulvestrant on the fertility of male animals were not studied but, in a 6-month toxicology study, male rats treated with intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days, or 10 mg/rat/15 days fulvestrant showed a loss of spermatozoa from the seminiferous tubules, seminiferous tubular atrophy, and degenerative changes in the epididymides. Changes in the testes and epididymides had not recovered 20 weeks after cessation of dosing. These fulvestrant doses correspond to 1.3-, 1.2- and 3.5-fold the systemic exposure [AUC0-30 days ] achieved in women receiving the recommended dose of 500 mg/month.
- Comparison of fulvestrant 500 mg and fulvestrant 250 mg (Study 1)
- A Phase 3 randomized, double-blind, controlled clinical trial (Study 1) was completed in 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease. This trial compared the efficacy and safety of fulvestrant 500 mg (n=362) with fulvestrant 250 mg (n=374).
- Fulvestrant 500 mg was administered as two 5 mL injections each containing fulvestrant 250 mg/5mL, one in each buttock, on Days 1, 15, 29 and every 28 (+/- 3) days thereafter. Fulvestrant 250 mg was administered as two 5 mL injections (one containing fulvestrant 250 mg/5mL injection plus one placebo injection), one in each buttock, on Days 1, 15 (2 placebo injections only), 29 and every 28 (+/- 3) days thereafter.
- The median age of study participants was 61. All patients had ER+ advanced breast cancer. Approximately 30% of subjects had no measurable disease. Approximately 55% of patients had visceral disease.
- Results of Study 1 are summarized in Table 4. The efficacy of fulvestrant 500 mg was compared to that of fulvestrant 250 mg. Figure 4 shows a Kaplan-Meier plot of the Progression Free Survival (PFS) data after a minimum follow-up duration of 18 months demonstrating statistically significant superiority of fulvestrant 500 mg vs fulvestrant 250 mg. In the initial Overall Survival (OS) analysis after a minimum follow-up duration of 18 months, there was no statistically significant difference in OS between the two treatment groups. After a minimum follow-up duration of 50 months, an updated OS analysis was performed. Figure 5 shows a Kaplan-Meier plot of the updated OS data.
Comparison of fulvestrant 250 mg and Anastrozole 1 mg in Combined Data (Studies 2 and 3)
- Efficacy of fulvestrant was established by comparison to the selective aromatase inhibitor anastrozole in two randomized, controlled clinical trials (one conducted in North America, Study 2; the other predominantly in Europe, Study 3) in postmenopausal women with locally advanced or metastatic breast cancer. All patients had progressed after previous therapy with an antiestrogen or progestin for breast cancer in the adjuvant or advanced disease setting.
- The median age of study participants was 64. 81.6% of patients had ER+ and/or PgR+ tumors. Patients with ER- /PgR- or unknown tumors were required to have demonstrated a prior response to endocrine therapy. Sites of metastases occurred as follows: visceral only 18.2%; viscera – liver involvement 23.0%; lung involvement 28.1%; bone only 19.7%; soft tissue only 5.2%; skin and soft tissue 18.7%.
- In both trials, eligible patients with measurable and/or evaluable disease were randomized to receive either fulvestrant 250 mg intramuscularly once a month (28 days + 3 days) or anastrozole 1 mg orally once a day. All patients were assessed monthly for the first three months and every three months thereafter. Study 2 was a double-blind, randomized trial in 400 postmenopausal women. Study 3 was an open-label, randomized trial conducted in 451 postmenopausal women. Patients on the fulvestrant arm of Study 2 received two separate injections (2 X 2.5 mL), whereas fulvestrant patients received a single injection (1 X 5 mL) in Study 3. In both trials, patients were initially randomized to a 125 mg per month dose as well, but interim analysis showed a very low response rate, and low dose groups were dropped.
- Results of the trials, after a minimum follow-up duration of 14.6 months, are summarized in Table 5. The effectiveness of fulvestrant 250 mg was determined by comparing Objective Response Rate (ORR) and Time to Progression (TTP) results to anastrozole 1 mg, the active control. The two studies ruled out (by one-sided 97.7% confidence limit) inferiority of fulvestrant to anastrozole of 6.3% and 1.4% in terms of ORR. There was no statistically significant difference in overall survival (OS) between the two treatment groups after a follow-up duration of 28.2 months in Study 2 and 24.4 months in Study 3.
- There are no efficacy data for the use of fulvestrant in premenopausal women with advanced breast cancer (women with functioning ovaries as evidenced by menstruation and/or premenopausal LH, FSH and estradiol levels).
- NDC 0310–0720–10
- The syringes are presented in a tray with polystyrene plunger rod and safety needles for connection to the barrel.
- TO PROTECT FROM LIGHT, STORE IN THE ORIGINAL CARTON UNTIL TIME OF USE.
Women of childbearing potential should be advised not to become pregnant while receiving fulvestrant. fulvestrant can cause fetal harm when administered to a pregnant woman.
### Blood Disorders
Because fulvestrant is administered intramuscularly, it should be used with caution in patients with bleeding disorders, decreased platelet count, or in patients receiving anticoagulants (for example, warfarin)
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a0a018f6441dba5a1772b1dbad7be1108635cb74 | wikidoc | Fayaz Shawl | Fayaz Shawl
Fayaz Shawl, MD, FACP, FCCP, FACC
Dr. Shawl is currently the Director of Interventional Cardiology at Washington Adventist Hospital in Takoma Park, Maryland, as well as Professor and Director of Interventional Cardiovascular Medicine at George Washington University School of Medicine in Washington, D.C., USA. He is best known as a pioneer in interventional cardiology and has played an active role in all aspects of Interventional Cardiology Dr. Shawl is considered to have performed every known interventional technique with regards to cardiac procedures and has pioneered several new techniques that provide less risk and less invasion during these lifesaving surgeries. He is very active in scientific research and is currently researching new innovations in stroke prevention.
Dr. Shawl received his medical degree from Kashmir Medical College in 1972 and completed his residency in England. In 1977, Dr. Shawl moved to the United States and completed his cardiology fellowship at The Walter Reed Army Medical Center. Dr. Shawl brought the military into the ‘balloon age’ when he performed the first PTCA in the United States Military (Army, Navy, Air Force) at Walter Reed Army Medical Center in 1980.
Between 1979 and 2003, Dr. Shawl retained clinical appointments at Georgetown University School of Medicine, George Washington University School of Medicine and the Uniformed Services University School of Medicine, while developing leadership roles in Interventional Cardiology at both Washington Adventist Hospital and George Washington University Hospital.
Dr. Shawl is a member of the American College of Physicians, the Royal College of Physicians of the United Kingdom, General Medical Council of the United Kingdom, the American Medical Association and American Heart Association. He is a Fellow of the American College of Cardiology, the American College of Chest Physicians, American College of Physicians, the American College of Angiology and The Society for Cardiac Angiography and Interventions.
While he has lectured widely on every topic of Interventional Cardiology, he has been a leading proponent and innovator in the development of the percutaneous approach (known as 'Shawl Technique') to cardiopulmonary bypass support in "High Risk Angioplasty and Cardiac Arrest" performing the first percutaneous bypass-supported coronary intervention in the world in 1988. This lifesaving technology (when available in the Cardiac Catheterization Laboratory) makes death during the procedure impossible. Since its invention in 1988, there has not been a single death in the Cardiac Catheterization Laboratory at Washington Adventist while Dr. Shawl performed coronary interventions. He has lectured on this topic and trained physicians through out the world.
In a study involving 23,472 patients undergoing elective coronary interventions at Washington Adventist Hospital using percutaneous CPS standby rather than formal surgical backup for elective coronary interventions, resulted in NO deaths during the procedure. However, 39 patients (0.2%) did develop refractory hemodynamic collapse (imminent death) during which emergency CPS was instituted within 12 minutes. Of these 39 patients, 31 patients were discharged from the hospital (Shawl, et al. JACC 2001; 37(2A), 175A).
He has been teaching his colleagues with live demonstrations the other techniques of interventional cardiology (including coronary, carotid and other peripheral and non-cardiac interventions like valvuloplasty, ablative technique for IHSS, etc.) at Washington Adventist Hospital from 1987 - 1998 and all over the world. Such types of teaching seminars are done through satellite or local broadcast live from the CATH lab.
A true innovator in working with the high risk patient, Dr. Shawl was the first Interventional Cardiologist to use both the Eclipse Holmium Laser as well as the AngioTrax mechanical device (1999) for Percutaneous Transluminal Myocardial Revascularization in the investigational treatment of end-stage atherosclerotic heart disease (patients with no options). He did both procedures as part of research first in world at New Delhi, India. He was also first to perform mitral valvuloplasty in the Washington, DC metropolitan area in 1985.
Dr. Shawl is a member of the renowned International Gruentzig Society and was recognized as one of the world's most talented interventionists in an interview for the Journal of Invasive Cardiology in April 2001 (JIC, Vol. 13, No. 4, April 2001). He was acknowledged to have performed the most interventional procedures as a single operator (over 19,000)than any other interventionist in the world.
Currently in pursuit of stroke prevention, the number two cause of death, Dr. Shawl and others have pioneered the technique of carotid artery stenting. Dr. Shawl performed the first percutaneous carotid artery stenting in this region in 1995. The results of this new avenue of endovascular therapy may challenge the accepted practice of surgical carotid endarterectomy. Having done over 600 carotid stent cases at Washington Adventist Hospital, using present technique, what he calls "meticulous technique" has resulted in a complication rate of <0.5% in the last 300 cases.
Dr. Shawl has a very active, accredited interventional fellowship program at Washington Adventist Hospital in association with the program at George Washington University Hospital in Washington, D.C. Out of 179 available interventional training positions throughout the U.S., he has three positions in his interventional program.
Dr. Shawl has authored over 150 leading articles, abstracts, editorials and book chapters. He has also published a book entitled "Supported Complex and High Risk Coronary Angioplasty". Some of his more recent awards include the dedication of the Fayaz Shawl Advanced Interventional Catheterization Laboratory at Washington Adventist Hospital in 1998, 2002 Innovators Award from the Alliance of Cardiovascular Professionals, as well as several recognition awards from the Maryland State Senate and the United States House of Representatives. Dr. Shawl received nomination as International Health Professional of the Year (2003). This prestigious award is given to individuals whose achievements and leadership stand out in the International Community as decreed by the Research and Advisory Board sitting at the International Biographical Center in Cambridge, England.
Dr. Shawl is also involved in giving back to the community -
Plans are underway to create hospital facilities wherever deemed essential to treat the indigenous who are impoverished and cannot afford the cost of such medical attention. Kashmir, the country of the birth of Dr. Shawl, will be the first hospital ground breaking in the Spring of 2007 with proceeds emanating from his own personal coffers. Goa, India, with the help of Mr. Pratapsing Rane, Chief Minister and Mr. Ravi Jaipuria, is also being considered along with Wakefield, England and the Washington, DC area.
In Dubai, he has just signed with the "Cardiovascular Institute and Research Center at Zulekha Hospital to provide along with Dr. Zulekha's generosity to also help poor and needy, in addition to treat and teach the physicians from the entire region. The income generated by his services at this Cardiac Center, Dubai will go into his foundation in the U.S. | Fayaz Shawl
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Fayaz Shawl, MD, FACP, FCCP, FACC
Dr. Shawl is currently the Director of Interventional Cardiology at Washington Adventist Hospital in Takoma Park, Maryland, as well as Professor and Director of Interventional Cardiovascular Medicine at George Washington University School of Medicine in Washington, D.C., USA. He is best known as a pioneer in interventional cardiology and has played an active role in all aspects of Interventional Cardiology Dr. Shawl is considered to have performed every known interventional technique with regards to cardiac procedures and has pioneered several new techniques that provide less risk and less invasion during these lifesaving surgeries. He is very active in scientific research and is currently researching new innovations in stroke prevention.
Dr. Shawl received his medical degree from Kashmir Medical College in 1972 and completed his residency in England. In 1977, Dr. Shawl moved to the United States and completed his cardiology fellowship at The Walter Reed Army Medical Center. Dr. Shawl brought the military into the ‘balloon age’ when he performed the first PTCA in the United States Military (Army, Navy, Air Force) at Walter Reed Army Medical Center in 1980.
Between 1979 and 2003, Dr. Shawl retained clinical appointments at Georgetown University School of Medicine, George Washington University School of Medicine and the Uniformed Services University School of Medicine, while developing leadership roles in Interventional Cardiology at both Washington Adventist Hospital and George Washington University Hospital.
Dr. Shawl is a member of the American College of Physicians, the Royal College of Physicians of the United Kingdom, General Medical Council of the United Kingdom, the American Medical Association and American Heart Association. He is a Fellow of the American College of Cardiology, the American College of Chest Physicians, American College of Physicians, the American College of Angiology and The Society for Cardiac Angiography and Interventions.
While he has lectured widely on every topic of Interventional Cardiology, he has been a leading proponent and innovator in the development of the percutaneous approach (known as 'Shawl Technique') to cardiopulmonary bypass support in "High Risk Angioplasty and Cardiac Arrest" performing the first percutaneous bypass-supported coronary intervention in the world in 1988. This lifesaving technology (when available in the Cardiac Catheterization Laboratory) makes death during the procedure impossible. Since its invention in 1988, there has not been a single death in the Cardiac Catheterization Laboratory at Washington Adventist while Dr. Shawl performed coronary interventions. He has lectured on this topic and trained physicians through out the world.
In a study involving 23,472 patients undergoing elective coronary interventions at Washington Adventist Hospital using percutaneous CPS standby rather than formal surgical backup for elective coronary interventions, resulted in NO deaths during the procedure. However, 39 patients (0.2%) did develop refractory hemodynamic collapse (imminent death) during which emergency CPS was instituted within 12 minutes. Of these 39 patients, 31 patients were discharged from the hospital (Shawl, et al. JACC 2001; 37(2A), 175A).
He has been teaching his colleagues with live demonstrations the other techniques of interventional cardiology (including coronary, carotid and other peripheral and non-cardiac interventions like valvuloplasty, ablative technique for IHSS, etc.) at Washington Adventist Hospital from 1987 - 1998 and all over the world. Such types of teaching seminars are done through satellite or local broadcast live from the CATH lab.
A true innovator in working with the high risk patient, Dr. Shawl was the first Interventional Cardiologist to use both the Eclipse Holmium Laser as well as the AngioTrax mechanical device (1999) for Percutaneous Transluminal Myocardial Revascularization in the investigational treatment of end-stage atherosclerotic heart disease (patients with no options). He did both procedures as part of research first in world at New Delhi, India. He was also first to perform mitral valvuloplasty in the Washington, DC metropolitan area in 1985.
Dr. Shawl is a member of the renowned International Gruentzig Society and was recognized as one of the world's most talented interventionists in an interview for the Journal of Invasive Cardiology in April 2001 (JIC, Vol. 13, No. 4, April 2001). He was acknowledged to have performed the most interventional procedures as a single operator (over 19,000)than any other interventionist in the world.
Currently in pursuit of stroke prevention, the number two cause of death, Dr. Shawl and others have pioneered the technique of carotid artery stenting. Dr. Shawl performed the first percutaneous carotid artery stenting in this region in 1995. The results of this new avenue of endovascular therapy may challenge the accepted practice of surgical carotid endarterectomy. Having done over 600 carotid stent cases at Washington Adventist Hospital, using present technique, what he calls "meticulous technique" has resulted in a complication rate of <0.5% in the last 300 cases.
Dr. Shawl has a very active, accredited interventional fellowship program at Washington Adventist Hospital in association with the program at George Washington University Hospital in Washington, D.C. Out of 179 available interventional training positions throughout the U.S., he has three positions in his interventional program.
Dr. Shawl has authored over 150 leading articles, abstracts, editorials and book chapters. He has also published a book entitled "Supported Complex and High Risk Coronary Angioplasty". Some of his more recent awards include the dedication of the Fayaz Shawl Advanced Interventional Catheterization Laboratory at Washington Adventist Hospital in 1998, 2002 Innovators Award from the Alliance of Cardiovascular Professionals, as well as several recognition awards from the Maryland State Senate and the United States House of Representatives. Dr. Shawl received nomination as International Health Professional of the Year (2003). This prestigious award is given to individuals whose achievements and leadership stand out in the International Community as decreed by the Research and Advisory Board sitting at the International Biographical Center in Cambridge, England.
Dr. Shawl is also involved in giving back to the community -
Plans are underway to create hospital facilities wherever deemed essential to treat the indigenous who are impoverished and cannot afford the cost of such medical attention. Kashmir, the country of the birth of Dr. Shawl, will be the first hospital ground breaking in the Spring of 2007 with proceeds emanating from his own personal coffers. Goa, India, with the help of Mr. Pratapsing Rane, Chief Minister and Mr. Ravi Jaipuria, is also being considered along with Wakefield, England and the Washington, DC area.
In Dubai, he has just signed with the "Cardiovascular Institute and Research Center at Zulekha Hospital to provide along with Dr. Zulekha's generosity to also help poor and needy, in addition to treat and teach the physicians from the entire region. The income generated by his services at this Cardiac Center, Dubai will go into his foundation in the U.S.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Fayaz_Shawl | |
06c38f7fda700619a1b58fa59c9afd75b57b27f0 | wikidoc | Felypressin | Felypressin
Felypressin is added to some local anaesthetics such as prilocaine in a concentration of 0.003 i.u./ml. Felypressin is a non-catecholamine vasoconstrictor that is chemically related to vasopressin, the posterior pituitary hormone. Felypressin is a V1 Agonist, and will thus have affects at all V1 receptors. It will, however, have its main physiological effects on vascular SMC's due to the form in which it is administered.
V1 receptors are found in various sites around the body. The major points include the CNS, Liver, Anterior Pituitary, Muscle (both vascular and non-vascular smooth muscle), and Platelets (CLAMP).
Another example of a V1 Agonist is Terlipressin - which is used in Oesophageal Varices. | Felypressin
Felypressin is added to some local anaesthetics such as prilocaine in a concentration of 0.003 i.u./ml. Felypressin is a non-catecholamine vasoconstrictor that is chemically related to vasopressin, the posterior pituitary hormone. Felypressin is a V1 Agonist, and will thus have affects at all V1 receptors. It will, however, have its main physiological effects on vascular SMC's due to the form in which it is administered.
V1 receptors are found in various sites around the body. The major points include the CNS, Liver, Anterior Pituitary, Muscle (both vascular and non-vascular smooth muscle), and Platelets (CLAMP).
Another example of a V1 Agonist is Terlipressin - which is used in Oesophageal Varices. | https://www.wikidoc.org/index.php/Felypressin | |
039a154f3724f93a765afef51b6662aba2890896 | wikidoc | Fenetylline | Fenetylline
# Overview
Fenethylline (BAN, USAN), also spelled phenethylline and fenetylline (INN), and also known as amphetaminoethyltheophylline and amfetyline, is a chemical linkage of amphetamine and theophylline which behaves as a prodrug to both of the aforementioned drugs. It is marketed for use as a psychostimulant under the brand names Captagon, Biocapton, and Fitton.
# History
Fenethylline was invented by Degussa AG in 1961 and used for around 25 years as a milder alternative to amphetamines. Despite no accepted FDA indication for fenethylline, it was used in applications such as treating "hyperkinetic children" (what would now be referred to as Attention Deficit Hyperactivity Disorder), and also less commonly for treating narcolepsy or as an antidepressant. One of the main advantages of fenethylline was that it does not tend to increase blood pressure to the same extent as amphetamines and so could be used in patients with cardiovascular conditions.
Fenethylline was considered to have fewer side effects and less potential for abuse than amphetamine. Nevertheless, fenethylline was listed in 1981 as a schedule I controlled substance in the US, and it became illegal in most countries in 1986 after being listed by the World Health Organization for international scheduling under the Convention on Psychotropic Substances, even though the actual incidence of fenethylline abuse was quite low.
# Pharmacology
Fenethylline is metabolized by the body to form two drugs amphetamine (24.5% of oral dose) and theophylline (13.7% of oral dose), both of which are active stimulants themselves. The physiological effects of fenethylline therefore result from a combination of all three drugs.
# Abuse
Abuse of fenethylline of the brand name Captagon is most common in Arab countries and counterfeit versions of the drug continue to be available despite its illegality.
Many of these counterfeit "Captagon" tablets actually contain other amphetamine derivatives that are easier to produce, but are pressed and stamped to look like Captagon pills. Some counterfeit Captagon pills analyzed do contain fenethylline however, indicating that illicit production of this drug continues to take place.
Fenethylline is a popular drug, allegedly used by militant groups in Syria and Lebanon. It is manufactured locally in a cheap and simple process. According to some leaks, militant groups would also export the drug in exchange for weapons and cash. | Fenetylline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Fenethylline (BAN, USAN), also spelled phenethylline and fenetylline (INN), and also known as amphetaminoethyltheophylline and amfetyline, is a chemical linkage of amphetamine and theophylline which behaves as a prodrug to both of the aforementioned drugs.[1][2] It is marketed for use as a psychostimulant under the brand names Captagon, Biocapton, and Fitton.[1][2]
# History
Fenethylline was invented by Degussa AG in 1961[3] and used for around 25 years as a milder alternative to amphetamines. Despite no accepted FDA indication for fenethylline, it was used in applications such as treating "hyperkinetic children" (what would now be referred to as Attention Deficit Hyperactivity Disorder), and also less commonly for treating narcolepsy or as an antidepressant. One of the main advantages of fenethylline was that it does not tend to increase blood pressure to the same extent as amphetamines and so could be used in patients with cardiovascular conditions.
Fenethylline was considered to have fewer side effects and less potential for abuse than amphetamine. Nevertheless, fenethylline was listed in 1981 as a schedule I controlled substance in the US, and it became illegal in most countries in 1986 after being listed by the World Health Organization for international scheduling under the Convention on Psychotropic Substances, even though the actual incidence of fenethylline abuse was quite low.
# Pharmacology
Fenethylline is metabolized by the body to form two drugs amphetamine (24.5% of oral dose) and theophylline (13.7% of oral dose), both of which are active stimulants themselves.[4] The physiological effects of fenethylline therefore result from a combination of all three drugs.[5]
# Abuse
Abuse of fenethylline of the brand name Captagon is most common in Arab countries and counterfeit versions of the drug continue to be available despite its illegality.[6] [7]
Many of these counterfeit "Captagon" tablets actually contain other amphetamine derivatives that are easier to produce, but are pressed and stamped to look like Captagon pills. Some counterfeit Captagon pills analyzed do contain fenethylline however, indicating that illicit production of this drug continues to take place.[citation needed]
Fenethylline is a popular drug, allegedly used by militant groups in Syria and Lebanon. It is manufactured locally in a cheap and simple process. According to some leaks, militant groups would also export the drug in exchange for weapons and cash.[8][9] | https://www.wikidoc.org/index.php/Fenetylline | |
858905b5449faec906ac1f2e2629a6335881fa29 | wikidoc | Ferroportin | Ferroportin
Ferroportin-1, also known as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 (IREG1), is a protein that in humans is encoded by the SLC40A1 gene, and is part of the Ferroportin (Fpn) Family (TC# 2.A.100). Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell. After iron is absorbed into the cells of the intestine, ferroportin allows that iron to be transported out of those cells and into the bloodstream. Ferroportin is the only known iron exporter.
# Structure
Members of the FPN family consist of 400-800 amino acid residues, with a highly conserved histidine at residue position 32 (H32), and exhibit 8-11 putative transmembrane segments (TMSs). When H32 is mutated, lower activity in its iron transport role is observed. Ferroportin can also function as a manganese exporter. Because ferroportin extrudes Fe2+ from the cell, ferroportin is presumed to function by cation (H+ or Na+) antiport.
# Transport reaction
The transport reaction catalyzed by ferroportin is:
# Tissue distribution
Ferroportin is found on the basolateral membranes of intestinal epithelia of mammals, including:
- Enterocytes in the duodenum
- Hepatocytes
- Macrophages of the reticuloendothelial system
- Adipocytes
# Role in development
Ferroportin-1 plays an important role in neural tube closure and forebrain patterning. Mouse embyros lacking the Scl40a1 gene are aborted before gastrulation occurs, suggesting that the Fpn1 protein encoded is necessary and essential for normal embryonic development. Fpn1 is expressed in the syncytiotrophoblast cells in the placenta and visceral endoderm of mice at E7.5. Further, several retrospective studies have noted an increased incidence of spina bifida occurring after low maternal intake of iron during embryonic and fetal development.
A study examining the consequences of several different mutations of the Slc40a1 mouse gene suggested that several serious neural tube and patterning defects were produced as a result, including spina bifida, exencephaly, and forebrain truncations, among others. Given the findings of studies to date, there appears to be significant evidence that intact iron transport mechanisms are critical to normal neural tube closure. Furthermore, other experiments have suggested that Fpn1 product and activity is required along the entire anterior-posterior axis of the animal to ensure proper closure of the neural tube.
# Role in fertility
It is known that ferroportin (SLC40A1) gene is expressed at a low level in infertile women. Its mRNA levels were discovered to be down-regulated in these women, specifically in granulosa cells. What's more, low expression of ferroportin is also associated with infertily when some features like age and smoking habits are considered.
It is also important to mention that, not only is ferroportin down-regulated in granulosa cells, but also in cervical cells of infertile women, and that the association between infertility and low ferroportin levels in these cells can be seen, again, when mRNA ferroportin levels was adjusted by age and smoking status.
# Role in iron metabolism
Ferroportin is inhibited by hepcidin, which binds to ferroportin and internalizes it within the cell. This results in the retention of iron within enterocytes, hepatocytes, and macrophages with a consequent reduction in iron levels within the blood serum. This is especially significant with enterocytes which, when shed at the end of their lifespan, results in significant iron loss. This is part of the mechanism that causes anaemia of chronic disease; hepcidin is released from the liver in response to inflammatory cytokines, namely interleukin-6, which results in an increased hepcidin concentration and a consequent decrease in plasma iron levels.
Ferroportin expression is also regulated by the IRP regulatory mechanism. If the iron concentration is too low, the IRP concentration increases, thus inhibiting the ferroportin translation. The ferroportin translation is also regulated by the micro RNA miR-485-3p.
# Clinical significance
Mutations in the ferroportin gene are known to cause an autosomal dominant form of iron overload known as type IV haemochromatosis or Ferroportin Disease. The effects of the mutations are generally not severe but a spectrum of clinical outcomes are seen with different mutations. Ferroportin is also associated with African iron overload. Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. | Ferroportin
Ferroportin-1, also known as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 (IREG1), is a protein that in humans is encoded by the SLC40A1 gene, and is part of the Ferroportin (Fpn) Family (TC# 2.A.100).[1] Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell. After iron is absorbed into the cells of the intestine, ferroportin allows that iron to be transported out of those cells and into the bloodstream. Ferroportin is the only known iron exporter.[2]
# Structure
Members of the FPN family consist of 400-800 amino acid residues,[3] with a highly conserved histidine at residue position 32 (H32), and exhibit 8-11 putative transmembrane segments (TMSs). When H32 is mutated, lower activity in its iron transport role is observed.[4] Ferroportin can also function as a manganese exporter.[5] Because ferroportin extrudes Fe2+ from the cell, ferroportin is presumed to function by cation (H+ or Na+) antiport.
# Transport reaction
The transport reaction catalyzed by ferroportin is:
# Tissue distribution
Ferroportin is found on the basolateral membranes of intestinal epithelia of mammals, including:[6][7]
- Enterocytes in the duodenum
- Hepatocytes
- Macrophages of the reticuloendothelial system
- Adipocytes
# Role in development
Ferroportin-1 plays an important role in neural tube closure and forebrain patterning.[8] Mouse embyros lacking the Scl40a1 gene are aborted before gastrulation occurs, suggesting that the Fpn1 protein encoded is necessary and essential for normal embryonic development.[6] Fpn1 is expressed in the syncytiotrophoblast cells in the placenta and visceral endoderm of mice at E7.5.[1][6] Further, several retrospective studies have noted an increased incidence of spina bifida occurring after low maternal intake of iron during embryonic and fetal development.[9][10]
A study examining the consequences of several different mutations of the Slc40a1 mouse gene suggested that several serious neural tube and patterning defects were produced as a result, including spina bifida, exencephaly, and forebrain truncations, among others.[8] Given the findings of studies to date, there appears to be significant evidence that intact iron transport mechanisms are critical to normal neural tube closure. Furthermore, other experiments have suggested that Fpn1 product and activity is required along the entire anterior-posterior axis of the animal to ensure proper closure of the neural tube.[8]
# Role in fertility
It is known that ferroportin (SLC40A1) gene is expressed at a low level in infertile women. Its mRNA levels were discovered to be down-regulated in these women, specifically in granulosa cells. What's more, low expression of ferroportin is also associated with infertily when some features like age and smoking habits are considered.
It is also important to mention that, not only is ferroportin down-regulated in granulosa cells, but also in cervical cells of infertile women, and that the association between infertility and low ferroportin levels in these cells can be seen, again, when mRNA ferroportin levels was adjusted by age and smoking status.[11]
# Role in iron metabolism
Ferroportin is inhibited by hepcidin, which binds to ferroportin and internalizes it within the cell.[12] This results in the retention of iron within enterocytes, hepatocytes, and macrophages with a consequent reduction in iron levels within the blood serum. This is especially significant with enterocytes which, when shed at the end of their lifespan, results in significant iron loss. This is part of the mechanism that causes anaemia of chronic disease; hepcidin is released from the liver in response to inflammatory cytokines, namely interleukin-6, which results in an increased hepcidin concentration and a consequent decrease in plasma iron levels.[13]
Ferroportin expression is also regulated by the IRP regulatory mechanism. If the iron concentration is too low, the IRP concentration increases, thus inhibiting the ferroportin translation. The ferroportin translation is also regulated by the micro RNA miR-485-3p.[14]
# Clinical significance
Mutations in the ferroportin gene are known to cause an autosomal dominant form of iron overload known as type IV haemochromatosis or Ferroportin Disease. The effects of the mutations are generally not severe but a spectrum of clinical outcomes are seen with different mutations. Ferroportin is also associated with African iron overload. Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. | https://www.wikidoc.org/index.php/Ferroportin | |
9377f120ed6882c1bb79eaf7d1360f9c91dfa018 | wikidoc | Ferumoxytol | Ferumoxytol
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Ferumoxytol is a iron replacement product that is FDA approved for the treatment of iron deficiency anemia in adult patients with chronic kidney disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, nausea, dizziness, hypotension, constipation, and peripheral edema.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Feraheme is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD)
### Dosage
- The recommended dose of Feraheme is an initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later. Administer Feraheme as an intravenous infusion in 50-200 mL 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes. Administer while the patient is in a reclined or semi-reclined position.
- Feraheme, when added to intravenous infusion bags containing either 0.9% Sodium Chloride Injection, USP (normal saline), or 5% Dextrose Injection, USP, at concentrations of 2-8 mg elemental iron per mL, should be used immediately but may be stored at controlled room temperature (25°C ± 2°C) for up to 4 hours.
- The dosage is expressed in terms of mg of elemental iron, with each mL of Feraheme containing 30 mg of elemental iron. Evaluate the hematologic response (hemoglobin, ferritin, iron and transferrin saturation) at least one month following the second Feraheme infusion. The recommended Feraheme dose may be readministered to patients with persistent or recurrent iron deficiency anemia.
- For patients receiving hemodialysis, administer Feraheme once the blood pressure is stable and the patient has completed at least one hour of hemodialysis. Monitor for signs and symptoms of hypotension following each Feraheme infusion.
- Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions and/or hypotension, such as chemotherapeutic agents or monoclonal antibodies.
- Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ferumoxytol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ferumoxytol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ferumoxytol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ferumoxytol in pediatric patients.
# Contraindications
- Known hypersensitivity to Feraheme or any of its components
History of allergic reaction to any intravenous iron product
# Warnings
- Fatal and serious hypersensitivity reactions including anaphylaxis, presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, or unresponsiveness have occurred in patients receiving Feraheme. Other adverse reactions potentially associated with hypersensitivity have occurred (pruritus, rash, urticaria, and wheezing). These reactions have occurred following the first dose or subsequent doses in patients in whom a previous Feraheme dose was tolerated.
- Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.
- Only administer Feraheme when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions. Closely observe patients for signs and symptoms of hypersensitivity including monitoring of blood pressure and pulse during and after Feraheme administration for at least 30 minutes and until clinically stable following completion of each infusion.
- In clinical studies predominantly in patients with CKD, serious hypersensitivity reactions were reported in 0.2% (3/1,726) of subjects receiving Feraheme. Other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.7% (63/1,726) of these subjects. In other trials excluding patients with Stages 4 and 5 CKD, moderate to severe hypersensitivity reactions were reported in 2.6% (26/1014) of patients treated with Feraheme.
- In the post-marketing experience, fatal and serious anaphylactic type reactions presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, and unresponsiveness have been reported. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of Feraheme may have more severe outcomes.
- Severe adverse reactions of clinically significant hypotension have been reported. In clinical studies, hypotension was reported in 1.9% (33/1,726) of subjects, including three patients with serious hypotensive reactions. Hypotension has also been reported in the post-marketing experience. Monitor patients for signs and symptoms of hypotension following each Feraheme administration.
- Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Regularly monitor the hematologic response during parenteral iron therapy. Do not administer Feraheme to patients with iron overload.
- In the 24 hours following administration of Feraheme, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in the Feraheme complex.
- Administration of Feraheme may transiently affect the diagnostic ability of MR imaging. Anticipated MR imaging studies should be conducted prior to the administration of Feraheme. Alteration of MR imaging studies may persist for up to 3 months following the last Feraheme dose. If MR imaging is required within 3 months after Feraheme administration, use T1- or proton density-weighted MR pulse sequences to minimize the Feraheme effects; MR imaging using T2-weighted pulse sequences should not be performed earlier than 4 weeks after the administration of Feraheme. Maximum alteration of vascular MR imaging is anticipated to be evident for 1 – 2 days following Feraheme administration.
- Feraheme will not interfere with X-ray, computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), ultrasound or nuclear medicine imaging.
# Adverse Reactions
## Clinical Trials Experience
- Feraheme administration may cause serious hypersensitivity reactions and hypotension.
- In clinical studies, 1,726 subjects were exposed to Feraheme; 1,562 of these had CKD and 164 did not have CKD. Of these subjects 46% were male and the median age was 63 years (range of 18 to 96 years).
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.
- Across the three randomized clinical trials, a total of 605 patients were exposed to two injections of 510 mg of Feraheme and a total of 280 patients were exposed to 200 mg/day of oral iron for 21 days. Most patients received their second Feraheme injection 3 to 8 days after the first injection.
- Adverse reactions related to Feraheme and reported by ≥ 1% of Feraheme-treated patients in the randomized clinical trials are listed in Table 1. Diarrhea (4.0%), constipation (2.1%) and hypertension (1.0%) have also been reported in Feraheme-treated patients.
- In clinical trials, adverse reactions leading to treatment discontinuation and occurring in ≥ 2 Feraheme-treated patients included hypotension, infusion site swelling, increased serum ferritin level, chest pain, diarrhea, dizziness, ecchymosis, pruritus, chronic renal failure, and urticaria.
- Following completion of the controlled phase of the trials, 69 patients received two additional 510 mg intravenous injections of Feraheme (for a total cumulative dose of 2.04 g). Adverse reactions following this repeat Feraheme dosing were similar in character and frequency to those observed following the first two intravenous injections.
- In a placebo-controlled, cross-over trial, 713 patients with CKD received a single 510 mg dose of Feraheme. Adverse reactions reported by these patients were similar in character and frequency to those observed in other clinical trials.
## Postmarketing Experience
- Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- The following serious adverse reactions have been reported from the post-marketing experience with Feraheme: fatal, life-threatening, and serious anaphylactic-type reactions, cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, unresponsiveness, loss of consciousness, tachycardia/rhythm abnormalities, angioedema, ischemic myocardial events, congestive heart failure, pulse absent, and cyanosis. These adverse reactions have usually occurred within 30 minutes after the administration of Feraheme. Reactions have occurred following the first dose or subsequent doses of Feraheme.
# Drug Interactions
- Drug-drug interaction studies with Feraheme were not conducted. Feraheme may reduce the absorption of concomitantly administered oral iron preparations.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no studies of Feraheme in pregnant women. In animal studies, ferumoxytol caused fetal malformations and decreased fetal weights at maternally toxic doses of 6 times the estimated human daily dose. Use Feraheme during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Administration of ferumoxytol during organogenesis, at doses of 31.6 mg Fe/kg/day in rats and 16.5 mg Fe/kg/day in rabbits, did not result in maternal or fetal effects. These doses are approximately 2 times the estimated human daily dose based on body surface area. In rats, administration of ferumoxytol during organogenesis at a maternally toxic dose of 100 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, caused a decrease in fetal weights. In rabbits, administration of ferumoxytol during organogenesis at a maternally toxic dose of 45 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, was associated with external and/or soft tissue fetal malformations and decreased fetal weights.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ferumoxytol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ferumoxytol during labor and delivery.
### Nursing Mothers
- It is not known whether Feraheme is present in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to avoid Feraheme, taking into account the importance of Feraheme to the mother and the known benefits of nursing.
### Pediatric Use
- The safety and effectiveness of Feraheme in pediatric patients (less than 18 years old) have not been established.
### Geriatic Use
- In controlled clinical trials, 330 patients ≥ 65 years of age were treated with Feraheme. No overall differences in safety and efficacy were observed between older and younger patients in these trials, but greater sensitivity of older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of Feraheme may have more severe outcomes. The potential risks and benefits of Feraheme administration should be carefully considered in these patients
### Gender
There is no FDA guidance on the use of Ferumoxytol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ferumoxytol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ferumoxytol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ferumoxytol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ferumoxytol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ferumoxytol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Closely observe patients for signs and symptoms of hypersensitivity including monitoring of blood pressure and pulse during and after Feraheme administration for at least 30 minutes and until clinically stable following completion of each infusion
- Monitor patients for signs and symptoms of hypotension following each Feraheme administration
- Regularly monitor the hematologic response during parenteral iron therapy
# IV Compatibility
There is limited information regarding IV Compatibility of Ferumoxytol in the drug label.
# Overdosage
- Limited data are available regarding overdosage of Feraheme in humans.
- Excessive dosages of Feraheme may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. Do not administer Feraheme to patients with iron overload
# Pharmacology
## Mechanism of Action
- Feraheme consists of a superparamagnetic iron oxide that is coated with a carbohydrate shell, which helps to isolate the bioactive iron from plasma components until the iron-carbohydrate complex enters the reticuloendothelial system macrophages of the liver, spleen and bone marrow. The iron is released from the iron-carbohydrate complex within vesicles in the macrophages. Iron then either enters the intracellular storage iron pool (e.g., ferritin) or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into hemoglobin.
## Structure
- Feraheme, an iron replacement product, is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethylether. The overall colloidal particle size is 17-31 nm in diameter. The chemical formula of Feraheme is Fe5874O8752-C11719H18682O9933Na414 with an apparent molecular weight of 750 kDa.
- Feraheme Injection is an aqueous colloidal product that is formulated with mannitol. It is a black to reddish brown liquid, and is provided in single use vials containing 510 mg of elemental iron. Each mL of the sterile colloidal solution of Feraheme Injection contains 30 mg of elemental iron and 44 mg of mannitol, and has low bleomycin-detectable iron. The formulation is isotonic with an osmolality of 270-330 mOsm/kg. The product contains no preservatives, and has a pH of 6 to 8.
## Pharmacodynamics
- In a randomized, positive- and placebo-controlled, parallel-group study, healthy subjects received a supratherapeutic regimen of Feraheme (1.02 g given as two 510 mg doses within 24 hours), placebo or a single dose of 400 mg moxifloxacin (positive control). Results demonstrated no effect of Feraheme on QT interval durations. No clinically meaningful effect of Feraheme on heart rate was observed.
## Pharmacokinetics
- The pharmacokinetic (PK) behavior of Feraheme has been examined in healthy subjects and in patients with CKD stage 5D on hemodialysis. Feraheme exhibited dose-dependent, capacity-limited elimination from plasma with a half life of approximately 15 hours in humans. The clearance (CL) was decreased by increasing the dose of Feraheme. Volume of distribution (Vd) was consistent with plasma volume, and the mean maximum observed plasma concentration (Cmax) and terminal half-life (t1/2) values increased with dose. The estimated values of CL and Vd following two 510 mg doses of Feraheme administered intravenously within 24 hours were 69.1 mL/hr and 3.16 L, respectively. The Cmax and time of maximum concentration (tmax) were 206 mcg/mL and 0.32 hr, respectively. Rate of infusion had no influence on Feraheme PK parameters. No gender differences in Feraheme PK parameters were observed. Feraheme is not removed by hemodialysis.
## Nonclinical Toxicology
- Ferumoxytol was not tested for carcinogenic effects. In standard genotoxicity tests, ferumoxytol showed no evidence of mutagenic activity in an in vitro Ames test or clastogenic activity in either an in vitro chromosomal aberration assay or an in vivo micronucleus assay.
- No adverse effects on fertility or general reproductive performance were noted in animal studies. Ferumoxytol had no effect on male or female fertility or general reproductive function in rats.
# Clinical Studies
- The safety and efficacy of Feraheme for the episodic treatment of iron deficiency anemia in patients with CKD were assessed in three randomized, open-label, controlled clinical trials (Trial 1, 2 and 3). These trials also included an uncontrolled, follow-up phase in which patients with persistent iron deficiency anemia could receive two additional 510 mg intravenous injections of Feraheme. The major efficacy results from the controlled phase of each study are shown in Table 2.
- In all three trials, patients with CKD and iron deficiency anemia were randomized to treatment with Feraheme or oral iron. Feraheme was administered as two 510 mg intravenous single doses and oral iron (ferrous fumarate) was administered as a total daily dose of 200 mg elemental iron daily for 21 days. The major trial outcomes assessed the change in hemoglobin from baseline to Day 35. Trial 1 and 2 enrolled patients with non-dialysis dependent CKD and Trial 3 enrolled patients who were undergoing hemodialysis.
- In Trial 1, the mean age of patients was 66 years (range, 23 to 95); 60% were female; 65% were Caucasian, 32% were Black, and 2% were other races. In the Feraheme and oral iron groups, 42% and 44% of patients, respectively, were receiving erythropoiesis stimulating agents (ESAs) at baseline.
- In Trial 2, the mean age of patients was 65 years (range, 31 to 96); 61% were female; 58% were Caucasian, 35% were Black, and 7% were other races. In the Feraheme and oral iron groups, 36% and 43% of patients, respectively, were receiving ESAs at baseline.
- In Trial 3, the mean age of patients was 60 years (range, 24 to 87); 43% were female; 34% were Caucasian, 59% were Black, and 7% were other races. All patients were receiving ESAs.
- Table 2 shows the Baseline and mean change to Day 35 in hemoglobin (Hgb, g/dL), transferrin saturation (TSAT, %) and ferritin (ng/mL) in each treatment group for Trial 1, 2, and 3.
- Following completion of the controlled phase of each of the Phase 3 trials, patients who were iron deficient and anemic could receive two additional 510 mg intravenous injections of Feraheme for a total cumulative dose of 2.04 g. Overall, 69 patients received two additional 510 mg intravenous injections of Feraheme, and on Day 35 following these additional injections, the majority of these patients (70%) experienced an increase in hemoglobin and iron parameters (TSAT and ferritin). The mean change (±SD) in hemoglobin level from the retreatment baseline for patients with an increase in hemoglobin was 0.86 (± 0.68) g/dL and was 0.5 (± 0.8) g/dL for all patients.
# How Supplied
- Feraheme is available in single use vials in the following package sizes
## Storage
- Store at 20° to 25°C (68° to 77°F). Excursions permitted to 15° – 30°C (59° – 86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
Prior to Feraheme administration:
- Question patients regarding a history of allergy to intravenous iron or any medications.
- Advise patients of the serious risks associated with Feraheme.
- Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as rash, itching, dizziness, lightheadedness, swelling and breathing problems. Advise patients to seek immediate medical attention if these occur
### PATIENT INFORMATION FERAHEME (FER-UH-HEEM) (FERUMOXYTOL) INJECTION
# Precautions with Alcohol
- Alcohol-Ferumoxytol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FERAHEME®
# Look-Alike Drug Names
There is limited information regarding the look alike drug names.
# Drug Shortage Status
# Price | Ferumoxytol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Ferumoxytol is a iron replacement product that is FDA approved for the treatment of iron deficiency anemia in adult patients with chronic kidney disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, nausea, dizziness, hypotension, constipation, and peripheral edema.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Feraheme is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD)
### Dosage
- The recommended dose of Feraheme is an initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later. Administer Feraheme as an intravenous infusion in 50-200 mL 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes. Administer while the patient is in a reclined or semi-reclined position.
- Feraheme, when added to intravenous infusion bags containing either 0.9% Sodium Chloride Injection, USP (normal saline), or 5% Dextrose Injection, USP, at concentrations of 2-8 mg elemental iron per mL, should be used immediately but may be stored at controlled room temperature (25°C ± 2°C) for up to 4 hours.
- The dosage is expressed in terms of mg of elemental iron, with each mL of Feraheme containing 30 mg of elemental iron. Evaluate the hematologic response (hemoglobin, ferritin, iron and transferrin saturation) at least one month following the second Feraheme infusion. The recommended Feraheme dose may be readministered to patients with persistent or recurrent iron deficiency anemia.
- For patients receiving hemodialysis, administer Feraheme once the blood pressure is stable and the patient has completed at least one hour of hemodialysis. Monitor for signs and symptoms of hypotension following each Feraheme infusion.
- Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions and/or hypotension, such as chemotherapeutic agents or monoclonal antibodies.
- Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ferumoxytol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ferumoxytol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ferumoxytol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ferumoxytol in pediatric patients.
# Contraindications
- Known hypersensitivity to Feraheme or any of its components
History of allergic reaction to any intravenous iron product
# Warnings
- Fatal and serious hypersensitivity reactions including anaphylaxis, presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, or unresponsiveness have occurred in patients receiving Feraheme. Other adverse reactions potentially associated with hypersensitivity have occurred (pruritus, rash, urticaria, and wheezing). These reactions have occurred following the first dose or subsequent doses in patients in whom a previous Feraheme dose was tolerated.
- Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.
- Only administer Feraheme when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions. Closely observe patients for signs and symptoms of hypersensitivity including monitoring of blood pressure and pulse during and after Feraheme administration for at least 30 minutes and until clinically stable following completion of each infusion.
- In clinical studies predominantly in patients with CKD, serious hypersensitivity reactions were reported in 0.2% (3/1,726) of subjects receiving Feraheme. Other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.7% (63/1,726) of these subjects. In other trials excluding patients with Stages 4 and 5 CKD, moderate to severe hypersensitivity reactions were reported in 2.6% (26/1014) of patients treated with Feraheme.
- In the post-marketing experience, fatal and serious anaphylactic type reactions presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, and unresponsiveness have been reported. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of Feraheme may have more severe outcomes.
- Severe adverse reactions of clinically significant hypotension have been reported. In clinical studies, hypotension was reported in 1.9% (33/1,726) of subjects, including three patients with serious hypotensive reactions. Hypotension has also been reported in the post-marketing experience. Monitor patients for signs and symptoms of hypotension following each Feraheme administration.
- Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Regularly monitor the hematologic response during parenteral iron therapy. Do not administer Feraheme to patients with iron overload.
- In the 24 hours following administration of Feraheme, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in the Feraheme complex.
- Administration of Feraheme may transiently affect the diagnostic ability of MR imaging. Anticipated MR imaging studies should be conducted prior to the administration of Feraheme. Alteration of MR imaging studies may persist for up to 3 months following the last Feraheme dose. If MR imaging is required within 3 months after Feraheme administration, use T1- or proton density-weighted MR pulse sequences to minimize the Feraheme effects; MR imaging using T2-weighted pulse sequences should not be performed earlier than 4 weeks after the administration of Feraheme. Maximum alteration of vascular MR imaging is anticipated to be evident for 1 – 2 days following Feraheme administration.
- Feraheme will not interfere with X-ray, computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), ultrasound or nuclear medicine imaging.
# Adverse Reactions
## Clinical Trials Experience
- Feraheme administration may cause serious hypersensitivity reactions and hypotension.
- In clinical studies, 1,726 subjects were exposed to Feraheme; 1,562 of these had CKD and 164 did not have CKD. Of these subjects 46% were male and the median age was 63 years (range of 18 to 96 years).
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.
- Across the three randomized clinical trials, a total of 605 patients were exposed to two injections of 510 mg of Feraheme and a total of 280 patients were exposed to 200 mg/day of oral iron for 21 days. Most patients received their second Feraheme injection 3 to 8 days after the first injection.
- Adverse reactions related to Feraheme and reported by ≥ 1% of Feraheme-treated patients in the randomized clinical trials are listed in Table 1. Diarrhea (4.0%), constipation (2.1%) and hypertension (1.0%) have also been reported in Feraheme-treated patients.
- In clinical trials, adverse reactions leading to treatment discontinuation and occurring in ≥ 2 Feraheme-treated patients included hypotension, infusion site swelling, increased serum ferritin level, chest pain, diarrhea, dizziness, ecchymosis, pruritus, chronic renal failure, and urticaria.
- Following completion of the controlled phase of the trials, 69 patients received two additional 510 mg intravenous injections of Feraheme (for a total cumulative dose of 2.04 g). Adverse reactions following this repeat Feraheme dosing were similar in character and frequency to those observed following the first two intravenous injections.
- In a placebo-controlled, cross-over trial, 713 patients with CKD received a single 510 mg dose of Feraheme. Adverse reactions reported by these patients were similar in character and frequency to those observed in other clinical trials.
## Postmarketing Experience
- Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- The following serious adverse reactions have been reported from the post-marketing experience with Feraheme: fatal, life-threatening, and serious anaphylactic-type reactions, cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, unresponsiveness, loss of consciousness, tachycardia/rhythm abnormalities, angioedema, ischemic myocardial events, congestive heart failure, pulse absent, and cyanosis. These adverse reactions have usually occurred within 30 minutes after the administration of Feraheme. Reactions have occurred following the first dose or subsequent doses of Feraheme.
# Drug Interactions
- Drug-drug interaction studies with Feraheme were not conducted. Feraheme may reduce the absorption of concomitantly administered oral iron preparations.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no studies of Feraheme in pregnant women. In animal studies, ferumoxytol caused fetal malformations and decreased fetal weights at maternally toxic doses of 6 times the estimated human daily dose. Use Feraheme during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Administration of ferumoxytol during organogenesis, at doses of 31.6 mg Fe/kg/day in rats and 16.5 mg Fe/kg/day in rabbits, did not result in maternal or fetal effects. These doses are approximately 2 times the estimated human daily dose based on body surface area. In rats, administration of ferumoxytol during organogenesis at a maternally toxic dose of 100 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, caused a decrease in fetal weights. In rabbits, administration of ferumoxytol during organogenesis at a maternally toxic dose of 45 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, was associated with external and/or soft tissue fetal malformations and decreased fetal weights.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ferumoxytol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ferumoxytol during labor and delivery.
### Nursing Mothers
- It is not known whether Feraheme is present in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to avoid Feraheme, taking into account the importance of Feraheme to the mother and the known benefits of nursing.
### Pediatric Use
- The safety and effectiveness of Feraheme in pediatric patients (less than 18 years old) have not been established.
### Geriatic Use
- In controlled clinical trials, 330 patients ≥ 65 years of age were treated with Feraheme. No overall differences in safety and efficacy were observed between older and younger patients in these trials, but greater sensitivity of older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of Feraheme may have more severe outcomes. The potential risks and benefits of Feraheme administration should be carefully considered in these patients
### Gender
There is no FDA guidance on the use of Ferumoxytol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ferumoxytol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ferumoxytol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ferumoxytol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ferumoxytol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ferumoxytol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Closely observe patients for signs and symptoms of hypersensitivity including monitoring of blood pressure and pulse during and after Feraheme administration for at least 30 minutes and until clinically stable following completion of each infusion
- Monitor patients for signs and symptoms of hypotension following each Feraheme administration
- Regularly monitor the hematologic response during parenteral iron therapy
# IV Compatibility
There is limited information regarding IV Compatibility of Ferumoxytol in the drug label.
# Overdosage
- Limited data are available regarding overdosage of Feraheme in humans.
- Excessive dosages of Feraheme may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. Do not administer Feraheme to patients with iron overload
# Pharmacology
## Mechanism of Action
- Feraheme consists of a superparamagnetic iron oxide that is coated with a carbohydrate shell, which helps to isolate the bioactive iron from plasma components until the iron-carbohydrate complex enters the reticuloendothelial system macrophages of the liver, spleen and bone marrow. The iron is released from the iron-carbohydrate complex within vesicles in the macrophages. Iron then either enters the intracellular storage iron pool (e.g., ferritin) or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into hemoglobin.
## Structure
- Feraheme, an iron replacement product, is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethylether. The overall colloidal particle size is 17-31 nm in diameter. The chemical formula of Feraheme is Fe5874O8752-C11719H18682O9933Na414 with an apparent molecular weight of 750 kDa.
- Feraheme Injection is an aqueous colloidal product that is formulated with mannitol. It is a black to reddish brown liquid, and is provided in single use vials containing 510 mg of elemental iron. Each mL of the sterile colloidal solution of Feraheme Injection contains 30 mg of elemental iron and 44 mg of mannitol, and has low bleomycin-detectable iron. The formulation is isotonic with an osmolality of 270-330 mOsm/kg. The product contains no preservatives, and has a pH of 6 to 8.
## Pharmacodynamics
- In a randomized, positive- and placebo-controlled, parallel-group study, healthy subjects received a supratherapeutic regimen of Feraheme (1.02 g given as two 510 mg doses within 24 hours), placebo or a single dose of 400 mg moxifloxacin (positive control). Results demonstrated no effect of Feraheme on QT interval durations. No clinically meaningful effect of Feraheme on heart rate was observed.
## Pharmacokinetics
- The pharmacokinetic (PK) behavior of Feraheme has been examined in healthy subjects and in patients with CKD stage 5D on hemodialysis. Feraheme exhibited dose-dependent, capacity-limited elimination from plasma with a half life of approximately 15 hours in humans. The clearance (CL) was decreased by increasing the dose of Feraheme. Volume of distribution (Vd) was consistent with plasma volume, and the mean maximum observed plasma concentration (Cmax) and terminal half-life (t1/2) values increased with dose. The estimated values of CL and Vd following two 510 mg doses of Feraheme administered intravenously within 24 hours were 69.1 mL/hr and 3.16 L, respectively. The Cmax and time of maximum concentration (tmax) were 206 mcg/mL and 0.32 hr, respectively. Rate of infusion had no influence on Feraheme PK parameters. No gender differences in Feraheme PK parameters were observed. Feraheme is not removed by hemodialysis.
## Nonclinical Toxicology
- Ferumoxytol was not tested for carcinogenic effects. In standard genotoxicity tests, ferumoxytol showed no evidence of mutagenic activity in an in vitro Ames test or clastogenic activity in either an in vitro chromosomal aberration assay or an in vivo micronucleus assay.
- No adverse effects on fertility or general reproductive performance were noted in animal studies. Ferumoxytol had no effect on male or female fertility or general reproductive function in rats.
# Clinical Studies
- The safety and efficacy of Feraheme for the episodic treatment of iron deficiency anemia in patients with CKD were assessed in three randomized, open-label, controlled clinical trials (Trial 1, 2 and 3). These trials also included an uncontrolled, follow-up phase in which patients with persistent iron deficiency anemia could receive two additional 510 mg intravenous injections of Feraheme. The major efficacy results from the controlled phase of each study are shown in Table 2.
- In all three trials, patients with CKD and iron deficiency anemia were randomized to treatment with Feraheme or oral iron. Feraheme was administered as two 510 mg intravenous single doses and oral iron (ferrous fumarate) was administered as a total daily dose of 200 mg elemental iron daily for 21 days. The major trial outcomes assessed the change in hemoglobin from baseline to Day 35. Trial 1 and 2 enrolled patients with non-dialysis dependent CKD and Trial 3 enrolled patients who were undergoing hemodialysis.
- In Trial 1, the mean age of patients was 66 years (range, 23 to 95); 60% were female; 65% were Caucasian, 32% were Black, and 2% were other races. In the Feraheme and oral iron groups, 42% and 44% of patients, respectively, were receiving erythropoiesis stimulating agents (ESAs) at baseline.
- In Trial 2, the mean age of patients was 65 years (range, 31 to 96); 61% were female; 58% were Caucasian, 35% were Black, and 7% were other races. In the Feraheme and oral iron groups, 36% and 43% of patients, respectively, were receiving ESAs at baseline.
- In Trial 3, the mean age of patients was 60 years (range, 24 to 87); 43% were female; 34% were Caucasian, 59% were Black, and 7% were other races. All patients were receiving ESAs.
- Table 2 shows the Baseline and mean change to Day 35 in hemoglobin (Hgb, g/dL), transferrin saturation (TSAT, %) and ferritin (ng/mL) in each treatment group for Trial 1, 2, and 3.
- Following completion of the controlled phase of each of the Phase 3 trials, patients who were iron deficient and anemic could receive two additional 510 mg intravenous injections of Feraheme for a total cumulative dose of 2.04 g. Overall, 69 patients received two additional 510 mg intravenous injections of Feraheme, and on Day 35 following these additional injections, the majority of these patients (70%) experienced an increase in hemoglobin and iron parameters (TSAT and ferritin). The mean change (±SD) in hemoglobin level from the retreatment baseline for patients with an increase in hemoglobin was 0.86 (± 0.68) g/dL and was 0.5 (± 0.8) g/dL for all patients.
# How Supplied
- Feraheme is available in single use vials in the following package sizes
## Storage
- Store at 20° to 25°C (68° to 77°F). Excursions permitted to 15° – 30°C (59° – 86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
Prior to Feraheme administration:
- Question patients regarding a history of allergy to intravenous iron or any medications.
- Advise patients of the serious risks associated with Feraheme.
- Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as rash, itching, dizziness, lightheadedness, swelling and breathing problems. Advise patients to seek immediate medical attention if these occur
### PATIENT INFORMATION FERAHEME (FER-UH-HEEM) (FERUMOXYTOL) INJECTION
# Precautions with Alcohol
- Alcohol-Ferumoxytol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FERAHEME®[2]
# Look-Alike Drug Names
There is limited information regarding the look alike drug names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ferumoxytol | |
60e768357a90767e742f6ad8d9163f941f568bbf | wikidoc | Thalidomide | Thalidomide
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Thalidomide is a leprostatic that is FDA approved for the treatment of newly diagnosed multiple myeloma in combination with dexamethasone and cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). There is a Black Box Warning for this drug as shown here. Common adverse reactions include fatigue, hypocalcemia, edema, constipation, sensory neuropathy, dyspnea, muscle weakness, leukopenia, neutropenia, rash/desquamation, confusion, anorexia, nausea, anxiety/agitation, asthenia, tremor, fever, weight loss, thrombosis/embolism, motor neuropathy, weight gain, dizziness, and dry skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- THALOMID is administered in combination with dexamethasone in 28-day treatment cycles. The dose of THALOMID is 200 mg administered orally once daily with water, preferably at bedtime and at least 1 hour after the evening meal. The dose of dexamethasone is 40 mg daily administered orally on days 1-4, 9-12, and 17-20 every 28 days.
- Patients who develop adverse reactions such as constipation, somnolence, or peripheral neuropathy may benefit by either temporarily discontinuing the drug or continuing at a lower dose. With the abatement of these adverse reactions, the drug may be started at a lower dose or at the previous dose based on clinical judgment.
- For an episode of cutaneous ENL, THALOMID dosing should be initiated at 100 to 300 mg/day, administered once daily with water, preferably at bedtime and at least 1 hour after the evening meal. Patients weighing less than 50 kilograms should be started at the low end of the dose range.
- In patients with a severe cutaneous ENL reaction, or in those who have previously required higher doses to control the reaction, THALOMID dosing may be initiated at higher doses up to 400 mg/day once daily at bedtime or in divided doses with water, at least 1 hour after meals.
- In patients with moderate to severe neuritis associated with a severe ENL reaction, corticosteroids may be started concomitantly with THALOMID. Steroid usage can be tapered and discontinued when the neuritis has ameliorated.
- Dosing with THALOMID should usually continue until signs and symptoms of active reaction have subsided, usually a period of at least 2 weeks. Patients may then be tapered off medication in 50 mg decrements every 2 to 4 weeks.
- Patients who have a documented history of requiring prolonged maintenance treatment to prevent the recurrence of cutaneous ENL or who flare during tapering should be maintained on the minimum dose necessary to control the reaction. Tapering off medication should be attempted every 3 to 6 months, in decrements of 50 mg every 2 to 4 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thalidomide in adult patients.
### Non–Guideline-Supported Use
- Thalidomide 100 mg daily for 1 month.
- Thalidomide 100 mg daily for 8 weeks.
- Thalidomide 150 mg/day for 6 weeks.
- Thalidomide 200 mg.
- Thalidomide 300 mg daily.
- Thalidomide 200 mg orally each day for 2 weeks.
- Thalidomide (25 mg once daily increasing to 200 mg once daily; doubling the dose every second week for 12 weeks).
- Daily oral doses of thalidomide 50 mg or 100 mg.
- Thalidomide 800 mg/day for the first 2 weeks, followed by a dose escalation of 200 mg/day every 2 weeks to a maximum dose of 1200 mg/day.
- Thalidomide dose of 50 mg 4 times daily.
- Thalidomide was initiated at 100 mg per day (50 to 200 mg/day).
- Thalidomide (doses ranging from 50 to 600 mg/day).
- Thalidomide 200 mg orally daily.
- 200 mg of oral thalidomide nightly for 12 weeks.
- Thalidomide was 300 mg/day.
- 4 months of thalidomide treatment; 50 mg at night for the first month, 100 mg at night for the second month, and 200 mg at night for the third and fourth months.
- Thalidomide was started at 50 mg orally daily and increased by 50 mg daily every month to a maximum of 200 mg daily.
- Thalidomide (initial dose of 200 mg daily, followed by dose escalation of 200 mg every 14 days as tolerated).
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Thalidomide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thalidomide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Thalidomide in pediatric patients.
# Contraindications
- Pregnancy
- THALOMID can cause fetal harm when administered to a pregnant female. Thalidomide is contraindicated in females who are pregnant. Thalidomide is a powerful human teratogen, inducing a high frequency of severe and life-threatening birth defects, even after a single dose. Mortality at or shortly after birth has been reported in about 40% of infants. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs during thalidomide treatment, the drug should be discontinued immediately.
- Hypersensitivity
- THALOMID is contraindicated in patients who have demonstrated hypersensitivity to the drug or its components.
# Warnings
### Precautions
- Embryo-Fetal Toxicity
- Thalidomide is a powerful human teratogen that induces a high frequency of severe and life-threatening birth defects, even after a single dose. Mortality at or shortly after birth has been reported in about 40% of infants. When there is no satisfactory alternative treatment, females of reproductive potential may be treated with thalidomide provided adequate precautions are taken to avoid pregnancy. THALOMID® (thalidomide) is only available through the THALOMID REMS™ program (formerly known as the “S.T.E.P.S.® program”).
- Oral ingestion is the only type of maternal thalidomide exposure known to result in drug-associated birth defects. There are no specific data available regarding the reproductive risks of cutaneous absorption or inhalation of thalidomide; however, females of reproductive potential should avoid contact with THALOMID® (thalidomide) Capsules. THALOMID Capsules should be stored in blister packs until ingestion. If there is contact with non-intact thalidomide capsules or the powder contents, the exposed area should be washed with soap and water.
- If healthcare providers or other care givers are exposed to body fluids from patients receiving THALOMID (thalidomide) the exposed area should be washed with soap and water. Appropriate precautions should be utilized, such as wearing gloves to prevent the potential cutaneous exposure to THALOMID.
- Females of Reproductive Potential
Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning THALOMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.
Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with THALOMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of THALOMID therapy.
Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing THALOMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles.
- Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning THALOMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.
- Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with THALOMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of THALOMID therapy.
- Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing THALOMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles.
- Males
Thalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID and for up to 28 days after discontinuing THALOMID, even if they have undergone a successful vasectomy. Male patients taking THALOMID must not donate sperm.
- Thalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID and for up to 28 days after discontinuing THALOMID, even if they have undergone a successful vasectomy. Male patients taking THALOMID must not donate sperm.
- Blood Donation
Patients must not donate blood during treatment with THALOMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to THALOMID.
- Patients must not donate blood during treatment with THALOMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to THALOMID.
- THALOMID REMS™ Program
- Because of the embryo-fetal risk, THALOMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the THALOMID REMS™ program (formerly known as the “S.T.E.P.S.®” program).
- Required components of the THALOMID REMS™ program include the following:
Prescribers must be certified with the THALOMID REMS™ program by enrolling and complying with the REMS requirements.
Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements.
Pharmacies must be certified with the THALOMID REMS™ program, must only dispense to patients who are authorized to receive THALOMID and comply with REMS requirements.
- Prescribers must be certified with the THALOMID REMS™ program by enrolling and complying with the REMS requirements.
- Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements.
- Pharmacies must be certified with the THALOMID REMS™ program, must only dispense to patients who are authorized to receive THALOMID and comply with REMS requirements.
- Further information about the THALOMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.
- Venous and Arterial Thromboembolism
- The use of THALOMID in patients with MM results in an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. This risk increases significantly when thalidomide is used in combination with standard chemotherapeutic agents including dexamethasone. In one controlled trial, the rate of venous thromboembolism was 22.5% in patients receiving thalidomide in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002).
- Ischemic heart disease (11.1%), including myocardial infarction (1.3%), and stroke (cerebrovascular accident, 2.6%) have also occurred in patients with previously untreated MM treated with THALOMID and dexamethasone compared to placebo and dexamethasone (4.7%, 1.7%, and 0.9%, respectively) in one clinical trial.
- Consider thromboprophylaxis based on an assessment of individual patients’ underlying risk factors. Patients and physicians should be observant for the signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Agents that also may increase the risk of thromboembolism should be used with caution in patients receiving THALOMID.
- Drowsiness and Somnolence
- Thalidomide frequently causes drowsiness and somnolence. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Advise patients as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery. Dose reductions may be required.
- Peripheral Neuropathy
- Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (≥10%) and potentially severe adverse reaction of treatment with thalidomide that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months; however, peripheral neuropathy following relatively short-term use has been reported. The correlation with cumulative dose is unclear. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all.
- Few reports of neuropathy have arisen in the treatment of ENL despite long-term thalidomide treatment. However, the inability clinically to differentiate thalidomide neuropathy from the neuropathy often seen in Hansen’s disease makes it difficult to determine accurately the incidence of thalidomide-related neuropathy in ENL patients treated with thalidomide.
- Patients should be examined at monthly intervals for the first 3 months of thalidomide therapy to enable the clinician to detect early signs of neuropathy, which include numbness, tingling or pain in the hands and feet. Patients should be evaluated periodically thereafter during treatment. Patients should be regularly counseled, questioned, and evaluated for signs or symptoms of peripheral neuropathy. Consideration should be given to electrophysiological testing, consisting of measurement of sensory nerve action potential (SNAP) amplitudes at baseline and thereafter every 6 months in an effort to detect asymptomatic neuropathy. If symptoms of drug-induced neuropathy develop, thalidomide should be discontinued immediately to limit further damage, if clinically appropriate. Usually, treatment with thalidomide should only be reinitiated if the neuropathy returns to baseline status.
- Medications known to be associated with neuropathy should be used with caution in patients receiving thalidomide.
- Dizziness and Orthostatic Hypotension
- Patients should also be advised that thalidomide may cause dizziness and orthostatic hypotension and that, therefore, they should sit upright for a few minutes prior to standing up from a recumbent position.
- Neutropenia
- Decreased white blood cell counts, including neutropenia, have been reported in association with the clinical use of thalidomide. Treatment should not be initiated with an absolute neutrophil count (ANC) of <;<750/mm3. White blood cell count and differential should be monitored on an ongoing basis, especially in patients who may be more prone to neutropenia, such as patients who are HIV-seropositive. If ANC decreases to below 750/mm3 while on treatment, the patient’s medication regimen should be re-evaluated and, if the neutropenia persists, consideration should be given to withholding thalidomide if clinically appropriate.
- Increased HIV Viral Load
- In a randomized, placebo-controlled trial of thalidomide in an HIV-seropositive patient population, plasma HIV RNA levels were found to increase (median change = 0.42 log10 copies HIV RNA/mL, p = 0.04 compared to placebo). A similar trend was observed in a second, unpublished study conducted in patients who were HIV-seropositive. The clinical significance of this increase is unknown. Both studies were conducted prior to availability of highly active antiretroviral therapy. Until the clinical significance of this finding is further understood, in HIV-seropositive patients, viral load should be measured after the first and third months of treatment and every 3 months thereafter.
- Bradycardia
- Bradycardia in association with thalidomide use has been reported. Cases of bradycardia have been reported, some required medical interventions. The clinical significance and underlying etiology of the bradycardia noted in some thalidomide-treated patients are presently unknown. Monitor patients for bradycardia and syncope. Dose reduction or discontinuation may be required.
- Medications known to decrease heart rate should be used with caution in patients receiving thalidomide.
- Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
- Serious dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be fatal, have been reported. THALOMID should be discontinued if a skin rash occurs and only resumed following appropriate clinical evaluation. If the rash is exfoliative, purpuric, or bullous or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, use of THALOMID should not be resumed.
- Seizures
- Although not reported from pre-marketing controlled clinical trials, seizures, including grand mal convulsions, have been reported during post-approval use of THALOMID in clinical practice. Because these events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. Most patients had disorders that may have predisposed them to seizure activity, and it is not currently known whether thalidomide has any epileptogenic influence. During therapy with thalidomide, patients with a history of seizures or with other risk factors for the development of seizures should be monitored closely for clinical changes that could precipitate acute seizure activity.
- Tumor Lysis Syndrome
- Monitor patients at risk of tumor lysis syndrome (e.g., patients with high tumor burden prior to treatment) and take appropriate precautions.
- Contraceptive Risks
- Some contraceptive methods may pose a higher risk of adverse effects or may be medically contraindicated in some patients treated with THALOMID. Because some patients may develop sudden, severe neutropenia and/or thrombocytopenia, use of an intrauterine device (IUD) or implantable contraception in these patients may carry an increased risk for infection or bleeding either at insertion, removal or during use. Treatment with THALOMID, the presence of an underlying malignancy, and/or use of an estrogen-containing contraceptive can each increase the risk of thromboembolism. It is not known if these risks of thromboembolism are additive. However, they should be taken into consideration when choosing contraceptive methods.
- Hypersensitivity
- Hypersensitivity to THALOMID has been reported. Signs and symptoms have included the occurrence of erythematous macular rash, possibly associated with fever, tachycardia, and hypotension, and if severe, may necessitate interruption of therapy. If the reaction recurs when dosing is resumed, THALOMID should be discontinued.
# Adverse Reactions
## Clinical Trials Experience
- Teratogenicity
- The most serious toxicity associated with thalidomide is its documented human teratogenicity. The risk of severe birth defects, primarily phocomelia or death to the fetus, is extremely high during the critical period of pregnancy. The critical period is estimated, depending on the source of information, to range from 35 to 50 days after the last menstrual period. The risk of other potentially severe birth defects outside this critical period is unknown, but may be significant. Based on present knowledge, thalidomide must not be used at any time during pregnancy.
- Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if he has undergone a successful vasectomy.
- Venous and Arterial Thromboembolism
- An increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism), ischemic heart disease (including myocardial infarction), and stroke have been reported in patients with multiple myeloma treated with thalidomide.
- Peripheral Neuropathy
- Peripheral Neuropathy is a very common, potentially severe, adverse reaction of treatment with thalidomide that may result in irreversible damage. Peripheral neuropathy generally occurs following chronic use over a period of months. However, reports following relatively short-term use also exist.Incidence of neuropathy events leading to discontinuation, dose reduction or interruption increases with cumulative dose and duration of therapy. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all.
- Somnolence, dizziness, and rash are the most commonly observed adverse reactions associated with the use of thalidomide. Adverse event profiles from clinical trials are summarized in the sections that follow.
- Adverse Reactions in Multiple Myeloma Controlled Clinical Trials
- The safety analyses were conducted in two controlled clinical studies (Study 1 and Study 2). The safety analysis in Study 1 was conducted on 204 patients who received treatment. Table 1 lists the most common adverse drug reactions (≥ 10%). The most frequently reported adverse reactions were fatigue, hypocalcemia, edema, constipation, sensory neuropathy, dyspnea, muscle weakness, leukopenia, neutropenia, rash/desquamation, confusion, anorexia, nausea, anxiety/agitation , tremor, fever, weight loss, thrombosis/embolism, neuropathy-motor, weight gain, dizziness, and dry skin .
- Twenty-three percent of patients (47/204) discontinued due to adverse reactions; 30% (31/102) from the THALOMID/dexamethasone arm and 16% (16/102) from the dexamethasone alone arm.
- The safety analysis in Study 2 was conducted on 466 patients who received treatment. Table 2 lists the most common adverse drug reactions (≥ 10%) that were observed. Table 3 lists the most common Grade 3/4 adverse drug reactions (occurring at > 2%) that were observed. The adverse reactions most often reported by patients treated with THALOMID/dexamethasone were constipation, peripheral edema, tremor, asthenia, dizziness and fatigue. Adverse reactions with a frequency at least 2-fold higher in the THALOMID/dexamethasone group than in the placebo/dexamethasone group include constipation, tremor, deep vein thrombosis and peripheral sensory neuropathy.
- Twenty-six percent of patients (121/466) discontinued due to adverse events; 37% (86/234) from the THALOMID/dexamethasone arm and 15% (35/232) from the placebo/dexamethasone arm.
- Less Common Adverse Drug Reactions in Multiple Myeloma Controlled Clinical Trials
- In Study 2, THALOMID in combination with dexamethasone in patients with multiple myeloma, the following adverse drug reactions not described above were reported*:
Vomiting NOS, dry mouth, peritonitis, diverticular perforation
Somnolence, hypoesthesia, polyneuropathy NOS, transient ischemic attack
Bronchitis NOS
Mood alteration NOS
Hypotension NOS, orthostatic hypotension
Bradycardia NOS
Blurred vision
- All adverse reactions with ≥3% of patients in THALOMID/dexamethasone arm and with a ≥1% difference in proportion of patients between the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm. All grade 3/4 and serious adverse reactions reported >2 patients in THALOMID/dexamethasone arm and with a percentage higher in the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm have been considered for possible inclusion. In any cases medical judgment has been applied for consideration of causality assessment.
- Adverse Reactions in Erythema Nodosum Leprosum (ENL) Clinical Trials
- Table 4 lists treatment-emergent signs and symptoms that occurred in THALOMID-treated patients in clinical trials in ENL. The most common adverse reactions (≥10%) reported in patients with ENL were somnolence, rash, headache. Doses ranged from 50 to 300 mg/day. All adverse reactions were mild to moderate in severity, and none resulted in discontinuation.
- Other Adverse Events Observed in ENL Patients
- THALOMID in doses up to 400 mg/day has been administered investigationally in the United States over a 19-year period in 1465 patients with ENL. The published literature describes the treatment of an additional 1678 patients. To provide a meaningful estimate of the proportion of the individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using a modified COSTART dictionary/terminology. These categories are used in the listing below. All reported events are included except those already listed in the previous table. Due to the fact that these data were collected from uncontrolled studies, the incidence rate cannot be determined. No causal relationship between THALOMID and these events can be conclusively determined at this time. These are reports of all adverse events noted by investigators in patients to whom they had administered thalidomide.
Abdomen enlarged, fever, photosensitivity, upper extremity pain.
Bradycardia, hypertension, hypotension, peripheral vascular disorder, tachycardia, vasodilation.
Anorexia, appetite increase/weight gain, dry mouth, dyspepsia, enlarged liver, eructation, flatulence, increased liver function tests, intestinal obstruction, vomiting.
ESR decrease, eosinophilia, granulocytopenia, hypochromic anemia, leukemia, leukocytosis, leukopenia, MCV elevated, RBC abnormal, spleen palpable, thrombocytopenia.
ADH inappropriate, amyloidosis, bilirubinemia, BUN increased, creatinine increased, cyanosis, diabetes, edema, electrolyte abnormalities, hyperglycemia, hyperkalemia, hyperuricemia, hypocalcemia, hypoproteinemia, LDH increased, phosphorus decreased, SGPT increased.
Arthritis, bone tenderness, hypertonia, joint disorder, leg cramps, myalgia, myasthenia, periosteal disorder.
Abnormal thinking, agitation, amnesia, anxiety, causalgia, circumoral paresthesia, confusion, depression, euphoria, hyperesthesia, insomnia, nervousness, neuralgia, neuritis, neuropathy, paresthesia, peripheral neuritis, psychosis.
Cough, emphysema, epistaxis, pulmonary embolus, rales, upper respiratory infection, voice alteration.
Acne, alopecia, dry skin, eczematous rash, exfoliative dermatitis, ichthyosis, perifollicular thickening, skin necrosis, seborrhea, sweating, urticaria, vesiculobullous rash.
Amblyopia, deafness, dry eye, eye pain, tinnitus.
Decreased creatinine clearance, hematuria, orchitis, proteinuria, pyuria, urinary frequency.
- Other Adverse Events Observed in HIV-seropositive Patients
- In addition to controlled clinical trials, THALOMID has been used in uncontrolled studies in 145 patients. Less frequent adverse events that have been reported in these HIV-seropositive patients treated with THALOMID were grouped into a smaller number of standardized categories using modified COSTART dictionary/terminology and these categories are used in the listing below. Adverse events that have already been included in the tables and narrative above, or that are too general to be informative are not listed.
Ascites, AIDS, allergic reaction, cellulitis, chest pain, chills and fever, cyst, decreased CD4 count, facial edema, flu syndrome, hernia, thyroid hormone level altered, moniliasis, photosensitivity reaction, sarcoma, sepsis, viral infection.
Angina pectoris, arrhythmia, atrial fibrillation, bradycardia, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, heart arrest, heart failure, hypertension, hypotension, murmur, myocardial infarct, palpitation, pericarditis, peripheral vascular disorder, postural hypotension, syncope, tachycardia, thrombophlebitis, thrombosis.
Cholangitis, cholestatic jaundice, colitis, dyspepsia, dysphagia, esophagitis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, gum disorder, hepatitis, pancreatitis, parotid gland enlargement, periodontitis, stomatitis, tongue discoloration, tooth disorder.
Aplastic anemia, macrocytic anemia, megaloblastic anemia, microcytic anemia.
Avitaminosis, bilirubinemia, dehydration, hypercholesteremia, hypoglycemia, increased alkaline phosphatase, increased lipase, increased serum creatinine, peripheral edema.
Myalgia, myasthenia.
Abnormal gait, ataxia, decreased libido, decreased reflexes, dementia, dysesthesia, dyskinesia, emotional lability, hostility, hypalgesia, hyperkinesia, incoordination, meningitis, neurologic disorder, tremor, vertigo.
Apnea, bronchitis, lung disorder, lung edema, pneumonia (including Pneumocystis carinii pneumonia), rhinitis.
Angioedema, benign skin neoplasm, eczema, herpes simplex, incomplete Stevens-Johnson syndrome, nail disorder, pruritus, psoriasis, skin discoloration, skin disorder.
Conjunctivitis, eye disorder, lacrimation disorder, retinitis, taste perversion.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of THALOMID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiac arrhythmias including atrial fibrillation, bradycardia, tachycardia, sick sinus syndrome, EKG abnormalities, myocardial infarction.
Intestinal perforation, gastrointestinal perforations, intestinal obstruction.
Electrolyte imbalance including hypercalcemia or hypocalcemia, hyperkalemia and hypokalemia, hyponatremia, hypothyroidism, increased alkaline phosphatase, tumor lysis syndrome.
Changes in mental status or mood including depression and suicide attempts, disturbances in consciousness including lethargy, syncope, loss of consciousness or stupor, seizures including grand mal convulsions and status epilepticus, Parkinson’s disease, stroke.
Erythema multiforme, toxic epidermal necrolysis.
Decreased white blood cell counts including neutropenia and febrile neutropenia, changes in prothrombin time, pancytopenia.
Pleural effusion.
Amenorrhea, sexual dysfunction.
Hypersensitivity, angioedema/urticaria.
Hearing impairment/deafness.
Renal failure.
- Other Adverse Events in the Published Literature or Reported from Other Sources
- The following additional events have been identified either in the published literature or from spontaneous reports from other sources: acute renal failure, amenorrhea, aphthous stomatitis, bile duct obstruction, carpal tunnel, chronic myelogenous leukemia, diplopia, dysesthesia, dyspnea, enuresis, erythema nodosum, erythroleukemia, foot drop, galactorrhea, gynecomastia, hangover effect, hypomagnesemia, hypothyroidism, lymphedema, lymphopenia, metrorrhagia, migraine, myxedema, nodular sclerosing Hodgkin’s disease, nystagmus, oliguria, pancytopenia, petechiae, purpura, Raynaud’s syndrome, stomach ulcer, suicide attempt, interstitial lung disease and severe infections (e.g., fatal sepsis including septic shock).
# Drug Interactions
- Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, or Other CNS Depressants (Including Alcohol)
- The use of opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants concomitantly with THALOMID may cause an additive sedative effect and should be avoided.
- Drugs which Cause Bradycardia
- The use of drugs which slow cardiac conduction concomitantly with THALOMID may cause an additive bradycardic effect and should be used with caution. Cardiovascular medications which may cause bradycardia include calcium channel blockers, beta blockers, alpha/beta-adrenergic blockers, and digoxin. Non-cardiac drugs that may cause bradycardia include H2 blockers (e.g., famotidine, cimetidine), lithium, tricyclic antidepressants and neuromuscular blockers (succinylcholine).
- In 16 healthy men, the pharmacokinetic profile of a single 0.5 mg digoxin dose was similar with and without the coadministration of thalidomide 200 mg/day at steady state levels. The single dose of digoxin had no effect on the pharmacokinetic profile of thalidomide. The safety of long-term concomitant use of THALOMID and digoxin has not been evaluated.
- Drugs which Cause Peripheral Neuropathy
- The use of drugs which cause peripheral neuropathy (e.g., bortezomib, amiodarone, cisplatin, docetaxel, paclitaxel, vincristine, disulfiram, phenytoin, metronidazole, alcohol) can cause an additive effect and should be used with caution.
- Hormonal Contraceptives
- Hormonal contraceptives increase the risk of thromboembolism. It is not known whether concomitant use of hormonal contraceptives further increases the risk of thromboembolism with THALOMID.
- In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 µg of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels.
- Warfarin
- In 13 healthy men, the pharmacokinetic profile and international normalized ratio (INR) of prothrombin time for warfarin, following a single oral dose of 25 mg, were similar with and without the coadministration of thalidomide 200 mg/day at steady-state levels. The single dose of warfarin had no effect on the pharmacokinetic profile of thalidomide.
- Drugs that Interfere with Hormonal Contraceptives
- Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John’s Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception up to one month after discontinuation of these concomitant therapies. Therefore, females requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception while taking thalidomide.
- Concomitant Therapies that may Increase the Risk of Thromboembolism
- Erythropoietic agents, or other agents that may increase the risk of thromboembolism, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving thalidomide with dexamethasone.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Risk Summary
- THALOMID can cause embryofetal harm when administered to a pregnant female and is contraindicated during pregnancy.
- THALOMID is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Even a single dose taken by a pregnant woman can cause birth defects. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to THALOMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
- Animal data
- A pre- and postnatal reproductive toxicity study was conducted in pregnant female rabbits. Compound-related increased abortion incidences and elevated fetotoxicity were observed at the lowest oral dose level of 30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA) and all higher dose levels. Neonatal mortality was elevated at oral dose levels to the lactating female rabbits ≥150 mg/kg/day (approximately 7.5-fold the maximum human dose based upon BSA). No delay in postnatal development, including learning and memory functions, were noted at the oral dose level to the lactating female rabbits of 150 mg/kg/day (average thalidomide concentrations in milk ranged from 22 to 36 µg/mL).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Thalidomide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Thalidomide during labor and delivery.
### Nursing Mothers
- It is not known whether thalidomide is excreted in human milk. Thalidomide is excreted in the milk of lactating rabbits. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from THALOMID, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
### Geriatic Use
- One hundred and seventy-six (52%) of 336 patients treated with THALOMID in combination with dexamethasone were ≥ 65 of age while 50 (15%) were ≥75. Patients ≥65 years of age on Study 2 had higher incidences of atrial fibrillation, constipation, fatigue, nausea, hypokalemia, deep venous thrombosis, hyperglycemia, pulmonary embolism, and asthenia compared to patients <65.
### Gender
There is no FDA guidance on the use of Thalidomide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Thalidomide with respect to specific racial populations.
### Renal Impairment
- No clinical studies were conducted with THALOMID in patients with mild, moderate or severe renal function. Renal impairment is not expected to influence drug exposure since <3.5% of the dose is excreted in the urine as unchanged drug.
- In a study of 6 patients with end-stage renal disease, thalidomide (200 mg/day) was administered on a non-dialysis day and on a dialysis day and blood samples for pharmacokinetics were collected at least 10 hours following the dose. Comparison of concentration-time profiles on a non-dialysis day and during dialysis showed that the mean total clearance increased by a 2.5-fold during hemodialysis. Because the dialysis was performed 10 hours following administration of the dose, the drug-concentration time curves were not statistically significantly different for days patients were on and off of dialysis. In addition, there were no major differences in thalidomide PK between patients with end-stage renal disease and healthy volunteers. Thus, no dosage adjustment is needed for patients with renal impairment or patients on dialysis.
### Hepatic Impairment
- No clinical studies have been conducted in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- THALOMID can cause fetal harm when administered during pregnancy. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking THALOMID, during dose interruptions and for at least 4 weeks after completing therapy.
- Females
- Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with THALOMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of THALOMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.
- Females of reproductive potential must have 2 negative pregnancy tests before initiating THALOMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing THALOMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. THALOMID treatment must be discontinued during this evaluation.
- Males
- Thalidomide is present in the semen of males who take THALOMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID, during dose interruptions and for up to 28 days after discontinuing THALOMID, even if they have undergone a successful vasectomy. Male patients taking THALOMID must not donate sperm.
### Immunocompromised Patients
There is no FDA guidance one the use of Thalidomide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Thalidomide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Thalidomide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdosages of up to 14.4 g have been reported in the literature. No fatalities have been reported and all overdosed patients recovered without sequelae.
### Management
- There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Thalidomide in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of THALOMID is not fully understood. THALOMID possesses immunomodulatory, antiinflammatory and antiangiogenic properties. Available data from in vitro studies and clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-α) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-α in patients with erythema nodosum leprosum (ENL); however, it has also been shown to increase plasma TNF-α levels in HIV-seropositive patients. Other anti-inflammatory and immunomodulatory properties of thalidomide may include suppression of macrophage involvement in prostaglandin synthesis, and modulation of interleukin-10 and interleukin-12 production by peripheral blood mononuclear cells. Thalidomide treatment of multiple myeloma patients is accompanied by an increase in the number of circulating natural killer cells, and an increase in plasma levels of interleukin-2 and interferon-gamma (T cell-derived cytokines associated with cytotoxic activity). Thalidomide was found to inhibit angiogenesis in a human umbilical artery explant model in vitro. The cellular processes of angiogenesis inhibited by thalidomide may include the proliferation of endothelial cells.
## Structure
- THALOMID, α-(N-phthalimido) glutarimide, is an immunomodulatory agent. The empirical formula for thalidomide is C13H10N2O4 and the gram molecular weight is 258.2. The CAS number of thalidomide is 50-35-1.
- Thalidomide is an off-white to white, odorless, crystalline powder that is soluble at 25°C in dimethyl sulfoxide and sparingly soluble in water and ethanol. The glutarimide moiety contains a single asymmetric center and, therefore, may exist in either of two optically active forms designated S-(-) or R-(+). THALOMID is an equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical rotation of zero.
- THALOMID is available in 50 mg, 100 mg, 150 mg and 200 mg capsules for oral administration. Active ingredient: thalidomide. Inactive ingredients: pregelatinized starch and magnesium stearate. The 50 mg capsule shell contains gelatin, titanium dioxide, and black ink. The 100 mg capsule shell contains black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black ink. The 150 mg capsule shell contains FD&C blue #2, black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black and white ink. The 200 mg capsule shell contains FD&C blue #2, titanium dioxide, gelatin, and white ink.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Thalidomide in the drug label.
## Pharmacokinetics
- Absorption
- Absorption of THALOMID is slow after oral administration. The maximum plasma concentrations are reached approximately 2-5 hours after administration. The absolute bioavailability of thalidomide from thalidomide capsules has not yet been characterized in human subjects due to its poor aqueous solubility. Based on the 14C-radiolabel thalidomide study in human, greater than 90% of the total radioactivity is recovered in urine suggesting good oral absorption. While the extent of absorption (as measured by area under the curve ) is proportional to dose in healthy subjects, the observed peak concentration (Cmax) increased in a less than proportional manner (see Table 5 below). This lack of Cmax dose proportionality, coupled with the observed increase in Tmax values, suggests that the poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.
- Coadministration of THALOMID® (thalidomide) with a high-fat meal causes minor (<10%) changes in the observed AUC and Cmax values; however, it causes an increase in Tmax to approximately 6 hours.
- Distribution
- In human plasma, the geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide. In a pharmacokinetic study of thalidomide in HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide was detectable in the semen.
- Metabolism
- In a 14C-radiolabel ADME study in humans, unchanged drug is the predominant circulating component. Thalidomide is not a substrate of the cytochrome P450 system. At therapeutic concentrations, thalidomide is not an inhibitor or inducer of human cytochrome P450 enzymes in vitro. Pharmacokinetic drug-drug interactions with substrates, inhibitors or inducers of CYP450 are not anticipated.
- Elimination
- The mean elimination half-life of thalidomide in plasma following single oral doses between 50 mg and 400 mg was 5.5 to 7.3 hours. Following a single 400 mg oral dose of radiolabeled thalidomide, the total mean recovery was 93.6% of the administered dose by Day 8. The majority of the radioactive dose was excreted within 48 hours following dose administration. In humans, 14C-thalidomide is primarily excreted in urine (91.9% of the radioactive dose) mainly as hydrolytic metabolites while fecal excretion is minor (<2% of the dose). Unchanged thalidomide is not eliminated by the kidney to a notable degree (<3.5% of the dose).
- Effects of Weight
- There is a linear relationship between body weight and estimated thalidomide clearance. In MM patients with body weight from 47-133 kg, thalidomide clearance ranged from approximately 6-12 L/h, representing an increase in thalidomide clearance of 0.605 L/h per 10 kg body weight increase.
- Effects of Age, Gender and Race
- Analysis of the data from pharmacokinetic studies in healthy volunteers and patients with Hansen’s disease ranging in age from 20 to 69 years does not reveal any age-related changes.
- While a comparative trial of the effects of gender on thalidomide pharmacokinetics has not been conducted, examination of the data for thalidomide does not reveal any significant gender differences in pharmacokinetic parameter values.
- Pharmacokinetic differences due to race have not been studied.
- Pharmacokinetic Data in Special Populations
- HIV-seropositive Subjects: There is no apparent significant difference in measured pharmacokinetic parameter values between healthy human subjects and HIV-seropositive subjects following single-dose administration of THALOMID Capsules.
- Patients with Hansen’s Disease: Analysis of data from a small study in Hansen’s patients suggests that these patients, relative to healthy subjects, may have an increased bioavailability of THALOMID. The increase is reflected both in an increased area under the curve and in increased peak plasma levels. The clinical significance of this increase is unknown.
- Pediatric: No pharmacokinetic data are available in subjects below the age of 18 years.
## Nonclinical Toxicology
- Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area ), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA).
- Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test.
- Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25-fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA).
# Clinical Studies
- The efficacy and safety of THALOMID in patients with multiple myeloma were evaluated in two randomized, multi-center studies (Study 1 and Study 2). Study 1 was an open-label study which randomized 207 symptomatic patients with newly diagnosed MM to THALOMID plus dexamethasone (N = 103) versus dexamethasone alone (N=104). The THALOMID dose was 200 mg daily and the dexamethasone dose was 40 mg orally once daily on days 1-4, 9-12, and 17-20 every 28-days. Each group was treated for four 28-day cycles.
- Study 2 randomized 470 newly diagnosed patients with MM to THALOMID plus dexamethasone (N=235) versus placebo plus dexamethasone (N=235). In the THALOMID/dexamethasone arm, a starting dose of thalidomide 50 mg was escalated to 200 mg/day (cycle 2) once daily for 28 days. Patients in both treatment groups took 40 mg of dexamethasone once daily given on days 1-4, 9-12, and 17-20 (every 28 days). Beginning with Cycle 5, the dose of dexamethasone was reduced to 40 mg once daily on Days 1 to 4 of each cycle. Treatment continued as tolerated until disease progression.
- Baseline demographics for both studies are presented in Table 6 and disease characteristics for the study population are summarized in Tables 7 (Study 1) and 8 (Study 2).
- In Study 1, response rate was the primary endpoint. Response rates based on serum or urine paraprotein measurements were significantly higher in the combination arm (52% vs. 36%). The primary efficacy endpoint in Study 2 was time to progression (TTP), defined as the time from randomization to the first documentation of disease progression, based on the myeloma response criteria. A preplanned interim analysis for Study 2 demonstrated that the combination of THALOMID plus dexamethasone was superior to placebo plus dexamethasone with respect to TTP (Table 9).
- The primary data demonstrating the efficacy of thalidomide in the treatment of the cutaneous manifestations of moderate to severe ENL are derived from the published medical literature and from a retrospective study of 102 patients treated by the U.S. Public Health Service.
- Two double-blind, randomized, controlled trials reported the dermatologic response to a 7-day course of 100 mg thalidomide (four times daily) or control. Dosage was lower for patients under 50 kg in weight.
- Waters reported the results of two studies, both double-blind, randomized, placebo-controlled, crossover trials in a total of 10 hospitalized, steroid-dependent patients with chronic ENL treated with 100 mg thalidomide or placebo (three times daily). All patients also received dapsone. The primary endpoint was reduction in weekly steroid dosage.
- Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a retrospective evaluation of 102 patients treated under the auspices of the U.S. Public Health Service. A subset of patients with ENL controlled on thalidomide demonstrated repeated relapse upon drug withdrawal and remission with reinstitution of therapy.
- Twenty U.S. patients between the ages of 11 and 17 years were treated with thalidomide, generally at 100 mg daily. Response rates and safety profiles were similar to that observed in the adult population.
- Thirty-two other published studies containing over 1600 patients consistently report generally successful treatment of the cutaneous manifestations of moderate to severe ENL with thalidomide.
# How Supplied
- 50 mg capsules , imprinted “Celgene/50 mg” with a “Do Not Get Pregnant” logo.
- Individual blister packs of 1 capsule (NDC 59572-205-17).
- Individual blister packs of 28 capsules (NDC 59572-205-14).
- Boxes of 280 containing 10 prescription packs of 28 capsules each (NDC 59572-205-94).
- 100 mg capsules , imprinted “Celgene/100 mg” with a “Do Not Get Pregnant” logo.
- Individual blister packs of 28 capsules (NDC 59572-210-15).
- Boxes of 140 containing 5 prescription packs of 28 capsules each (NDC 59572-210-95).
- 150 mg capsules , imprinted “Celgene/150 mg” with a “Do Not Get Pregnant” logo.
- Individual blister packs of 28 capsules (NDC 59572-215-13).
- Boxes of 112 containing 4 prescription packs of 28 capsules (NDC 59572-215-93).
- 200 mg capsules , imprinted “Celgene/200 mg” with a “Do Not Get Pregnant” logo.
- Individual blister packs of 28 capsules (NDC 59572-220-16).
- Boxes of 84 containing 3 prescription packs of 28 capsules each (NDC 59572-220-96).
- Storage
- This drug must not be repackaged.
- Store at 20°C- 25°C (68°F -77°F); excursions permitted to 15-30° C (59-86° F). Protect from light.
- Handling and Disposal
- Care should be exercised in handling of THALOMID. THALOMID capsules should not be opened or crushed. If powder from THALOMID contacts the skin, wash the skin immediately and thoroughly with soap and water. If THALOMID contacts the mucous membranes, flush thoroughly with water.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.
## Storage
There is limited information regarding Thalidomide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Embryo-Fetal Toxicity
- Advise patients that THALOMID is contraindicated in pregnancy and can cause serious birth defects or death to a developing baby.
- Advise females of reproductive potential that they must avoid pregnancy while taking THALOMID and for at least 4 weeks after completing therapy.
- Initiate THALOMID treatment in females of reproductive potential only following a negative pregnancy test.
- Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during THALOMID therapy, during therapy interruption and for 4 weeks after she has completely finished taking THALOMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.
- Instruct patient to immediately stop taking THALOMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.
- Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception.
- Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID and for up to 28 days after discontinuing THALOMID, even if they have undergone a successful vasectomy.
- Advise male patients taking THALOMID that they must not donate sperm.
- All patients must be instructed to not donate blood while taking THALOMID and for 1 month following discontinuation of THALOMID.
- THALOMID REMS™ Program
- Because of the risk of embryo-fetal toxicity, THALOMID is only available through a restricted program called the THALOMID REMS™ program (formerly known as the “S.T.E.P.S.®” program).
- Patients must sign a Patient-Physician Agreement Form and comply with the requirements to receive THALOMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements.
- THALOMID is available only from pharmacies that are certified in THALOMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product.
- Venous and Arterial Thromboembolism
- Inform patients of the potential risk of developing venous thromboembolism (such as DVT and PE), ischemic heart disease (including myocardial infarction), and stroke, and discuss the need for appropriate prophylactic treatment.
- Drowsiness and Somnolence
- Inform patients of the risk of drowsiness and somnolence with the drug and to avoid situations where drowsiness or somnolence may be a problem and not to take other medications that may cause drowsiness or somnolence without adequate medical advice.
- Peripheral Neuropathy
- Inform patients of the risk of peripheral neuropathy and report the signs and symptoms associated with this event to their health care provider for further evaluation.
- Dizziness and Orthostatic Hypotension
- Inform patients of the risk of dizziness and orthostatic hypotension with the drug. Inform patients to sit upright for a few minutes prior to standing.
- Neutropenia
- Inform patients on the risk of developing neutropenia and the need to monitor their white blood cell count.
- Increased HIV Viral Load
- Inform HIV seropositive patients of the risk of increased viral load and the need to monitor viral load.
- Bradycardia
- Inform patients of the risk of bradycardia and report signs and symptoms associated with this event to their healthcare provider for evaluation.
- Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
- Inform patients of the potential risk for Stevens Johnson syndrome and toxic epidermal necrolysis and report any signs and symptoms associated with these events to their healthcare provider for evaluation.
- Seizures
- Inform patients of the risk of seizures and report any seizure while taking THALOMID.
- Tumor Lysis Syndrome
- Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation.
- Contraceptive Risks
- Inform patients that some contraceptive methods may pose a higher risk of adverse effects or may be medically contraindicated in some patients treated with THALOMID.
- Hypersensitivity
- Inform patients of the potential for a hypersensitivity reaction to THALOMID if they have had such a reaction in the past to Revlimid.
# Precautions with Alcohol
- Alcohol-Thalidomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- THALOMID®
# Look-Alike Drug Names
- Thalomid® — thiamine®
# Drug Shortage Status
# Price | Thalidomide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Thalidomide is a leprostatic that is FDA approved for the treatment of newly diagnosed multiple myeloma in combination with dexamethasone and cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). There is a Black Box Warning for this drug as shown here. Common adverse reactions include fatigue, hypocalcemia, edema, constipation, sensory neuropathy, dyspnea, muscle weakness, leukopenia, neutropenia, rash/desquamation, confusion, anorexia, nausea, anxiety/agitation, asthenia, tremor, fever, weight loss, thrombosis/embolism, motor neuropathy, weight gain, dizziness, and dry skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- THALOMID is administered in combination with dexamethasone in 28-day treatment cycles. The dose of THALOMID is 200 mg administered orally once daily with water, preferably at bedtime and at least 1 hour after the evening meal. The dose of dexamethasone is 40 mg daily administered orally on days 1-4, 9-12, and 17-20 every 28 days.
- Patients who develop adverse reactions such as constipation, somnolence, or peripheral neuropathy may benefit by either temporarily discontinuing the drug or continuing at a lower dose. With the abatement of these adverse reactions, the drug may be started at a lower dose or at the previous dose based on clinical judgment.
- For an episode of cutaneous ENL, THALOMID dosing should be initiated at 100 to 300 mg/day, administered once daily with water, preferably at bedtime and at least 1 hour after the evening meal. Patients weighing less than 50 kilograms should be started at the low end of the dose range.
- In patients with a severe cutaneous ENL reaction, or in those who have previously required higher doses to control the reaction, THALOMID dosing may be initiated at higher doses up to 400 mg/day once daily at bedtime or in divided doses with water, at least 1 hour after meals.
- In patients with moderate to severe neuritis associated with a severe ENL reaction, corticosteroids may be started concomitantly with THALOMID. Steroid usage can be tapered and discontinued when the neuritis has ameliorated.
- Dosing with THALOMID should usually continue until signs and symptoms of active reaction have subsided, usually a period of at least 2 weeks. Patients may then be tapered off medication in 50 mg decrements every 2 to 4 weeks.
- Patients who have a documented history of requiring prolonged maintenance treatment to prevent the recurrence of cutaneous ENL or who flare during tapering should be maintained on the minimum dose necessary to control the reaction. Tapering off medication should be attempted every 3 to 6 months, in decrements of 50 mg every 2 to 4 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thalidomide in adult patients.
### Non–Guideline-Supported Use
- Thalidomide 100 mg daily for 1 month.[1]
- Thalidomide 100 mg daily for 8 weeks.[2]
- Thalidomide 150 mg/day for 6 weeks.[3]
- Thalidomide 200 mg.[4]
- Thalidomide 300 mg daily.[5]
- Thalidomide 200 mg orally each day for 2 weeks.[6]
- Thalidomide (25 mg once daily increasing to 200 mg once daily; doubling the dose every second week for 12 weeks).[7]
- Daily oral doses of thalidomide 50 mg or 100 mg.[8]
- Thalidomide 800 mg/day for the first 2 weeks, followed by a dose escalation of 200 mg/day every 2 weeks to a maximum dose of 1200 mg/day.[9]
- Thalidomide dose of 50 mg 4 times daily.[10]
- Thalidomide was initiated at 100 mg per day (50 to 200 mg/day).[11]
- Thalidomide (doses ranging from 50 to 600 mg/day).[12]
- Thalidomide 200 mg orally daily.[13]
- 200 mg of oral thalidomide nightly for 12 weeks.[14]
- Thalidomide was 300 mg/day.[15]
- 4 months of thalidomide treatment; 50 mg at night for the first month, 100 mg at night for the second month, and 200 mg at night for the third and fourth months.[16]
- Thalidomide was started at 50 mg orally daily and increased by 50 mg daily every month to a maximum of 200 mg daily.[17]
- Thalidomide (initial dose of 200 mg daily, followed by dose escalation of 200 mg every 14 days as tolerated).[18]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Thalidomide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thalidomide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Thalidomide in pediatric patients.
# Contraindications
- Pregnancy
- THALOMID can cause fetal harm when administered to a pregnant female. Thalidomide is contraindicated in females who are pregnant. Thalidomide is a powerful human teratogen, inducing a high frequency of severe and life-threatening birth defects, even after a single dose. Mortality at or shortly after birth has been reported in about 40% of infants. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs during thalidomide treatment, the drug should be discontinued immediately.
- Hypersensitivity
- THALOMID is contraindicated in patients who have demonstrated hypersensitivity to the drug or its components.
# Warnings
### Precautions
- Embryo-Fetal Toxicity
- Thalidomide is a powerful human teratogen that induces a high frequency of severe and life-threatening birth defects, even after a single dose. Mortality at or shortly after birth has been reported in about 40% of infants. When there is no satisfactory alternative treatment, females of reproductive potential may be treated with thalidomide provided adequate precautions are taken to avoid pregnancy. THALOMID® (thalidomide) is only available through the THALOMID REMS™ program (formerly known as the “S.T.E.P.S.® program”).
- Oral ingestion is the only type of maternal thalidomide exposure known to result in drug-associated birth defects. There are no specific data available regarding the reproductive risks of cutaneous absorption or inhalation of thalidomide; however, females of reproductive potential should avoid contact with THALOMID® (thalidomide) Capsules. THALOMID Capsules should be stored in blister packs until ingestion. If there is contact with non-intact thalidomide capsules or the powder contents, the exposed area should be washed with soap and water.
- If healthcare providers or other care givers are exposed to body fluids from patients receiving THALOMID (thalidomide) the exposed area should be washed with soap and water. Appropriate precautions should be utilized, such as wearing gloves to prevent the potential cutaneous exposure to THALOMID.
- Females of Reproductive Potential
Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning THALOMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.
Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with THALOMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of THALOMID therapy.
Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing THALOMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles.
- Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning THALOMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.
- Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with THALOMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of THALOMID therapy.
- Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing THALOMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles.
- Males
Thalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID and for up to 28 days after discontinuing THALOMID, even if they have undergone a successful vasectomy. Male patients taking THALOMID must not donate sperm.
- Thalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID and for up to 28 days after discontinuing THALOMID, even if they have undergone a successful vasectomy. Male patients taking THALOMID must not donate sperm.
- Blood Donation
Patients must not donate blood during treatment with THALOMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to THALOMID.
- Patients must not donate blood during treatment with THALOMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to THALOMID.
- THALOMID REMS™ Program
- Because of the embryo-fetal risk, THALOMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the THALOMID REMS™ program (formerly known as the “S.T.E.P.S.®” program).
- Required components of the THALOMID REMS™ program include the following:
Prescribers must be certified with the THALOMID REMS™ program by enrolling and complying with the REMS requirements.
Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements.
Pharmacies must be certified with the THALOMID REMS™ program, must only dispense to patients who are authorized to receive THALOMID and comply with REMS requirements.
- Prescribers must be certified with the THALOMID REMS™ program by enrolling and complying with the REMS requirements.
- Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements.
- Pharmacies must be certified with the THALOMID REMS™ program, must only dispense to patients who are authorized to receive THALOMID and comply with REMS requirements.
- Further information about the THALOMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.
- Venous and Arterial Thromboembolism
- The use of THALOMID in patients with MM results in an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. This risk increases significantly when thalidomide is used in combination with standard chemotherapeutic agents including dexamethasone. In one controlled trial, the rate of venous thromboembolism was 22.5% in patients receiving thalidomide in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002).
- Ischemic heart disease (11.1%), including myocardial infarction (1.3%), and stroke (cerebrovascular accident, 2.6%) have also occurred in patients with previously untreated MM treated with THALOMID and dexamethasone compared to placebo and dexamethasone (4.7%, 1.7%, and 0.9%, respectively) in one clinical trial.
- Consider thromboprophylaxis based on an assessment of individual patients’ underlying risk factors. Patients and physicians should be observant for the signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Agents that also may increase the risk of thromboembolism should be used with caution in patients receiving THALOMID.
- Drowsiness and Somnolence
- Thalidomide frequently causes drowsiness and somnolence. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Advise patients as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery. Dose reductions may be required.
- Peripheral Neuropathy
- Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (≥10%) and potentially severe adverse reaction of treatment with thalidomide that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months; however, peripheral neuropathy following relatively short-term use has been reported. The correlation with cumulative dose is unclear. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all.
- Few reports of neuropathy have arisen in the treatment of ENL despite long-term thalidomide treatment. However, the inability clinically to differentiate thalidomide neuropathy from the neuropathy often seen in Hansen’s disease makes it difficult to determine accurately the incidence of thalidomide-related neuropathy in ENL patients treated with thalidomide.
- Patients should be examined at monthly intervals for the first 3 months of thalidomide therapy to enable the clinician to detect early signs of neuropathy, which include numbness, tingling or pain in the hands and feet. Patients should be evaluated periodically thereafter during treatment. Patients should be regularly counseled, questioned, and evaluated for signs or symptoms of peripheral neuropathy. Consideration should be given to electrophysiological testing, consisting of measurement of sensory nerve action potential (SNAP) amplitudes at baseline and thereafter every 6 months in an effort to detect asymptomatic neuropathy. If symptoms of drug-induced neuropathy develop, thalidomide should be discontinued immediately to limit further damage, if clinically appropriate. Usually, treatment with thalidomide should only be reinitiated if the neuropathy returns to baseline status.
- Medications known to be associated with neuropathy should be used with caution in patients receiving thalidomide.
- Dizziness and Orthostatic Hypotension
- Patients should also be advised that thalidomide may cause dizziness and orthostatic hypotension and that, therefore, they should sit upright for a few minutes prior to standing up from a recumbent position.
- Neutropenia
- Decreased white blood cell counts, including neutropenia, have been reported in association with the clinical use of thalidomide. Treatment should not be initiated with an absolute neutrophil count (ANC) of <;<750/mm3. White blood cell count and differential should be monitored on an ongoing basis, especially in patients who may be more prone to neutropenia, such as patients who are HIV-seropositive. If ANC decreases to below 750/mm3 while on treatment, the patient’s medication regimen should be re-evaluated and, if the neutropenia persists, consideration should be given to withholding thalidomide if clinically appropriate.
- Increased HIV Viral Load
- In a randomized, placebo-controlled trial of thalidomide in an HIV-seropositive patient population, plasma HIV RNA levels were found to increase (median change = 0.42 log10 copies HIV RNA/mL, p = 0.04 compared to placebo). A similar trend was observed in a second, unpublished study conducted in patients who were HIV-seropositive. The clinical significance of this increase is unknown. Both studies were conducted prior to availability of highly active antiretroviral therapy. Until the clinical significance of this finding is further understood, in HIV-seropositive patients, viral load should be measured after the first and third months of treatment and every 3 months thereafter.
- Bradycardia
- Bradycardia in association with thalidomide use has been reported. Cases of bradycardia have been reported, some required medical interventions. The clinical significance and underlying etiology of the bradycardia noted in some thalidomide-treated patients are presently unknown. Monitor patients for bradycardia and syncope. Dose reduction or discontinuation may be required.
- Medications known to decrease heart rate should be used with caution in patients receiving thalidomide.
- Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
- Serious dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be fatal, have been reported. THALOMID should be discontinued if a skin rash occurs and only resumed following appropriate clinical evaluation. If the rash is exfoliative, purpuric, or bullous or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, use of THALOMID should not be resumed.
- Seizures
- Although not reported from pre-marketing controlled clinical trials, seizures, including grand mal convulsions, have been reported during post-approval use of THALOMID in clinical practice. Because these events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. Most patients had disorders that may have predisposed them to seizure activity, and it is not currently known whether thalidomide has any epileptogenic influence. During therapy with thalidomide, patients with a history of seizures or with other risk factors for the development of seizures should be monitored closely for clinical changes that could precipitate acute seizure activity.
- Tumor Lysis Syndrome
- Monitor patients at risk of tumor lysis syndrome (e.g., patients with high tumor burden prior to treatment) and take appropriate precautions.
- Contraceptive Risks
- Some contraceptive methods may pose a higher risk of adverse effects or may be medically contraindicated in some patients treated with THALOMID. Because some patients may develop sudden, severe neutropenia and/or thrombocytopenia, use of an intrauterine device (IUD) or implantable contraception in these patients may carry an increased risk for infection or bleeding either at insertion, removal or during use. Treatment with THALOMID, the presence of an underlying malignancy, and/or use of an estrogen-containing contraceptive can each increase the risk of thromboembolism. It is not known if these risks of thromboembolism are additive. However, they should be taken into consideration when choosing contraceptive methods.
- Hypersensitivity
- Hypersensitivity to THALOMID has been reported. Signs and symptoms have included the occurrence of erythematous macular rash, possibly associated with fever, tachycardia, and hypotension, and if severe, may necessitate interruption of therapy. If the reaction recurs when dosing is resumed, THALOMID should be discontinued.
# Adverse Reactions
## Clinical Trials Experience
- Teratogenicity
- The most serious toxicity associated with thalidomide is its documented human teratogenicity. The risk of severe birth defects, primarily phocomelia or death to the fetus, is extremely high during the critical period of pregnancy. The critical period is estimated, depending on the source of information, to range from 35 to 50 days after the last menstrual period. The risk of other potentially severe birth defects outside this critical period is unknown, but may be significant. Based on present knowledge, thalidomide must not be used at any time during pregnancy.
- Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if he has undergone a successful vasectomy.
- Venous and Arterial Thromboembolism
- An increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism), ischemic heart disease (including myocardial infarction), and stroke have been reported in patients with multiple myeloma treated with thalidomide.
- Peripheral Neuropathy
- Peripheral Neuropathy is a very common, potentially severe, adverse reaction of treatment with thalidomide that may result in irreversible damage. Peripheral neuropathy generally occurs following chronic use over a period of months. However, reports following relatively short-term use also exist.Incidence of neuropathy events leading to discontinuation, dose reduction or interruption increases with cumulative dose and duration of therapy. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all.
- Somnolence, dizziness, and rash are the most commonly observed adverse reactions associated with the use of thalidomide. Adverse event profiles from clinical trials are summarized in the sections that follow.
- Adverse Reactions in Multiple Myeloma Controlled Clinical Trials
- The safety analyses were conducted in two controlled clinical studies (Study 1 and Study 2). The safety analysis in Study 1 was conducted on 204 patients who received treatment. Table 1 lists the most common adverse drug reactions (≥ 10%). The most frequently reported adverse reactions were fatigue, hypocalcemia, edema, constipation, sensory neuropathy, dyspnea, muscle weakness, leukopenia, neutropenia, rash/desquamation, confusion, anorexia, nausea, anxiety/agitation , tremor, fever, weight loss, thrombosis/embolism, neuropathy-motor, weight gain, dizziness, and dry skin .
- Twenty-three percent of patients (47/204) discontinued due to adverse reactions; 30% (31/102) from the THALOMID/dexamethasone arm and 16% (16/102) from the dexamethasone alone arm.
- The safety analysis in Study 2 was conducted on 466 patients who received treatment. Table 2 lists the most common adverse drug reactions (≥ 10%) that were observed. Table 3 lists the most common Grade 3/4 adverse drug reactions (occurring at > 2%) that were observed. The adverse reactions most often reported by patients treated with THALOMID/dexamethasone were constipation, peripheral edema, tremor, asthenia, dizziness and fatigue. Adverse reactions with a frequency at least 2-fold higher in the THALOMID/dexamethasone group than in the placebo/dexamethasone group include constipation, tremor, deep vein thrombosis and peripheral sensory neuropathy.
- Twenty-six percent of patients (121/466) discontinued due to adverse events; 37% (86/234) from the THALOMID/dexamethasone arm and 15% (35/232) from the placebo/dexamethasone arm.
- Less Common Adverse Drug Reactions in Multiple Myeloma Controlled Clinical Trials
- In Study 2, THALOMID in combination with dexamethasone in patients with multiple myeloma, the following adverse drug reactions not described above were reported*:
Vomiting NOS, dry mouth, peritonitis, diverticular perforation
Somnolence, hypoesthesia, polyneuropathy NOS, transient ischemic attack
Bronchitis NOS
Mood alteration NOS
Hypotension NOS, orthostatic hypotension
Bradycardia NOS
Blurred vision
- All adverse reactions with ≥3% of patients in THALOMID/dexamethasone arm and with a ≥1% difference in proportion of patients between the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm. All grade 3/4 and serious adverse reactions reported >2 patients in THALOMID/dexamethasone arm and with a percentage higher in the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm have been considered for possible inclusion. In any cases medical judgment has been applied for consideration of causality assessment.
- Adverse Reactions in Erythema Nodosum Leprosum (ENL) Clinical Trials
- Table 4 lists treatment-emergent signs and symptoms that occurred in THALOMID-treated patients in clinical trials in ENL. The most common adverse reactions (≥10%) reported in patients with ENL were somnolence, rash, headache. Doses ranged from 50 to 300 mg/day. All adverse reactions were mild to moderate in severity, and none resulted in discontinuation.
- Other Adverse Events Observed in ENL Patients
- THALOMID in doses up to 400 mg/day has been administered investigationally in the United States over a 19-year period in 1465 patients with ENL. The published literature describes the treatment of an additional 1678 patients. To provide a meaningful estimate of the proportion of the individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using a modified COSTART dictionary/terminology. These categories are used in the listing below. All reported events are included except those already listed in the previous table. Due to the fact that these data were collected from uncontrolled studies, the incidence rate cannot be determined. No causal relationship between THALOMID and these events can be conclusively determined at this time. These are reports of all adverse events noted by investigators in patients to whom they had administered thalidomide.
Abdomen enlarged, fever, photosensitivity, upper extremity pain.
Bradycardia, hypertension, hypotension, peripheral vascular disorder, tachycardia, vasodilation.
Anorexia, appetite increase/weight gain, dry mouth, dyspepsia, enlarged liver, eructation, flatulence, increased liver function tests, intestinal obstruction, vomiting.
ESR decrease, eosinophilia, granulocytopenia, hypochromic anemia, leukemia, leukocytosis, leukopenia, MCV elevated, RBC abnormal, spleen palpable, thrombocytopenia.
ADH inappropriate, amyloidosis, bilirubinemia, BUN increased, creatinine increased, cyanosis, diabetes, edema, electrolyte abnormalities, hyperglycemia, hyperkalemia, hyperuricemia, hypocalcemia, hypoproteinemia, LDH increased, phosphorus decreased, SGPT increased.
Arthritis, bone tenderness, hypertonia, joint disorder, leg cramps, myalgia, myasthenia, periosteal disorder.
Abnormal thinking, agitation, amnesia, anxiety, causalgia, circumoral paresthesia, confusion, depression, euphoria, hyperesthesia, insomnia, nervousness, neuralgia, neuritis, neuropathy, paresthesia, peripheral neuritis, psychosis.
Cough, emphysema, epistaxis, pulmonary embolus, rales, upper respiratory infection, voice alteration.
Acne, alopecia, dry skin, eczematous rash, exfoliative dermatitis, ichthyosis, perifollicular thickening, skin necrosis, seborrhea, sweating, urticaria, vesiculobullous rash.
Amblyopia, deafness, dry eye, eye pain, tinnitus.
Decreased creatinine clearance, hematuria, orchitis, proteinuria, pyuria, urinary frequency.
- Other Adverse Events Observed in HIV-seropositive Patients
- In addition to controlled clinical trials, THALOMID has been used in uncontrolled studies in 145 patients. Less frequent adverse events that have been reported in these HIV-seropositive patients treated with THALOMID were grouped into a smaller number of standardized categories using modified COSTART dictionary/terminology and these categories are used in the listing below. Adverse events that have already been included in the tables and narrative above, or that are too general to be informative are not listed.
Ascites, AIDS, allergic reaction, cellulitis, chest pain, chills and fever, cyst, decreased CD4 count, facial edema, flu syndrome, hernia, thyroid hormone level altered, moniliasis, photosensitivity reaction, sarcoma, sepsis, viral infection.
Angina pectoris, arrhythmia, atrial fibrillation, bradycardia, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, heart arrest, heart failure, hypertension, hypotension, murmur, myocardial infarct, palpitation, pericarditis, peripheral vascular disorder, postural hypotension, syncope, tachycardia, thrombophlebitis, thrombosis.
Cholangitis, cholestatic jaundice, colitis, dyspepsia, dysphagia, esophagitis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, gum disorder, hepatitis, pancreatitis, parotid gland enlargement, periodontitis, stomatitis, tongue discoloration, tooth disorder.
Aplastic anemia, macrocytic anemia, megaloblastic anemia, microcytic anemia.
Avitaminosis, bilirubinemia, dehydration, hypercholesteremia, hypoglycemia, increased alkaline phosphatase, increased lipase, increased serum creatinine, peripheral edema.
Myalgia, myasthenia.
Abnormal gait, ataxia, decreased libido, decreased reflexes, dementia, dysesthesia, dyskinesia, emotional lability, hostility, hypalgesia, hyperkinesia, incoordination, meningitis, neurologic disorder, tremor, vertigo.
Apnea, bronchitis, lung disorder, lung edema, pneumonia (including Pneumocystis carinii pneumonia), rhinitis.
Angioedema, benign skin neoplasm, eczema, herpes simplex, incomplete Stevens-Johnson syndrome, nail disorder, pruritus, psoriasis, skin discoloration, skin disorder.
Conjunctivitis, eye disorder, lacrimation disorder, retinitis, taste perversion.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of THALOMID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiac arrhythmias including atrial fibrillation, bradycardia, tachycardia, sick sinus syndrome, EKG abnormalities, myocardial infarction.
Intestinal perforation, gastrointestinal perforations, intestinal obstruction.
Electrolyte imbalance including hypercalcemia or hypocalcemia, hyperkalemia and hypokalemia, hyponatremia, hypothyroidism, increased alkaline phosphatase, tumor lysis syndrome.
Changes in mental status or mood including depression and suicide attempts, disturbances in consciousness including lethargy, syncope, loss of consciousness or stupor, seizures including grand mal convulsions and status epilepticus, Parkinson’s disease, stroke.
Erythema multiforme, toxic epidermal necrolysis.
Decreased white blood cell counts including neutropenia and febrile neutropenia, changes in prothrombin time, pancytopenia.
Pleural effusion.
Amenorrhea, sexual dysfunction.
Hypersensitivity, angioedema/urticaria.
Hearing impairment/deafness.
Renal failure.
- Other Adverse Events in the Published Literature or Reported from Other Sources
- The following additional events have been identified either in the published literature or from spontaneous reports from other sources: acute renal failure, amenorrhea, aphthous stomatitis, bile duct obstruction, carpal tunnel, chronic myelogenous leukemia, diplopia, dysesthesia, dyspnea, enuresis, erythema nodosum, erythroleukemia, foot drop, galactorrhea, gynecomastia, hangover effect, hypomagnesemia, hypothyroidism, lymphedema, lymphopenia, metrorrhagia, migraine, myxedema, nodular sclerosing Hodgkin’s disease, nystagmus, oliguria, pancytopenia, petechiae, purpura, Raynaud’s syndrome, stomach ulcer, suicide attempt, interstitial lung disease and severe infections (e.g., fatal sepsis including septic shock).
# Drug Interactions
- Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, or Other CNS Depressants (Including Alcohol)
- The use of opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants concomitantly with THALOMID may cause an additive sedative effect and should be avoided.
- Drugs which Cause Bradycardia
- The use of drugs which slow cardiac conduction concomitantly with THALOMID may cause an additive bradycardic effect and should be used with caution. Cardiovascular medications which may cause bradycardia include calcium channel blockers, beta blockers, alpha/beta-adrenergic blockers, and digoxin. Non-cardiac drugs that may cause bradycardia include H2 blockers (e.g., famotidine, cimetidine), lithium, tricyclic antidepressants and neuromuscular blockers (succinylcholine).
- In 16 healthy men, the pharmacokinetic profile of a single 0.5 mg digoxin dose was similar with and without the coadministration of thalidomide 200 mg/day at steady state levels. The single dose of digoxin had no effect on the pharmacokinetic profile of thalidomide. The safety of long-term concomitant use of THALOMID and digoxin has not been evaluated.
- Drugs which Cause Peripheral Neuropathy
- The use of drugs which cause peripheral neuropathy (e.g., bortezomib, amiodarone, cisplatin, docetaxel, paclitaxel, vincristine, disulfiram, phenytoin, metronidazole, alcohol) can cause an additive effect and should be used with caution.
- Hormonal Contraceptives
- Hormonal contraceptives increase the risk of thromboembolism. It is not known whether concomitant use of hormonal contraceptives further increases the risk of thromboembolism with THALOMID.
- In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 µg of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels.
- Warfarin
- In 13 healthy men, the pharmacokinetic profile and international normalized ratio (INR) of prothrombin time for warfarin, following a single oral dose of 25 mg, were similar with and without the coadministration of thalidomide 200 mg/day at steady-state levels. The single dose of warfarin had no effect on the pharmacokinetic profile of thalidomide.
- Drugs that Interfere with Hormonal Contraceptives
- Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John’s Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception up to one month after discontinuation of these concomitant therapies. Therefore, females requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception while taking thalidomide.
- Concomitant Therapies that may Increase the Risk of Thromboembolism
- Erythropoietic agents, or other agents that may increase the risk of thromboembolism, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving thalidomide with dexamethasone.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Risk Summary
- THALOMID can cause embryofetal harm when administered to a pregnant female and is contraindicated during pregnancy.
- THALOMID is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Even a single dose taken by a pregnant woman can cause birth defects. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to THALOMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
- Animal data
- A pre- and postnatal reproductive toxicity study was conducted in pregnant female rabbits. Compound-related increased abortion incidences and elevated fetotoxicity were observed at the lowest oral dose level of 30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA) and all higher dose levels. Neonatal mortality was elevated at oral dose levels to the lactating female rabbits ≥150 mg/kg/day (approximately 7.5-fold the maximum human dose based upon BSA). No delay in postnatal development, including learning and memory functions, were noted at the oral dose level to the lactating female rabbits of 150 mg/kg/day (average thalidomide concentrations in milk ranged from 22 to 36 µg/mL).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Thalidomide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Thalidomide during labor and delivery.
### Nursing Mothers
- It is not known whether thalidomide is excreted in human milk. Thalidomide is excreted in the milk of lactating rabbits. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from THALOMID, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
### Geriatic Use
- One hundred and seventy-six (52%) of 336 patients treated with THALOMID in combination with dexamethasone were ≥ 65 of age while 50 (15%) were ≥75. Patients ≥65 years of age on Study 2 had higher incidences of atrial fibrillation, constipation, fatigue, nausea, hypokalemia, deep venous thrombosis, hyperglycemia, pulmonary embolism, and asthenia compared to patients <65.
### Gender
There is no FDA guidance on the use of Thalidomide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Thalidomide with respect to specific racial populations.
### Renal Impairment
- No clinical studies were conducted with THALOMID in patients with mild, moderate or severe renal function. Renal impairment is not expected to influence drug exposure since <3.5% of the dose is excreted in the urine as unchanged drug.
- In a study of 6 patients with end-stage renal disease, thalidomide (200 mg/day) was administered on a non-dialysis day and on a dialysis day and blood samples for pharmacokinetics were collected at least 10 hours following the dose. Comparison of concentration-time profiles on a non-dialysis day and during dialysis showed that the mean total clearance increased by a 2.5-fold during hemodialysis. Because the dialysis was performed 10 hours following administration of the dose, the drug-concentration time curves were not statistically significantly different for days patients were on and off of dialysis. In addition, there were no major differences in thalidomide PK between patients with end-stage renal disease and healthy volunteers. Thus, no dosage adjustment is needed for patients with renal impairment or patients on dialysis.
### Hepatic Impairment
- No clinical studies have been conducted in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- THALOMID can cause fetal harm when administered during pregnancy. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking THALOMID, during dose interruptions and for at least 4 weeks after completing therapy.
- Females
- Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with THALOMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of THALOMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.
- Females of reproductive potential must have 2 negative pregnancy tests before initiating THALOMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing THALOMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. THALOMID treatment must be discontinued during this evaluation.
- Males
- Thalidomide is present in the semen of males who take THALOMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID, during dose interruptions and for up to 28 days after discontinuing THALOMID, even if they have undergone a successful vasectomy. Male patients taking THALOMID must not donate sperm.
### Immunocompromised Patients
There is no FDA guidance one the use of Thalidomide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Thalidomide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Thalidomide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdosages of up to 14.4 g have been reported in the literature. No fatalities have been reported and all overdosed patients recovered without sequelae.
### Management
- There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Thalidomide in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of THALOMID is not fully understood. THALOMID possesses immunomodulatory, antiinflammatory and antiangiogenic properties. Available data from in vitro studies and clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-α) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-α in patients with erythema nodosum leprosum (ENL); however, it has also been shown to increase plasma TNF-α levels in HIV-seropositive patients. Other anti-inflammatory and immunomodulatory properties of thalidomide may include suppression of macrophage involvement in prostaglandin synthesis, and modulation of interleukin-10 and interleukin-12 production by peripheral blood mononuclear cells. Thalidomide treatment of multiple myeloma patients is accompanied by an increase in the number of circulating natural killer cells, and an increase in plasma levels of interleukin-2 and interferon-gamma (T cell-derived cytokines associated with cytotoxic activity). Thalidomide was found to inhibit angiogenesis in a human umbilical artery explant model in vitro. The cellular processes of angiogenesis inhibited by thalidomide may include the proliferation of endothelial cells.
## Structure
- THALOMID, α-(N-phthalimido) glutarimide, is an immunomodulatory agent. The empirical formula for thalidomide is C13H10N2O4 and the gram molecular weight is 258.2. The CAS number of thalidomide is 50-35-1.
- Thalidomide is an off-white to white, odorless, crystalline powder that is soluble at 25°C in dimethyl sulfoxide and sparingly soluble in water and ethanol. The glutarimide moiety contains a single asymmetric center and, therefore, may exist in either of two optically active forms designated S-(-) or R-(+). THALOMID is an equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical rotation of zero.
- THALOMID is available in 50 mg, 100 mg, 150 mg and 200 mg capsules for oral administration. Active ingredient: thalidomide. Inactive ingredients: pregelatinized starch and magnesium stearate. The 50 mg capsule shell contains gelatin, titanium dioxide, and black ink. The 100 mg capsule shell contains black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black ink. The 150 mg capsule shell contains FD&C blue #2, black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black and white ink. The 200 mg capsule shell contains FD&C blue #2, titanium dioxide, gelatin, and white ink.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Thalidomide in the drug label.
## Pharmacokinetics
- Absorption
- Absorption of THALOMID is slow after oral administration. The maximum plasma concentrations are reached approximately 2-5 hours after administration. The absolute bioavailability of thalidomide from thalidomide capsules has not yet been characterized in human subjects due to its poor aqueous solubility. Based on the 14C-radiolabel thalidomide study in human, greater than 90% of the total radioactivity is recovered in urine suggesting good oral absorption. While the extent of absorption (as measured by area under the curve [AUC]) is proportional to dose in healthy subjects, the observed peak concentration (Cmax) increased in a less than proportional manner (see Table 5 below). This lack of Cmax dose proportionality, coupled with the observed increase in Tmax values, suggests that the poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.
- Coadministration of THALOMID® (thalidomide) with a high-fat meal causes minor (<10%) changes in the observed AUC and Cmax values; however, it causes an increase in Tmax to approximately 6 hours.
- Distribution
- In human plasma, the geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide. In a pharmacokinetic study of thalidomide in HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide was detectable in the semen.
- Metabolism
- In a 14C-radiolabel ADME study in humans, unchanged drug is the predominant circulating component. Thalidomide is not a substrate of the cytochrome P450 system. At therapeutic concentrations, thalidomide is not an inhibitor or inducer of human cytochrome P450 enzymes in vitro. Pharmacokinetic drug-drug interactions with substrates, inhibitors or inducers of CYP450 are not anticipated.
- Elimination
- The mean elimination half-life of thalidomide in plasma following single oral doses between 50 mg and 400 mg was 5.5 to 7.3 hours. Following a single 400 mg oral dose of radiolabeled thalidomide, the total mean recovery was 93.6% of the administered dose by Day 8. The majority of the radioactive dose was excreted within 48 hours following dose administration. In humans, 14C-thalidomide is primarily excreted in urine (91.9% of the radioactive dose) mainly as hydrolytic metabolites while fecal excretion is minor (<2% of the dose). Unchanged thalidomide is not eliminated by the kidney to a notable degree (<3.5% of the dose).
- Effects of Weight
- There is a linear relationship between body weight and estimated thalidomide clearance. In MM patients with body weight from 47-133 kg, thalidomide clearance ranged from approximately 6-12 L/h, representing an increase in thalidomide clearance of 0.605 L/h per 10 kg body weight increase.
- Effects of Age, Gender and Race
- Analysis of the data from pharmacokinetic studies in healthy volunteers and patients with Hansen’s disease ranging in age from 20 to 69 years does not reveal any age-related changes.
- While a comparative trial of the effects of gender on thalidomide pharmacokinetics has not been conducted, examination of the data for thalidomide does not reveal any significant gender differences in pharmacokinetic parameter values.
- Pharmacokinetic differences due to race have not been studied.
- Pharmacokinetic Data in Special Populations
- HIV-seropositive Subjects: There is no apparent significant difference in measured pharmacokinetic parameter values between healthy human subjects and HIV-seropositive subjects following single-dose administration of THALOMID Capsules.
- Patients with Hansen’s Disease: Analysis of data from a small study in Hansen’s patients suggests that these patients, relative to healthy subjects, may have an increased bioavailability of THALOMID. The increase is reflected both in an increased area under the curve and in increased peak plasma levels. The clinical significance of this increase is unknown.
- Pediatric: No pharmacokinetic data are available in subjects below the age of 18 years.
## Nonclinical Toxicology
- Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA).
- Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test.
- Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25-fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA).
# Clinical Studies
- The efficacy and safety of THALOMID in patients with multiple myeloma were evaluated in two randomized, multi-center studies (Study 1 and Study 2). Study 1 was an open-label study which randomized 207 symptomatic patients with newly diagnosed MM to THALOMID plus dexamethasone (N = 103) versus dexamethasone alone (N=104). The THALOMID dose was 200 mg daily and the dexamethasone dose was 40 mg orally once daily on days 1-4, 9-12, and 17-20 every 28-days. Each group was treated for four 28-day cycles.
- Study 2 randomized 470 newly diagnosed patients with MM to THALOMID plus dexamethasone (N=235) versus placebo plus dexamethasone (N=235). In the THALOMID/dexamethasone arm, a starting dose of thalidomide 50 mg was escalated to 200 mg/day (cycle 2) once daily for 28 days. Patients in both treatment groups took 40 mg of dexamethasone once daily given on days 1-4, 9-12, and 17-20 (every 28 days). Beginning with Cycle 5, the dose of dexamethasone was reduced to 40 mg once daily on Days 1 to 4 of each cycle. Treatment continued as tolerated until disease progression.
- Baseline demographics for both studies are presented in Table 6 and disease characteristics for the study population are summarized in Tables 7 (Study 1) and 8 (Study 2).
- In Study 1, response rate was the primary endpoint. Response rates based on serum or urine paraprotein measurements were significantly higher in the combination arm (52% vs. 36%). The primary efficacy endpoint in Study 2 was time to progression (TTP), defined as the time from randomization to the first documentation of disease progression, based on the myeloma response criteria. A preplanned interim analysis for Study 2 demonstrated that the combination of THALOMID plus dexamethasone was superior to placebo plus dexamethasone with respect to TTP (Table 9).
- The primary data demonstrating the efficacy of thalidomide in the treatment of the cutaneous manifestations of moderate to severe ENL are derived from the published medical literature and from a retrospective study of 102 patients treated by the U.S. Public Health Service.
- Two double-blind, randomized, controlled trials reported the dermatologic response to a 7-day course of 100 mg thalidomide (four times daily) or control. Dosage was lower for patients under 50 kg in weight.
- Waters reported the results of two studies, both double-blind, randomized, placebo-controlled, crossover trials in a total of 10 hospitalized, steroid-dependent patients with chronic ENL treated with 100 mg thalidomide or placebo (three times daily). All patients also received dapsone. The primary endpoint was reduction in weekly steroid dosage.
- Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a retrospective evaluation of 102 patients treated under the auspices of the U.S. Public Health Service. A subset of patients with ENL controlled on thalidomide demonstrated repeated relapse upon drug withdrawal and remission with reinstitution of therapy.
- Twenty U.S. patients between the ages of 11 and 17 years were treated with thalidomide, generally at 100 mg daily. Response rates and safety profiles were similar to that observed in the adult population.
- Thirty-two other published studies containing over 1600 patients consistently report generally successful treatment of the cutaneous manifestations of moderate to severe ENL with thalidomide.
# How Supplied
- 50 mg capsules [white opaque], imprinted “Celgene/50 mg” with a “Do Not Get Pregnant” logo.
- Individual blister packs of 1 capsule (NDC 59572-205-17).
- Individual blister packs of 28 capsules (NDC 59572-205-14).
- Boxes of 280 containing 10 prescription packs of 28 capsules each (NDC 59572-205-94).
- 100 mg capsules [tan], imprinted “Celgene/100 mg” with a “Do Not Get Pregnant” logo.
- Individual blister packs of 28 capsules (NDC 59572-210-15).
- Boxes of 140 containing 5 prescription packs of 28 capsules each (NDC 59572-210-95).
- 150 mg capsules [tan and blue], imprinted “Celgene/150 mg” with a “Do Not Get Pregnant” logo.
- Individual blister packs of 28 capsules (NDC 59572-215-13).
- Boxes of 112 containing 4 prescription packs of 28 capsules (NDC 59572-215-93).
- 200 mg capsules [blue], imprinted “Celgene/200 mg” with a “Do Not Get Pregnant” logo.
- Individual blister packs of 28 capsules (NDC 59572-220-16).
- Boxes of 84 containing 3 prescription packs of 28 capsules each (NDC 59572-220-96).
- Storage
- This drug must not be repackaged.
- Store at 20°C- 25°C (68°F -77°F); excursions permitted to 15-30° C (59-86° F). Protect from light.
- Handling and Disposal
- Care should be exercised in handling of THALOMID. THALOMID capsules should not be opened or crushed. If powder from THALOMID contacts the skin, wash the skin immediately and thoroughly with soap and water. If THALOMID contacts the mucous membranes, flush thoroughly with water.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.
## Storage
There is limited information regarding Thalidomide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Embryo-Fetal Toxicity
- Advise patients that THALOMID is contraindicated in pregnancy and can cause serious birth defects or death to a developing baby.
- Advise females of reproductive potential that they must avoid pregnancy while taking THALOMID and for at least 4 weeks after completing therapy.
- Initiate THALOMID treatment in females of reproductive potential only following a negative pregnancy test.
- Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during THALOMID therapy, during therapy interruption and for 4 weeks after she has completely finished taking THALOMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.
- Instruct patient to immediately stop taking THALOMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.
- Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception.
- Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID and for up to 28 days after discontinuing THALOMID, even if they have undergone a successful vasectomy.
- Advise male patients taking THALOMID that they must not donate sperm.
- All patients must be instructed to not donate blood while taking THALOMID and for 1 month following discontinuation of THALOMID.
- THALOMID REMS™ Program
- Because of the risk of embryo-fetal toxicity, THALOMID is only available through a restricted program called the THALOMID REMS™ program (formerly known as the “S.T.E.P.S.®” program).
- Patients must sign a Patient-Physician Agreement Form and comply with the requirements to receive THALOMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements.
- THALOMID is available only from pharmacies that are certified in THALOMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product.
- Venous and Arterial Thromboembolism
- Inform patients of the potential risk of developing venous thromboembolism (such as DVT and PE), ischemic heart disease (including myocardial infarction), and stroke, and discuss the need for appropriate prophylactic treatment.
- Drowsiness and Somnolence
- Inform patients of the risk of drowsiness and somnolence with the drug and to avoid situations where drowsiness or somnolence may be a problem and not to take other medications that may cause drowsiness or somnolence without adequate medical advice.
- Peripheral Neuropathy
- Inform patients of the risk of peripheral neuropathy and report the signs and symptoms associated with this event to their health care provider for further evaluation.
- Dizziness and Orthostatic Hypotension
- Inform patients of the risk of dizziness and orthostatic hypotension with the drug. Inform patients to sit upright for a few minutes prior to standing.
- Neutropenia
- Inform patients on the risk of developing neutropenia and the need to monitor their white blood cell count.
- Increased HIV Viral Load
- Inform HIV seropositive patients of the risk of increased viral load and the need to monitor viral load.
- Bradycardia
- Inform patients of the risk of bradycardia and report signs and symptoms associated with this event to their healthcare provider for evaluation.
- Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
- Inform patients of the potential risk for Stevens Johnson syndrome and toxic epidermal necrolysis and report any signs and symptoms associated with these events to their healthcare provider for evaluation.
- Seizures
- Inform patients of the risk of seizures and report any seizure while taking THALOMID.
- Tumor Lysis Syndrome
- Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation.
- Contraceptive Risks
- Inform patients that some contraceptive methods may pose a higher risk of adverse effects or may be medically contraindicated in some patients treated with THALOMID.
- Hypersensitivity
- Inform patients of the potential for a hypersensitivity reaction to THALOMID if they have had such a reaction in the past to Revlimid.
# Precautions with Alcohol
- Alcohol-Thalidomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- THALOMID®[20]
# Look-Alike Drug Names
- Thalomid® — thiamine®[21]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Fetal_thalidomide_syndrome | |
ac6810a1cc951d920262c3c0f64dcf5d60f15938 | wikidoc | Fiber laser | Fiber laser
A fiber laser or fibre laser is a laser in which the active gain medium is an optical fiber doped with rare-earth elements such as erbium, ytterbium, neodymium, dysprosium, praseodymium, and thulium. They are related to doped fiber amplifiers, which provide light amplification without lasing. Fiber nonlinearities, such as stimulated Raman scattering or four-wave mixing can also provide gain and thus serve as gain media for a fiber laser.
# Applications
Applications of fiber lasers include material processing, telecommunications, spectroscopy, and medicine.
The advantage of the fiber laser is that the light is already coupled into the fiber and can be easily delivered to a movable focusing element.
Such a coupling is important for laser cutting or laser welding or laser folding of metals and polymers.
# Design and manufacturing of fiber lasers
Unlike most other types of lasers, the laser cavity in fiber lasers is constructed monolithically by fusion splicing the different types of fibers; most notably fiber Bragg gratings replace here conventional dielectric mirrors to provide optical feedback. To pump fiber lasers, semiconductor laser diodes or other fiber lasers are used almost exclusively. Fiber lasers can have active regions several kilometers long, and can provide very high optical gain. They can support kilowatt levels of continuous output power because the fiber's high surface area to volume ratio which allows efficient cooling. The fiber waveguiding properties reduce or remove completely thermal distortion of the optical path thus resulting in typically diffraction-limited high-quality optical beam. Fiber lasers are also compact compared to rod or gas lasers of comparable power, as the fiber can be bent to small diameters and coiled. Other advantages include high vibrational stability, extended lifetime and maintenance-free turnkey operation.
## Double-clad fibers
Many high-power fiber lasers are based on double-clad fiber. The gain medium forms the core of the fiber, which is surrounded by two layers of cladding. The lasing mode propagates in the core, while a multimode pump beam propagates in the inner cladding layer. The outer cladding keeps this pump light confined. This arrangement allows the core to be pumped with a much higher power beam than could otherwise be made to propagate in it, and allows the conversion of pump light with relatively low brightness into a much higher-brightness signal. As a result, fiber lasers and amplifiers are occasionally referred to as "brightness converters."
There is an important question about the shape of the double-clad fiber; a fiber with circular symmetry seems to be the worst possible design
. The design should allow the core to be small enough to support only a few (or even one) modes. It should provide sufficient cladding to confine the core and optical pump section over a relatively short piece of the fiber.
## Power scaling
Recent developments in fiber laser technology have led to a rapid and large rise in achieved diffraction-limited beam powers from diode-pumped solid-state lasers. Due to the introduction of large mode area (LMA) fibers as well as continuing advances in high power and high brightness diodes, continuous-wave single-transverse-mode powers from Yb-doped fiber lasers have increased from 100 W in 2001 to >1 kW.
Previously unattainable powers can now be achieved with commercially available off-the-shelf fibers and components. As a result, fiber laser technology is expected to have a profound effect on a broad variety of industrial applications. This white paper describes the technology in greater detail: "KW-power fiber lasers with single transverse mode output".
# Fiber disk lasers
Another type of fiber laser is the fiber disk laser. In such, the pump is not confined within the cladding of the fiber (as in the double-clad fiber), but pump light is delivered across the core multiple times because the core is coiled on itself like a rope. This configuration is suitable for power scaling in which many pump sources are used around the periphery of the coil. | Fiber laser
Template:Copyedit
A fiber laser or fibre laser is a laser in which the active gain medium is an optical fiber doped with rare-earth elements such as erbium, ytterbium, neodymium, dysprosium, praseodymium, and thulium. They are related to doped fiber amplifiers, which provide light amplification without lasing. Fiber nonlinearities, such as stimulated Raman scattering or four-wave mixing can also provide gain and thus serve as gain media for a fiber laser.
# Applications
Applications of fiber lasers include material processing, telecommunications, spectroscopy, and medicine.
The advantage of the fiber laser is that the light is already coupled into the fiber and can be easily delivered to a movable focusing element.
Such a coupling is important for laser cutting or laser welding or laser folding of metals and polymers.
# Design and manufacturing of fiber lasers
Unlike most other types of lasers, the laser cavity in fiber lasers is constructed monolithically by fusion splicing the different types of fibers; most notably fiber Bragg gratings replace here conventional dielectric mirrors to provide optical feedback. To pump fiber lasers, semiconductor laser diodes or other fiber lasers are used almost exclusively. Fiber lasers can have active regions several kilometers long, and can provide very high optical gain. They can support kilowatt levels of continuous output power because the fiber's high surface area to volume ratio which allows efficient cooling. The fiber waveguiding properties reduce or remove completely thermal distortion of the optical path thus resulting in typically diffraction-limited high-quality optical beam. Fiber lasers are also compact compared to rod or gas lasers of comparable power, as the fiber can be bent to small diameters and coiled. Other advantages include high vibrational stability, extended lifetime and maintenance-free turnkey operation.
## Double-clad fibers
Many high-power fiber lasers are based on double-clad fiber. The gain medium forms the core of the fiber, which is surrounded by two layers of cladding. The lasing mode propagates in the core, while a multimode pump beam propagates in the inner cladding layer. The outer cladding keeps this pump light confined. This arrangement allows the core to be pumped with a much higher power beam than could otherwise be made to propagate in it, and allows the conversion of pump light with relatively low brightness into a much higher-brightness signal. As a result, fiber lasers and amplifiers are occasionally referred to as "brightness converters."
There is an important question about the shape of the double-clad fiber; a fiber with circular symmetry seems to be the worst possible design[1][2][3][4][5]
[6]. The design should allow the core to be small enough to support only a few (or even one) modes. It should provide sufficient cladding to confine the core and optical pump section over a relatively short piece of the fiber.
## Power scaling
Recent developments in fiber laser technology have led to a rapid and large rise in achieved diffraction-limited beam powers from diode-pumped solid-state lasers. Due to the introduction of large mode area (LMA) fibers as well as continuing advances in high power and high brightness diodes, continuous-wave single-transverse-mode powers from Yb-doped fiber lasers have increased from 100 W in 2001 to >1 kW.
Previously unattainable powers can now be achieved with commercially available off-the-shelf fibers and components. As a result, fiber laser technology is expected to have a profound effect on a broad variety of industrial applications. This white paper describes the technology in greater detail: "KW-power fiber lasers with single transverse mode output".
# Fiber disk lasers
Another type of fiber laser is the fiber disk laser. In such, the pump is not confined within the cladding of the fiber (as in the double-clad fiber), but pump light is delivered across the core multiple times because the core is coiled on itself like a rope. This configuration is suitable for power scaling in which many pump sources are used around the periphery of the coil. [7][8][9][10] | https://www.wikidoc.org/index.php/Fiber_laser | |
e944addd2038cbc0971d3ab847936a8fe78858a8 | wikidoc | Fibrillarin | Fibrillarin
rRNA 2'-O-methyltransferase fibrillarin is an enzyme that in humans is encoded by the FBL gene.
# Function
This gene product is a component of a nucleolar small nuclear ribonucleoprotein (snRNP) particle thought to participate in the first step in processing pre-ribosomal (r)RNA. It is associated with the U3, U8, and U13 small nucleolar RNAs and is located in the dense fibrillar component (DFC) of the nucleolus. The encoded protein contains an N-terminal repetitive domain that is rich in glycine and arginine residues, like fibrillarins in other species. Its central region resembles an RNA-binding domain and contains an RNP consensus sequence. Antisera from approximately 8% of humans with the autoimmune disease scleroderma recognize fibrillarin.
Fibrillarin is a component of several ribonucleoproteins including a nucleolar small nuclear ribonucleoprotein (SnRNP) and one of the two classes of small nucleolar ribonucleoproteins (snoRNPs). SnRNAs function in RNA splicing while snoRNPs function in ribosomal RNA processing.
Fibrillarin is associated with U3, U8 and U13 small nuclear RNAs in mammals and is similar to the yeast NOP1 protein. Fibrillarin has a well conserved sequence of around 320 amino acids, and contains 3 domains, an N-terminal Gly/Arg-rich region; a central domain resembling other RNA-binding proteins and containing an RNP-2-like consensus sequence; and a C-terminal alpha-helical domain. An evolutionarily related pre-rRNA processing protein, which lacks the Gly/Arg-rich domain, has been found in various archaea.
A study by Schultz et al. indicated that the K-turn binding 15.5-kDa protein (called Snu13 in yeast) interacts with spliceosome proteins hPRP31, hPRP3, hPRP4, CYPH and the small nucleolar ribonucleoproteins NOP56, NOP58, and fibrillarin. The 15.5-kDa protein has sequence similarity to other RNA-binding proteins such as ribosomal proteins S12, L7a, and L30 and the snoRNP protein NHP2. The U4/U6 snRNP contains 15.5-kDa protein. The 15.5-kDa protein also exists in a ribonucleoprotein complex that binds the U3 box B/C motif. The 15.5-kDa protein also exists as one of the four core proteins of the C/D small nucleolar ribonucleoprotein that mediates methylation of pre-ribosomal RNAs.
Structural evidence supporting the idea that fibrillarin is the snoRNA methyltransferase has been reviewed.
# Interactions
Fibrillarin has been shown to interact with DDX5 and SMN1. | Fibrillarin
rRNA 2'-O-methyltransferase fibrillarin is an enzyme that in humans is encoded by the FBL gene.[1][2][3]
# Function
This gene product is a component of a nucleolar small nuclear ribonucleoprotein (snRNP) particle thought to participate in the first step in processing pre-ribosomal (r)RNA. It is associated with the U3, U8, and U13 small nucleolar RNAs and is located in the dense fibrillar component (DFC) of the nucleolus. The encoded protein contains an N-terminal repetitive domain that is rich in glycine and arginine residues, like fibrillarins in other species. Its central region resembles an RNA-binding domain and contains an RNP consensus sequence. Antisera from approximately 8% of humans with the autoimmune disease scleroderma recognize fibrillarin.[3]
Fibrillarin is a component of several ribonucleoproteins including a nucleolar small nuclear ribonucleoprotein (SnRNP) and one of the two classes of small nucleolar ribonucleoproteins (snoRNPs). SnRNAs function in RNA splicing while snoRNPs function in ribosomal RNA processing.
Fibrillarin is associated with U3, U8 and U13 small nuclear RNAs in mammals and is similar to the yeast NOP1 protein. Fibrillarin has a well conserved sequence of around 320 amino acids, and contains 3 domains, an N-terminal Gly/Arg-rich region; a central domain resembling other RNA-binding proteins and containing an RNP-2-like consensus sequence; and a C-terminal alpha-helical domain. An evolutionarily related pre-rRNA processing protein, which lacks the Gly/Arg-rich domain, has been found in various archaea.
A study by Schultz et al. indicated that the K-turn binding 15.5-kDa protein (called Snu13 in yeast) interacts with spliceosome proteins hPRP31, hPRP3, hPRP4, CYPH and the small nucleolar ribonucleoproteins NOP56, NOP58, and fibrillarin. The 15.5-kDa protein has sequence similarity to other RNA-binding proteins such as ribosomal proteins S12, L7a, and L30 and the snoRNP protein NHP2. The U4/U6 snRNP contains 15.5-kDa protein.[4] The 15.5-kDa protein also exists in a ribonucleoprotein complex that binds the U3 box B/C motif. The 15.5-kDa protein also exists as one of the four core proteins of the C/D small nucleolar ribonucleoprotein that mediates methylation of pre-ribosomal RNAs.
Structural evidence supporting the idea that fibrillarin is the snoRNA methyltransferase has been reviewed.[5]
# Interactions
Fibrillarin has been shown to interact with DDX5[6] and SMN1.[7] | https://www.wikidoc.org/index.php/Fibrillarin | |
19d438288f2895f1d73853e2dc3af7beff1689ac | wikidoc | Fibrillin 1 | Fibrillin 1
Fibrillin-1 is a protein that in humans is encoded by the FBN1 gene, located on chromosome 15.
FBN1 is a 230-kb gene with 65 coding exons that encode a 2,871-amino-acid long proprotein called profibrillin which is proteolytically cleaved near its C-terminus by the enzyme furin convertase to give fibrillin-1, a member of the fibrillin family, and the 140-amino-acid long protein hormone asprosin.
Fibrillin-1 is a large, extracellular matrix glycoprotein that serves as a structural component of 10-12 nm calcium-binding microfibrils. These microfibrils provide force bearing structural support in elastic and nonelastic connective tissue throughout the body.
# Structure
The sequence of fibrillin-1 includes 47 six-cysteine EGF-like domains, 7 eight-cysteine domains homologous with latent TGF-beta binding protein, and a proline-rich region.
# Fetal cardiovascular development
The FBN-1 gene is involved in a variety of embryonic developmental programs. The microfibrils that are made from fibrillin-1 contribute to both elastic and non-elastic structures. The formation of the elastic fibers in the heart valves and the aorta require the involvement of both FBN-1 and FBN-2. It has been shown that both FBN-1 and FBN-2, along with the other components of elastic fibers, are expressed in the embryonic semilunar valves as early as 4 weeks of gestation. These molecules interact to form the elastic fibers in the ventricularis layer of the semilunar valves. Fibrillin-1 and fibrillin-2 are also crucial for the development of elastic fibers in the aorta. While expression of fibrillin-2 decreases significantly after fetal development, the expression of fibrillin-1 continues into adulthood. This supports the idea that fibrilin-2 dictates the development of early elastic fibers, while fibrillin-1 provides the structural support of mature elastic fibers.
When mutations in the FBN-1 or FBN-2 genes occur, significant deformations can result from the damage to the extracellular matrix. Marfan Syndrome is a congenital disease that arises from a mutation in the FBN-1 gene. This leads to the malformation and subsequent weakening of the microfibrils in the patient’s body, including the structures of the cardiovascular system. The weakened elastic fibers will result in an impaired durability and distensibility in the heart valves and aorta. This provides the explanation for the aortic aneurysms and prolapsed valves that are commonly associated with Marfan Syndrome.
# Marfan Syndrome
Marfan syndrome (MFS) is an autosomal dominant disorder that affects the connective tissues of bodily systems such as the eyes, cardiovascular system, skeletal system, skin, pulmonary system and the dura. MFS affects approximately 1 in 5,000 individuals. MFS is not an easily diagnosed pathology with a scoring system called the Ghent nosology table used, rather than a single molecule test. To diagnose MFS individuals that have no previous family history, two criteria must be met. Firstly, two different major organ systems must be affected, and secondly, a third organ system must be involved.
MFS usually occurs from ‘’De Novo’’mutations and results in the individual phenotypically displaying long and thin limbs and extremities, curved spines usually resulting in thoracic scoliosis, hyperflexible joints, pectus excavatum, retinal detachment and sunken chests. ‘’De Novo’’ mutations resulting in severe MFS have high expected mortality rates for neonates. Classical MFS symptoms usually become noticeable during puberty or later in life; rarely does it develop in the earlier stages of life. The most common skin manifestation of MFS is striae distensae where bands of skin are coloured red, purple and then white. The skin epidermis is thin and flattened, and the upper protective skin layer is decreased in thickness. This manifestation is characterised histologically by straight, thin collagen bundles arranged in a parallel to the skin and the elastic fibres. Elastic fibres are denser in the upper dermis, and beneath this zone there is a localised absence of the elastic fibres. Between the borders of the striae and skin, there are curled, broken, reticular elastic fibres sometimes present. These symptoms are responsible for cobweblike skin appearances in patients with MFS.
Management of MFS is to operate on the individual through open heart surgery. Management of MFS includes standard implications such as counselling on lifestyle to reduce and restrict physical activity, endo prophylaxis, serial imaging the aorta, ß-blocker medication for aortic protection and prophylactic replacement of the aortic root. In MFS affected adults, it is recommended they reduce emotional and physical stress and switch from high impact sports such as martial arts, football, basketball etc to isotonic, low impact exercise such as swimming, biking or jogging where the pulse rate lies approximately at <110 beats per minute. Children should also follow similar guidelines to ensure correct management of MS.
MFS is caused by a mutation in the ‘’FBN1’’ gene positioned at chromosome 15q21.1 resulting in a deconstructed form of Fibrillin-1. Fibrillin-1 is a 350-kDa, 2871-amino acid cystine-rich glycoprotein that is responsible for the amalgamation of elastin into the elastic fibres of the connective tissue in the extracellular matrix (ECM).
The fragility of the connective tissue usually results in aortic aneurysms due to the wall having the inability to withstand intraluminal pressure. Defects in fibrillin-1 results in elevated TGF-ß levels that directly correlate to MFS.
# Role of TGF-ß in the expressions of Marfan Syndrome
TGF-ß is a paracrine regulatory protein responsible for embryonic processing, cell growth, apoptosis induction, and enhances collagen production and ECM remodelling. In a non-MFS affected individual, the TGF-ß protein is secreted from the cell to stimulate PAI-1 production and Smad2 phosphorylation. The TGF-ß protein binds with latency associated protein (LAP) at the N-terminal propertied and one of three latent TGF-ß binding proteins (LTBP1, 3 or 4) to form a small latent complex (SLC). SLC then binds extracellularly to latent TGF-ß binding protein (LTBP) forming a large latent complex (LLC), which includes an active cytokine. The LLC attaches to the microfibrils of Fibrillin-1 via LTBP, allowing the preservation of inactive TGF-ß . TGF-ß can only be activated through a series of regulated mechanisms; maintaining correct functioning in embryonic development. Mutations in Fibrillin-1 cause elevated levels of TGF-ß in the EC space due to LLC being unable to attach to the microfibrils and latent forms not being produced. TGF-ß forms a complex with its dimer receptors, to initiate a phosphorylation cascade. This phosphorylation can cause failures such as an aortic aneurysm and prolapsed valves.
Clinical symptoms of MFS such as aortic root dilation, pulmonary emphysema, atrioventricular valve changes and skeletal muscle myopathy are induced by altered TGF-ß activation and signalling.
Aortic specific symptoms are closely related to excessive TGF-ß signalling in the aortic root wall. TGF-ß antagonism via systemic administration of TGF-ß neutralising antibody (NAb) averted the development of aortic pathologies associated with MDS, more specifically changes in the aortic wall and progressive aortic dilation. Antagonism of TGF-ß also further reduced MFS symptoms where it helped muscle regeneration, architecture and strength, pulmonary alveolar septation and mitral valve morphology.
LLC that fails to be removed from the ECM is more vulnerable to be activated in a protease-dependent or independent manner. MMP2 and MMP9 are select TGF-ß activators and ligands and are found in higher levels in the tissues of patients affected with MFS. TGF-ß in its complex and free-form can leach into the circulation due to the mutated ECM sequestration and increased LLC activation.
# Mutations in the ‘’FBN1’’ gene
‘’FBN-1’’ is a gene approximately 200kb and is made up of a large coding sequence divided into 65 exons located on chromosome 15. This gene encodes for Fibrillin-1 protein. Fibrillin-1 is a large cysteine rich-glycoprotein approximately 350 kDa mainly composed of tandemly repeating domains of epidermal growth factor (ECF)-like modules. These domains are homologous to calcium binding epidermal growth factor module (cbEGF-like motifs) and of distinct 8-cysteine modules to make up elastic and non-elastic tissue. These elastic and non-elastic tissues are microfibrillar bundles, heteropolymers of both Fibrillin-1 and fibrillin-2. Elastogenesis is a biological process where microfibrils and elastic fibres are self-assembled via organised deposition by several macromolecules. Polymerised fibrillins can be characterised by their ‘beads-on-a-string’ microfibril structure; giving rise to a microfibril lattice via lateral communication of the individual polymers and structural components.
Fibrillin-1 mutations are the main mutated protein causing MFS. This mutation usually interferes with the assembly of microfibrils resulting in a dominant-negative mechanism
Mutations can include:
- Missense mutations caused by single base substitutions such as cysteine or those associated with calcium binding in Fibrillin-1.
- Premature terminations caused by nonsense mutations or frameshifts.
- Mutations within the exonic splice site allowing for insertions or deletions due to creations of cryptic splice sites.
- Intronic splice site base changes leading to alternative splicing and in-frame exon skipping or deletion.
The combination of the four types of mutations results in Fibrillin-1 being expressed incorrectly. There is no correlation between phenotype and genotype at a molecular level
The mutations of the FBN-1 gene at six chromosomal loci, TAAD1 at 5q13-14, FAA1 at 11q23-24, TAAD2 at 3p24-25, TAAD3 at 15q24-26, TAAD4 at 10q23-24 and MYH11 at 16p12-13 are known to be triggers of MFS. These loci tend to have genes that are involved in vascular function. The MYH11 gene is responsible for the smooth muscle myosin heavy chain and ACTA2 at TAAD4 loci encodes for smooth muscle alpha-actin.
A nonsynonymous amino acid change affecting conserved cysteine of the CaB-EGF-like domain encoded by exon 13 of the FBN1 gene can cause MFS to develop. Higher frequency and severity of MFS occurs when there are incorrect substitutions at the C1-C2 or C3-C4 disulphide bonds, therefore, correct cysteine localisation and disulphide bonding at these loci are critical to structural integrity. Mutations in the FBN1 gene resulting in incorrect bonding at the C5-C6 disulphide bond generally results in MFS of lesser severity. Concentrated mutations of the CaB-EGF domain along the FBN1 polypeptide affects MFS severity phenotype. Localised substitution mutations of the cysteine substitution at C538P on exon 13, C570R on exon 14 or C587Y on exon 15 result in MFS symptoms related to the eyes, specifically ectopia lentis. Microfibrils themselves can support the hemodynamic load in the circulatory systems of invertebrates and lesser vertebrates. Elastin and the development of the ECM system integrated with surrounding VSMC are needed for higher vertebrates to function correctly. Fibrillin-1 is not essential in the stabilisation of the elastic unit but instead in the assembly of the microfibril. Up-regulation of activin A works in conjunction with Fibrillin-1 and TGF-ß signalling molecules to produce a fibroproliferative response. CYR61 induction also functions to support cell adhesion and regulate matrix remodelling and is fundamental in the formation of large vessels and their integrity.
# Clinical significance
Mutations in the FBN1 gene are associated with Marfan syndrome and its variant Marfanoid–progeroid–lipodystrophy syndrome, autosomal dominant Weill-Marchesani syndrome, isolated ectopia lentis, MASS phenotype, and Shprintzen-Goldberg syndrome.
Mutations in FBN1 and FBN2 are associated with adolescent idiopathic scoliosis .
Clinical symptoms of MFS such as aortic root dilation, pulmonary emphysema, atrioventricular valve changes and skeletal muscle myopathy are induced by altered TGF-ß activation and signalling. Aortic specific symptoms are closely related to excessive TGF-ß signalling in the aortic root wall. TGF-ß antagonism via systemic administration of TGF-ß neutralising antibody (NAb) averted the development of aortic pathologies associated with MDS, more specifically changes in the aortic wall and progressive aortic dilation. Antagonism of TGF-ß also further reduced MFS symptoms where it helped muscle regeneration, architecture and strength, pulmonary alveolar septation and mitral valve morphology.
## Losartan
Losartan is an angiotensin II type 1 (AT1) receptor blocker known to antagonise TGF-ß signalling via inhibiting the expression and activation of TGF-ß. Losartan can work independently or with ß-blocker therapy to reduce rate of change in the aortic root diameter of MFS pathology. | Fibrillin 1
Fibrillin-1 is a protein that in humans is encoded by the FBN1 gene, located on chromosome 15.[1][2]
FBN1 is a 230-kb gene with 65 coding exons that encode a 2,871-amino-acid long proprotein called profibrillin which is proteolytically cleaved near its C-terminus by the enzyme furin convertase to give fibrillin-1, a member of the fibrillin family, and the 140-amino-acid long protein hormone asprosin.[3][4]
Fibrillin-1 is a large, extracellular matrix glycoprotein that serves as a structural component of 10-12 nm calcium-binding microfibrils. These microfibrils provide force bearing structural support in elastic and nonelastic connective tissue throughout the body.
# Structure
The sequence of fibrillin-1 includes 47 six-cysteine EGF-like domains, 7 eight-cysteine domains homologous with latent TGF-beta binding protein, and a proline-rich region.[5]
# Fetal cardiovascular development
The FBN-1 gene is involved in a variety of embryonic developmental programs. The microfibrils that are made from fibrillin-1 contribute to both elastic and non-elastic structures. The formation of the elastic fibers in the heart valves and the aorta require the involvement of both FBN-1 and FBN-2.[6] It has been shown that both FBN-1 and FBN-2, along with the other components of elastic fibers, are expressed in the embryonic semilunar valves as early as 4 weeks of gestation.[7] These molecules interact to form the elastic fibers in the ventricularis layer of the semilunar valves. Fibrillin-1 and fibrillin-2 are also crucial for the development of elastic fibers in the aorta. While expression of fibrillin-2 decreases significantly after fetal development, the expression of fibrillin-1 continues into adulthood. This supports the idea that fibrilin-2 dictates the development of early elastic fibers, while fibrillin-1 provides the structural support of mature elastic fibers.[7]
When mutations in the FBN-1 or FBN-2 genes occur, significant deformations can result from the damage to the extracellular matrix. Marfan Syndrome is a congenital disease that arises from a mutation in the FBN-1 gene. This leads to the malformation and subsequent weakening of the microfibrils in the patient’s body, including the structures of the cardiovascular system. The weakened elastic fibers will result in an impaired durability and distensibility in the heart valves and aorta. This provides the explanation for the aortic aneurysms and prolapsed valves that are commonly associated with Marfan Syndrome.[8]
# Marfan Syndrome
Marfan syndrome (MFS) is an autosomal dominant disorder that affects the connective tissues of bodily systems such as the eyes, cardiovascular system, skeletal system, skin, pulmonary system and the dura. MFS affects approximately 1 in 5,000 individuals.[9] MFS is not an easily diagnosed pathology with a scoring system called the Ghent nosology table used, rather than a single molecule test.[10] To diagnose MFS individuals that have no previous family history, two criteria must be met. Firstly, two different major organ systems must be affected, and secondly, a third organ system must be involved.[11]
MFS usually occurs from ‘’De Novo’’mutations and results in the individual phenotypically displaying long and thin limbs and extremities, curved spines usually resulting in thoracic scoliosis, hyperflexible joints, pectus excavatum, retinal detachment and sunken chests.[9] ‘’De Novo’’ mutations resulting in severe MFS have high expected mortality rates for neonates.[10] Classical MFS symptoms usually become noticeable during puberty or later in life; rarely does it develop in the earlier stages of life.[10] The most common skin manifestation of MFS is striae distensae where bands of skin are coloured red, purple and then white.[12] The skin epidermis is thin and flattened, and the upper protective skin layer is decreased in thickness.[12] This manifestation is characterised histologically by straight, thin collagen bundles arranged in a parallel to the skin and the elastic fibres.[12] Elastic fibres are denser in the upper dermis, and beneath this zone there is a localised absence of the elastic fibres. Between the borders of the striae and skin, there are curled, broken, reticular elastic fibres sometimes present.[13] These symptoms are responsible for cobweblike skin appearances in patients with MFS.[13]
Management of MFS is to operate on the individual through open heart surgery.[10] Management of MFS includes standard implications such as counselling on lifestyle to reduce and restrict physical activity, endo prophylaxis, serial imaging the aorta, ß-blocker medication for aortic protection and prophylactic replacement of the aortic root.[10] In MFS affected adults, it is recommended they reduce emotional and physical stress and switch from high impact sports such as martial arts, football, basketball etc to isotonic, low impact exercise such as swimming, biking or jogging where the pulse rate lies approximately at <110 beats per minute.[10] Children should also follow similar guidelines to ensure correct management of MS.[10]
MFS is caused by a mutation in the ‘’FBN1’’ gene positioned at chromosome 15q21.1 resulting in a deconstructed form of Fibrillin-1.[1] Fibrillin-1 is a 350-kDa, 2871-amino acid cystine-rich glycoprotein that is responsible for the amalgamation of elastin into the elastic fibres of the connective tissue in the extracellular matrix (ECM).[14][15]
The fragility of the connective tissue usually results in aortic aneurysms due to the wall having the inability to withstand intraluminal pressure.[16] Defects in fibrillin-1 results in elevated TGF-ß levels that directly correlate to MFS.[16]
# Role of TGF-ß in the expressions of Marfan Syndrome
TGF-ß is a paracrine regulatory protein responsible for embryonic processing, cell growth, apoptosis induction, and enhances collagen production and ECM remodelling.[16] In a non-MFS affected individual, the TGF-ß protein is secreted from the cell to stimulate PAI-1 production and Smad2 phosphorylation.[13] The TGF-ß protein binds with latency associated protein (LAP) at the N-terminal propertied and one of three latent TGF-ß binding proteins (LTBP1, 3 or 4) to form a small latent complex (SLC).[17] SLC then binds extracellularly to latent TGF-ß binding protein (LTBP) forming a large latent complex (LLC), which includes an active cytokine.[18] The LLC attaches to the microfibrils of Fibrillin-1 via LTBP, allowing the preservation of inactive TGF-ß [6]. TGF-ß can only be activated through a series of regulated mechanisms; maintaining correct functioning in embryonic development.[16] Mutations in Fibrillin-1 cause elevated levels of TGF-ß in the EC space due to LLC being unable to attach to the microfibrils and latent forms not being produced.[17] TGF-ß forms a complex with its dimer receptors, to initiate a phosphorylation cascade.[19] This phosphorylation can cause failures such as an aortic aneurysm and prolapsed valves.[9]
Clinical symptoms of MFS such as aortic root dilation, pulmonary emphysema, atrioventricular valve changes and skeletal muscle myopathy are induced by altered TGF-ß activation and signalling.[18]
Aortic specific symptoms are closely related to excessive TGF-ß signalling in the aortic root wall.[18] TGF-ß antagonism via systemic administration of TGF-ß neutralising antibody (NAb) averted the development of aortic pathologies associated with MDS, more specifically changes in the aortic wall and progressive aortic dilation.[18] Antagonism of TGF-ß also further reduced MFS symptoms where it helped muscle regeneration, architecture and strength, pulmonary alveolar septation and mitral valve morphology.[18]
LLC that fails to be removed from the ECM is more vulnerable to be activated in a protease-dependent or independent manner.[18] MMP2 and MMP9 are select TGF-ß activators and ligands and are found in higher levels in the tissues of patients affected with MFS. TGF-ß in its complex and free-form can leach into the circulation due to the mutated ECM sequestration and increased LLC activation.[18]
# Mutations in the ‘’FBN1’’ gene
‘’FBN-1’’ is a gene approximately 200kb and is made up of a large coding sequence divided into 65 exons located on chromosome 15. This gene encodes for Fibrillin-1 protein.[20] Fibrillin-1 is a large cysteine rich-glycoprotein approximately 350 kDa mainly composed of tandemly repeating domains of epidermal growth factor (ECF)-like modules. These domains are homologous to calcium binding epidermal growth factor module (cbEGF-like motifs) and of distinct 8-cysteine modules to make up elastic and non-elastic tissue.[10][12] These elastic and non-elastic tissues are microfibrillar bundles, heteropolymers of both Fibrillin-1 and fibrillin-2.[21] Elastogenesis is a biological process where microfibrils and elastic fibres are self-assembled via organised deposition by several macromolecules.[13] Polymerised fibrillins can be characterised by their ‘beads-on-a-string’ microfibril structure; giving rise to a microfibril lattice via lateral communication of the individual polymers and structural components.[13]
Fibrillin-1 mutations are the main mutated protein causing MFS. This mutation usually interferes with the assembly of microfibrils resulting in a dominant-negative mechanism [10][22]
Mutations can include:
- Missense mutations caused by single base substitutions such as cysteine or those associated with calcium binding in Fibrillin-1.[20]
- Premature terminations caused by nonsense mutations or frameshifts.[20]
- Mutations within the exonic splice site allowing for insertions or deletions due to creations of cryptic splice sites.[20]
- Intronic splice site base changes leading to alternative splicing and in-frame exon skipping or deletion.[20]
The combination of the four types of mutations results in Fibrillin-1 being expressed incorrectly. There is no correlation between phenotype and genotype at a molecular level [20]
The mutations of the FBN-1 gene at six chromosomal loci, TAAD1 at 5q13-14, FAA1 at 11q23-24, TAAD2 at 3p24-25, TAAD3 at 15q24-26, TAAD4 at 10q23-24 and MYH11 at 16p12-13 are known to be triggers of MFS.[23] These loci tend to have genes that are involved in vascular function.[23] The MYH11 gene is responsible for the smooth muscle myosin heavy chain and ACTA2 at TAAD4 loci encodes for smooth muscle alpha-actin.[23]
A nonsynonymous amino acid change affecting conserved cysteine of the CaB-EGF-like domain encoded by exon 13 of the FBN1 gene can cause MFS to develop.[13] Higher frequency and severity of MFS occurs when there are incorrect substitutions at the C1-C2 or C3-C4 disulphide bonds, therefore, correct cysteine localisation and disulphide bonding at these loci are critical to structural integrity.[13] Mutations in the FBN1 gene resulting in incorrect bonding at the C5-C6 disulphide bond generally results in MFS of lesser severity.[13] Concentrated mutations of the CaB-EGF domain along the FBN1 polypeptide affects MFS severity phenotype.[13] Localised substitution mutations of the cysteine substitution at C538P on exon 13, C570R on exon 14 or C587Y on exon 15 result in MFS symptoms related to the eyes, specifically ectopia lentis.[13] Microfibrils themselves can support the hemodynamic load in the circulatory systems of invertebrates and lesser vertebrates.[13] Elastin and the development of the ECM system integrated with surrounding VSMC are needed for higher vertebrates to function correctly.[13] Fibrillin-1 is not essential in the stabilisation of the elastic unit but instead in the assembly of the microfibril. Up-regulation of activin A works in conjunction with Fibrillin-1 and TGF-ß signalling molecules to produce a fibroproliferative response.[13] CYR61 induction also functions to support cell adhesion and regulate matrix remodelling and is fundamental in the formation of large vessels and their integrity.[13]
# Clinical significance
Mutations in the FBN1 gene are associated with Marfan syndrome and its variant Marfanoid–progeroid–lipodystrophy syndrome, autosomal dominant Weill-Marchesani syndrome, isolated ectopia lentis, MASS phenotype, and Shprintzen-Goldberg syndrome.[24][25]
Mutations in FBN1 and FBN2 are associated with adolescent idiopathic scoliosis .[26]
Clinical symptoms of MFS such as aortic root dilation, pulmonary emphysema, atrioventricular valve changes and skeletal muscle myopathy are induced by altered TGF-ß activation and signalling.[18] Aortic specific symptoms are closely related to excessive TGF-ß signalling in the aortic root wall.[18] TGF-ß antagonism via systemic administration of TGF-ß neutralising antibody (NAb) averted the development of aortic pathologies associated with MDS, more specifically changes in the aortic wall and progressive aortic dilation.[18] Antagonism of TGF-ß also further reduced MFS symptoms where it helped muscle regeneration, architecture and strength, pulmonary alveolar septation and mitral valve morphology.[18]
## Losartan
Losartan is an angiotensin II type 1 (AT1) receptor blocker known to antagonise TGF-ß signalling via inhibiting the expression and activation of TGF-ß.[18] Losartan can work independently or with ß-blocker therapy to reduce rate of change in the aortic root diameter of MFS pathology.[18] | https://www.wikidoc.org/index.php/Fibrillin_1 | |
47e1760dcad95e1e585dae6774cd6c73e614b03d | wikidoc | Fibrocystin | Fibrocystin
Fibrocystin is a large, receptor-like protein that is thought to be involved in the tubulogenesis and/or maintenance of duct-lumen architecture of epithelium.
FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2), suggesting that these two proteins may function in a common molecular pathway.
# Pathology
Mutations of its encoding gene (chromosomal locus 6p12.2) can cause autosomal recessive polycystic kidney disease. | Fibrocystin
Fibrocystin is a large, receptor-like protein that is thought to be involved in the tubulogenesis and/or maintenance of duct-lumen architecture of epithelium.[1]
FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2), suggesting that these two proteins may function in a common molecular pathway.
# Pathology
Mutations of its encoding gene (chromosomal locus 6p12.2) can cause autosomal recessive polycystic kidney disease. | https://www.wikidoc.org/index.php/Fibrocystin | |
6128898fcfd4e5e05e7b6300f8597f4f259e8fd6 | wikidoc | Fibronectin | Fibronectin
Fibronectin is a high-molecular weight (~440kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collagen, fibrin, and heparan sulfate proteoglycans (e.g. syndecans).
Fibronectin exists as a protein dimer, consisting of two nearly identical monomers linked by a pair of disulfide bonds. The fibronectin protein is produced from a single gene, but alternative splicing of its pre-mRNA leads to the creation of several isoforms.
Two types of fibronectin are present in vertebrates:
- soluble plasma fibronectin (formerly called "cold-insoluble globulin", or CIg) is a major protein component of blood plasma (300 μg/ml) and is produced in the liver by hepatocytes.
- insoluble cellular fibronectin is a major component of the extracellular matrix. It is secreted by various cells, primarily fibroblasts, as a soluble protein dimer and is then assembled into an insoluble matrix in a complex cell-mediated process.
Fibronectin plays a major role in cell adhesion, growth, migration, and differentiation, and it is important for processes such as wound healing and embryonic development. Altered fibronectin expression, degradation, and organization has been associated with a number of pathologies, including cancer and fibrosis.
# Structure
Fibronectin exists as a protein dimer, consisting of two nearly identical polypeptide chains linked by a pair of C-terminal disulfide bonds. Each fibronectin subunit has a molecular weight of 230–250 kDa and contains three types of modules: type I, II, and III. All three modules are composed of two anti-parallel β-sheets resulting in a Beta-sandwich; however, type I and type II are stabilized by intra-chain disulfide bonds, while type III modules do not contain any disulfide bonds. The absence of disulfide bonds in type III modules allows them to partially unfold under applied force.
Three regions of variable splicing occur along the length of the fibronectin protomer. One or both of the "extra" type III modules (EIIIA and EIIIB) may be present in cellular fibronectin, but they are never present in plasma fibronectin. A "variable" V-region exists between III14–15 (the 14th and 15th type III module). The V-region structure is different from the type I, II, and III modules, and its presence and length may vary. The V-region contains the binding site for α4β1 integrins. It is present in most cellular fibronectin, but only one of the two subunits in a plasma fibronectin dimer contains a V-region sequence.
The modules are arranged into several functional and protein-binding domains along the length of a fibronectin monomer. There are four fibronectin-binding domains, allowing fibronectin to associate with other fibronectin molecules. One of these fibronectin-binding domains, I1–5, is referred to as the "assembly domain", and it is required for the initiation of fibronectin matrix assembly. Modules III9–10 correspond to the "cell-binding domain" of fibronectin. The RGD sequence (Arg–Gly–Asp) is located in III10 and is the site of cell attachment via α5β1 and αVβ3 integrins on the cell surface. The "synergy site" is in III9 and has a role in modulating fibronectin's association with α5β1 integrins. Fibronectin also contains domains for fibrin-binding (I1–5, I10–12), collagen-binding (I6–9), fibulin-1-binding (III13–14), heparin-binding and syndecan-binding (III12–14).
# Function
Fibronectin has numerous functions that ensure the normal functioning of vertebrate organisms. It is involved in cell adhesion, growth, migration, and differentiation. Cellular fibronectin is assembled into the extracellular matrix, an insoluble network that separates and supports the organs and tissues of an organism.
Fibronectin plays a crucial role in wound healing. Along with fibrin, plasma fibronectin is deposited at the site of injury, forming a blood clot that stops bleeding and protects the underlying tissue. As repair of the injured tissue continues, fibroblasts and macrophages begin to remodel the area, degrading the proteins that form the provisional blood clot matrix and replacing them with a matrix that more resembles the normal, surrounding tissue. Fibroblasts secrete proteases, including matrix metalloproteinases, that digest the plasma fibronectin, and then the fibroblasts secrete cellular fibronectin and assemble it into an insoluble matrix. Fragmentation of fibronectin by proteases has been suggested to promote wound contraction, a critical step in wound healing. Fragmenting fibronectin further exposes its V-region, which contains the site for α4β1 integrin binding. These fragments of fibronectin are believed to enhance the binding of α4β1 integrin-expressing cells, allowing them to adhere to and forcefully contract the surrounding matrix.
Fibronectin is necessary for embryogenesis, and inactivating the gene for fibronectin results in early embryonic lethality. Fibronectin is important for guiding cell attachment and migration during embryonic development. In mammalian development, the absence of fibronectin leads to defects in mesodermal, neural tube, and vascular development. Similarly, the absence of a normal fibronectin matrix in developing amphibians causes defects in mesodermal patterning and inhibits gastrulation.
Fibronectin is also found in normal human saliva, which helps prevent colonization of the oral cavity and pharynx by potentially pathogenic bacteria.
# Matrix assembly
Cellular fibronectin is assembled into an insoluble fibrillar matrix in a complex cell-mediated process. Fibronectin matrix assembly begins when soluble, compact fibronectin dimers are secreted from cells, often fibroblasts. These soluble dimers bind to α5β1 integrin receptors on the cell surface and aid in clustering the integrins. The local concentration of integrin-bound fibronectin increases, allowing bound fibronectin molecules to more readily interact with one another. Short fibronectin fibrils then begin to form between adjacent cells. As matrix assembly proceeds, the soluble fibrils are converted into larger insoluble fibrils that comprise the extracellular matrix.
Fibronectin’s shift from soluble to insoluble fibrils proceeds when cryptic fibronectin-binding sites are exposed along the length of a bound fibronectin molecule. Cells are believed to stretch fibronectin by pulling on their fibronectin-bound integrin receptors. This force partially unfolds the fibronectin ligand, unmasking cryptic fibronectin-binding sites and allowing nearby fibronectin molecules to associate. This fibronectin-fibronectin interaction enables the soluble, cell-associated fibrils to branch and stabilize into an insoluble fibronectin matrix.
A transmembrane protein, CD93, has been shown to be essential for fibronectin matrix assembly (fibrillogenesis) in human dermal blood endothelial cells. As a consequence, knockdown of CD93 in these cells resulted in the disruption of the fibronectin fibrillogenesis. Moreover, the CD93 knockout mice retinas displayed disrupted fibronectin matrix at the retinal sprouting front.
# Role in cancer
Several morphological changes has been observed in tumors and tumor-derived cell lines that have been attributed to decreased fibronectin expression, increased fibronectin degradation, and/or decreased expression of fibronectin-binding receptors, such as α5β1 integrins.
Fibronectin has been implicated in carcinoma development. In lung carcinoma, fibronectin expression is increased especially in non-small cell lung carcinoma. The adhesion of lung carcinoma cells to fibronectin enhances tumorigenicity and confers resistance to apoptosis-inducing chemotherapeutic agents. Fibronectin has been shown to stimulate the gonadal steroids that interact with vertebrate androgen receptors, which are capable of controlling the expression of cyclin D and related genes involved in cell cycle control. These observations suggest that fibronectin may promote lung tumor growth/survival and resistance to therapy, and it could represent a novel target for the development of new anticancer drugs.
Fibronectin 1 acts as a potential biomarker for radioresistance.
FN1-FGFR1 fusion is frequent in phosphaturic mesenchymal tumours.
# Role in wound healing
Fibronectin has profound effects on wound healing, including the formation of proper substratum for migration and growth of cells during the development and organization of granulation tissue, as well as remodeling and resynthesis of the connective tissue matrix. The biological significance of fibronectin in vivo was studied during the mechanism of wound healing. Plasma fibronectin levels are decreased in acute inflammation or following surgical trauma and in patients with disseminated intravascular coagulation.
Fibronectin is located in the extracellular matrix of embryonic and adult tissues (not in the basement membranes of the adult tissues), but may be more widely distributed in inflammatory lesions. During blood clotting, the fibronectin remains associated with the clot, covalently cross-linked to fibrin with the help of Factor XIII (fibrin-stabilizing factor). Fibroblasts play a major role in wound healing by adhering to fibrin. Fibroblast adhesion to fibrin requires fibronectin, and was strongest when the fibronectin was cross-linked to the fibrin. Patients with Factor XIII deficiencies display impairment in wound healing as fibroblasts don't grow well in fibrin lacking Factor XIII. Fibronectin promotes particle phagocytosis by both macrophages and fibroblasts. Collagen deposition at the wound site by fibroblasts takes place with the help of fibronectin. Fibronectin was also observed to be closely associated with the newly deposited collagen fibrils. Based on the size and histological staining characteristics of the fibrils, it is likely that at least in part they are composed of type III collagen (reticulin). An in vitro study with native collagen demonstrated that fibronectin binds to type III collagen rather than other types.
# In vivo vs in vitro
Plasma fibronectin, which is synthesized by hepatocytes, and fibronectin synthesized by cultured fibroblasts are similar but not identical; immunological, structural, and functional differences have been reported. It is likely that these differences result from differential processing of a single nascent mRNA. Nevertheless, plasma fibronectin can be insolubilized into the tissue extracellular matrix in vitro and in vivo. Both plasma and cellular fibronectins in the matrix form high molecular weight, disulfide-bonded multimers. The mechanism of formation of these multimers is not presently known. Plasma fibronectin has been shown to contain two free sulfhydryls per subunit (X), and cellular fibronectin has been shown to contain at least one. These sulfhydryls probably are buried within the tertiary structure, because sulfhydryls are exposed when the fibronectin is denatured. Such denaturation results in the oxidation of free sulfhydryls and formation of disulfide-bonded fibronectin multimers. This has led to speculation that the free sulfhydryls may be involved in formation of disulfide-bonded fibronectin multimers in the extracellular matrix. Consistent with this, sulfhydryl modification of fibronectin with N-ethylmaleimide prevents binding to cell layers. Tryptic cleavage patterns of multimeric fibronectin do not reveal the disulfide-bonded fragments that would be expected if multimerization involved one or both of the free sulfhydryls. The free sulfhydryls of fibronectin are not required for the binding of fibronectin to the cell layer or for its subsequent incorporation into the extracellular matrix. Disulfide-bonded multimerization of fibronectin in the cell layer occurs by disulfide bond exchange in the disulfide-rich amino-terminal one-third of the molecule.
# Interactions
Besides integrin, fibronectin binds to many other host and non-host molecules. For example, it has been shown to interact with proteins such fibrin, tenascin, TNF-α, BMP-1, rotavirus NSP-4, and many fibronectin-binding proteins from bacteria (like FBP-A; FBP-B on the N-terminal domain), as well as the glycosaminoglycan, heparan sulfate.
Fibronectin has been shown to interact with:
- CD44
- COL7A1,
- LPA,
- IGFBP3,
- TNC, and
- TRIB3. | Fibronectin
Fibronectin is a high-molecular weight (~440kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins.[1] Fibronectin also binds to other extracellular matrix proteins such as collagen, fibrin, and heparan sulfate proteoglycans (e.g. syndecans).
Fibronectin exists as a protein dimer, consisting of two nearly identical monomers linked by a pair of disulfide bonds.[1] The fibronectin protein is produced from a single gene, but alternative splicing of its pre-mRNA leads to the creation of several isoforms.
Two types of fibronectin are present in vertebrates:[1]
- soluble plasma fibronectin (formerly called "cold-insoluble globulin", or CIg) is a major protein component of blood plasma (300 μg/ml) and is produced in the liver by hepatocytes.
- insoluble cellular fibronectin is a major component of the extracellular matrix. It is secreted by various cells, primarily fibroblasts, as a soluble protein dimer and is then assembled into an insoluble matrix in a complex cell-mediated process.
Fibronectin plays a major role in cell adhesion, growth, migration, and differentiation, and it is important for processes such as wound healing and embryonic development.[1] Altered fibronectin expression, degradation, and organization has been associated with a number of pathologies, including cancer and fibrosis.[2]
# Structure
Fibronectin exists as a protein dimer, consisting of two nearly identical polypeptide chains linked by a pair of C-terminal disulfide bonds.[3] Each fibronectin subunit has a molecular weight of 230–250 kDa and contains three types of modules: type I, II, and III. All three modules are composed of two anti-parallel β-sheets resulting in a Beta-sandwich; however, type I and type II are stabilized by intra-chain disulfide bonds, while type III modules do not contain any disulfide bonds. The absence of disulfide bonds in type III modules allows them to partially unfold under applied force.[4]
Three regions of variable splicing occur along the length of the fibronectin protomer. One or both of the "extra" type III modules (EIIIA and EIIIB) may be present in cellular fibronectin, but they are never present in plasma fibronectin. A "variable" V-region exists between III14–15 (the 14th and 15th type III module). The V-region structure is different from the type I, II, and III modules, and its presence and length may vary. The V-region contains the binding site for α4β1 integrins. It is present in most cellular fibronectin, but only one of the two subunits in a plasma fibronectin dimer contains a V-region sequence.
The modules are arranged into several functional and protein-binding domains along the length of a fibronectin monomer. There are four fibronectin-binding domains, allowing fibronectin to associate with other fibronectin molecules.[3] One of these fibronectin-binding domains, I1–5, is referred to as the "assembly domain", and it is required for the initiation of fibronectin matrix assembly. Modules III9–10 correspond to the "cell-binding domain" of fibronectin. The RGD sequence (Arg–Gly–Asp) is located in III10 and is the site of cell attachment via α5β1 and αVβ3 integrins on the cell surface. The "synergy site" is in III9 and has a role in modulating fibronectin's association with α5β1 integrins.[5] Fibronectin also contains domains for fibrin-binding (I1–5, I10–12), collagen-binding (I6–9), fibulin-1-binding (III13–14), heparin-binding and syndecan-binding (III12–14).[3]
# Function
Fibronectin has numerous functions that ensure the normal functioning of vertebrate organisms.[1] It is involved in cell adhesion, growth, migration, and differentiation. Cellular fibronectin is assembled into the extracellular matrix, an insoluble network that separates and supports the organs and tissues of an organism.
Fibronectin plays a crucial role in wound healing.[6][7] Along with fibrin, plasma fibronectin is deposited at the site of injury, forming a blood clot that stops bleeding and protects the underlying tissue. As repair of the injured tissue continues, fibroblasts and macrophages begin to remodel the area, degrading the proteins that form the provisional blood clot matrix and replacing them with a matrix that more resembles the normal, surrounding tissue. Fibroblasts secrete proteases, including matrix metalloproteinases, that digest the plasma fibronectin, and then the fibroblasts secrete cellular fibronectin and assemble it into an insoluble matrix. Fragmentation of fibronectin by proteases has been suggested to promote wound contraction, a critical step in wound healing. Fragmenting fibronectin further exposes its V-region, which contains the site for α4β1 integrin binding. These fragments of fibronectin are believed to enhance the binding of α4β1 integrin-expressing cells, allowing them to adhere to and forcefully contract the surrounding matrix.
Fibronectin is necessary for embryogenesis, and inactivating the gene for fibronectin results in early embryonic lethality.[8] Fibronectin is important for guiding cell attachment and migration during embryonic development. In mammalian development, the absence of fibronectin leads to defects in mesodermal, neural tube, and vascular development. Similarly, the absence of a normal fibronectin matrix in developing amphibians causes defects in mesodermal patterning and inhibits gastrulation.[9]
Fibronectin is also found in normal human saliva, which helps prevent colonization of the oral cavity and pharynx by potentially pathogenic bacteria.[10]
# Matrix assembly
Cellular fibronectin is assembled into an insoluble fibrillar matrix in a complex cell-mediated process.[11] Fibronectin matrix assembly begins when soluble, compact fibronectin dimers are secreted from cells, often fibroblasts. These soluble dimers bind to α5β1 integrin receptors on the cell surface and aid in clustering the integrins. The local concentration of integrin-bound fibronectin increases, allowing bound fibronectin molecules to more readily interact with one another. Short fibronectin fibrils then begin to form between adjacent cells. As matrix assembly proceeds, the soluble fibrils are converted into larger insoluble fibrils that comprise the extracellular matrix.
Fibronectin’s shift from soluble to insoluble fibrils proceeds when cryptic fibronectin-binding sites are exposed along the length of a bound fibronectin molecule. Cells are believed to stretch fibronectin by pulling on their fibronectin-bound integrin receptors. This force partially unfolds the fibronectin ligand, unmasking cryptic fibronectin-binding sites and allowing nearby fibronectin molecules to associate. This fibronectin-fibronectin interaction enables the soluble, cell-associated fibrils to branch and stabilize into an insoluble fibronectin matrix.
A transmembrane protein, CD93, has been shown to be essential for fibronectin matrix assembly (fibrillogenesis) in human dermal blood endothelial cells.[12] As a consequence, knockdown of CD93 in these cells resulted in the disruption of the fibronectin fibrillogenesis. Moreover, the CD93 knockout mice retinas displayed disrupted fibronectin matrix at the retinal sprouting front.[12]
# Role in cancer
Several morphological changes has been observed in tumors and tumor-derived cell lines that have been attributed to decreased fibronectin expression, increased fibronectin degradation, and/or decreased expression of fibronectin-binding receptors, such as α5β1 integrins.[13]
Fibronectin has been implicated in carcinoma development.[14] In lung carcinoma, fibronectin expression is increased especially in non-small cell lung carcinoma. The adhesion of lung carcinoma cells to fibronectin enhances tumorigenicity and confers resistance to apoptosis-inducing chemotherapeutic agents. Fibronectin has been shown to stimulate the gonadal steroids that interact with vertebrate androgen receptors, which are capable of controlling the expression of cyclin D and related genes involved in cell cycle control. These observations suggest that fibronectin may promote lung tumor growth/survival and resistance to therapy, and it could represent a novel target for the development of new anticancer drugs.
Fibronectin 1 acts as a potential biomarker for radioresistance.[15]
FN1-FGFR1 fusion is frequent in phosphaturic mesenchymal tumours.[16][17]
# Role in wound healing
Fibronectin has profound effects on wound healing, including the formation of proper substratum for migration and growth of cells during the development and organization of granulation tissue, as well as remodeling and resynthesis of the connective tissue matrix.[18] The biological significance of fibronectin in vivo was studied during the mechanism of wound healing.[18] Plasma fibronectin levels are decreased in acute inflammation or following surgical trauma and in patients with disseminated intravascular coagulation.[19]
Fibronectin is located in the extracellular matrix of embryonic and adult tissues (not in the basement membranes of the adult tissues), but may be more widely distributed in inflammatory lesions. During blood clotting, the fibronectin remains associated with the clot, covalently cross-linked to fibrin with the help of Factor XIII (fibrin-stabilizing factor).[20][21] Fibroblasts play a major role in wound healing by adhering to fibrin. Fibroblast adhesion to fibrin requires fibronectin, and was strongest when the fibronectin was cross-linked to the fibrin. Patients with Factor XIII deficiencies display impairment in wound healing as fibroblasts don't grow well in fibrin lacking Factor XIII. Fibronectin promotes particle phagocytosis by both macrophages and fibroblasts. Collagen deposition at the wound site by fibroblasts takes place with the help of fibronectin. Fibronectin was also observed to be closely associated with the newly deposited collagen fibrils. Based on the size and histological staining characteristics of the fibrils, it is likely that at least in part they are composed of type III collagen (reticulin). An in vitro study with native collagen demonstrated that fibronectin binds to type III collagen rather than other types.[22]
# In vivo vs in vitro
Plasma fibronectin, which is synthesized by hepatocytes,[23] and fibronectin synthesized by cultured fibroblasts are similar but not identical; immunological, structural, and functional differences have been reported.[24] It is likely that these differences result from differential processing of a single nascent mRNA. Nevertheless, plasma fibronectin can be insolubilized into the tissue extracellular matrix in vitro and in vivo. Both plasma and cellular fibronectins in the matrix form high molecular weight, disulfide-bonded multimers. The mechanism of formation of these multimers is not presently known. Plasma fibronectin has been shown to contain two free sulfhydryls per subunit (X), and cellular fibronectin has been shown to contain at least one. These sulfhydryls probably are buried within the tertiary structure, because sulfhydryls are exposed when the fibronectin is denatured. Such denaturation results in the oxidation of free sulfhydryls and formation of disulfide-bonded fibronectin multimers. This has led to speculation that the free sulfhydryls may be involved in formation of disulfide-bonded fibronectin multimers in the extracellular matrix. Consistent with this, sulfhydryl modification of fibronectin with N-ethylmaleimide prevents binding to cell layers. Tryptic cleavage patterns of multimeric fibronectin do not reveal the disulfide-bonded fragments that would be expected if multimerization involved one or both of the free sulfhydryls. The free sulfhydryls of fibronectin are not required for the binding of fibronectin to the cell layer or for its subsequent incorporation into the extracellular matrix. Disulfide-bonded multimerization of fibronectin in the cell layer occurs by disulfide bond exchange in the disulfide-rich amino-terminal one-third of the molecule.[24]
# Interactions
Besides integrin, fibronectin binds to many other host and non-host molecules. For example, it has been shown to interact with proteins such fibrin, tenascin, TNF-α, BMP-1, rotavirus NSP-4, and many fibronectin-binding proteins from bacteria (like FBP-A; FBP-B on the N-terminal domain), as well as the glycosaminoglycan, heparan sulfate.
Fibronectin has been shown to interact with:
- CD44[25]
- COL7A1,[26][27]
- LPA,[28]
- IGFBP3,[29][30]
- TNC,[31] and
- TRIB3.[32] | https://www.wikidoc.org/index.php/Fibronectin | |
84592775d1cb730c6132c35f9ef9f5bc85bea70d | wikidoc | Fibrothorax | Fibrothorax
Synonyms and keywords: Synonym 1; Synonym 2; Synonym 3
# Overview
# Historical Perspective
- was first discovered by , a , in during/following .
- In , mutations were first identified in the pathogenesis of .
- In , the first was developed by to treat/diagnose .
# Classification
- may be classified according to into subtypes/groups:
- Other variants of include , , and .
# Pathophysiology
- The pathogenesis of is characterized by , , and .
- The gene/Mutation in has been associated with the development of , involving the pathway.
- On gross pathology, , , and are characteristic findings of .
- On microscopic histopathological analysis, , , and are characteristic findings of .
# Causes
- may be caused by either , , or .
- is caused by a mutation in the , , or gene.
- There are no established causes for .
# Differentiating from other Diseases
- must be differentiated from other diseases that cause , , and , such as:
# Epidemiology and Demographics
- The prevalence of is approximately per 100,000 individuals worldwide.
- In , the incidence of was estimated to be cases per 100,000 individuals in .
## Age
- Patients of all age groups may develop .
- is more commonly observed among patients aged years old.
- is more commonly observed among .
## Gender
- affects men and women equally.
- are more commonly affected with than .
- The to ratio is approximately to 1.
## Race
- There is no racial predilection for .
- usually affects individuals of the race.
- individuals are less likely to develop .
# Risk Factors
- Common risk factors in the development of are , , , and .
# Natural History, Complications and Prognosis
- The majority of patients with remain asymptomatic for .
- Early clinical features include , , and .
- If left untreated, of patients with may progress to develop , , and .
- Common complications of include , , and .
- Prognosis is generally , and the of patients with is approximately .
# Diagnosis
## Diagnostic Criteria
- The diagnosis of is made when at least of the following diagnostic criteria are met:
## Symptoms
- is usually asymptomatic.
- Symptoms of may include the following:
## Physical Examination
- Patients with usually appear .
- Physical examination may be remarkable for:
## Laboratory Findings
- There are no specific laboratory findings associated with .
- A is diagnostic of .
- An concentration of is diagnostic of .
- Other laboratory findings consistent with the diagnosis of include , , and .
## Imaging Findings
- There are no findings associated with .
- is the imaging modality of choice for .
- On , is characterized by , , and .
- may demonstrate , , and .
## Other Diagnostic Studies
- may also be diagnosed using .
- Findings on include , , and .
# Treatment
## Medical Therapy
- There is no treatment for ; the mainstay of therapy is supportive care.
- The mainstay of therapy for is and .
- acts by .
- Response to can be monitored with every .
## Surgery
- Surgery is the mainstay of therapy for .
- in conjunction with is the most common approach to the treatment of .
- can only be performed for patients with .
## Prevention
- There are no primary preventive measures available for .
- Effective measures for the primary prevention of include , , and .
- Once diagnosed and successfully treated, patients with are followed-up every . Follow-up testing includes , , and . | Fibrothorax
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Synonym 1; Synonym 2; Synonym 3
# Overview
# Historical Perspective
- [Disease name] was first discovered by [scientist name], a [nationality + occupation], in [year] during/following [event].
- In [year], [gene] mutations were first identified in the pathogenesis of [disease name].
- In [year], the first [discovery] was developed by [scientist] to treat/diagnose [disease name].
# Classification
- [Disease name] may be classified according to [classification method] into [number] subtypes/groups:
- [group1]
- [group2]
- [group3]
- Other variants of [disease name] include [disease subtype 1], [disease subtype 2], and [disease subtype 3].
# Pathophysiology
- The pathogenesis of [disease name] is characterized by [feature1], [feature2], and [feature3].
- The [gene name] gene/Mutation in [gene name] has been associated with the development of [disease name], involving the [molecular pathway] pathway.
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
# Causes
- [Disease name] may be caused by either [cause1], [cause2], or [cause3].
- [Disease name] is caused by a mutation in the [gene1], [gene2], or [gene3] gene[s].
- There are no established causes for [disease name].
# Differentiating [disease name] from other Diseases
- [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as:
- [Differential dx1]
- [Differential dx2]
- [Differential dx3]
# Epidemiology and Demographics
- The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide.
- In [year], the incidence of [disease name] was estimated to be [number or range] cases per 100,000 individuals in [location].
## Age
- Patients of all age groups may develop [disease name].
- [Disease name] is more commonly observed among patients aged [age range] years old.
- [Disease name] is more commonly observed among [elderly patients/young patients/children].
## Gender
- [Disease name] affects men and women equally.
- [Gender 1] are more commonly affected with [disease name] than [gender 2].
- The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1.
## Race
- There is no racial predilection for [disease name].
- [Disease name] usually affects individuals of the [race 1] race.
- [Race 2] individuals are less likely to develop [disease name].
# Risk Factors
- Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
# Natural History, Complications and Prognosis
- The majority of patients with [disease name] remain asymptomatic for [duration/years].
- Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
- If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
- Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
- Prognosis is generally [excellent/good/poor], and the [1/5/10year mortality/survival rate] of patients with [disease name] is approximately [#%].
# Diagnosis
## Diagnostic Criteria
- The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:
- [criterion 1]
- [criterion 2]
- [criterion 3]
- [criterion 4]
## Symptoms
- [Disease name] is usually asymptomatic.
- Symptoms of [disease name] may include the following:
- [symptom 1]
- [symptom 2]
- [symptom 3]
- [symptom 4]
- [symptom 5]
- [symptom 6]
## Physical Examination
- Patients with [disease name] usually appear [general appearance].
- Physical examination may be remarkable for:
- [finding 1]
- [finding 2]
- [finding 3]
- [finding 4]
- [finding 5]
- [finding 6]
## Laboratory Findings
- There are no specific laboratory findings associated with [disease name].
- A [positive/negative] [test name] is diagnostic of [disease name].
- An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
- Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
## Imaging Findings
- There are no [imaging study] findings associated with [disease name].
- [Imaging study 1] is the imaging modality of choice for [disease name].
- On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
- [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].
## Other Diagnostic Studies
- [Disease name] may also be diagnosed using [diagnostic study name].
- Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].
# Treatment
## Medical Therapy
- There is no treatment for [disease name]; the mainstay of therapy is supportive care.
- The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
- [Medical therapy 1] acts by [mechanism of action 1].
- Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].
## Surgery
- Surgery is the mainstay of therapy for [disease name].
- [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
- [Surgical procedure] can only be performed for patients with [disease stage] [disease name].
## Prevention
- There are no primary preventive measures available for [disease name].
- Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].
- Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3]. | https://www.wikidoc.org/index.php/Fibrothorax | |
025cd48950c838200d85c7f7e574518a82c86ce1 | wikidoc | Fidaxomicin | Fidaxomicin
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# Overview
Fidaxomicin is a Macrolide that is FDA approved for the treatment of Clostridium difficile-Associated Diarrhea. Common adverse reactions include Abdominal pain, nausea, vomiting, anemia, neutropenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Clostridium difficile-Associated Diarrhea
- Dose is one 200 mg fidaxomicin tablet orally twice daily for 10 days with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fidaxomicin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fidaxomicin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Fidaxomicin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fidaxomicin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fidaxomicin in pediatric patients.
# Contraindications
- Hypersensitivity to fidaxomicin.
# Warnings
### Not for Systemic Infections
- Since there is minimal systemic absorption of fidaxomicin, fidaxomicin is not effective for treatment of systemic infections.
### Hypersensitivity Reactions
- Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin.
- If a severe hypersensitivity reaction occurs, fidaxomicin should be discontinued and appropriate therapy should be instituted.
- Some patients with hypersensitivity reactions also reported a history of allergy to other macrolides.
- Physicians prescribing fidaxomicin to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions.
### Development of Drug-Resistant Bacteria
- Prescribing fidaxomicin in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice.
The safety of fidaxomicin 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment.
Thirty-three patients receiving fidaxomicin (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies.
The following adverse reactions were reported in <2% of patients taking fidaxomicin tablets in controlled trials:
### Gastrointestinal Disorders
- Abdominal distension
- Abdominal tenderness
- Dyspepsia
- Dysphagia
- Flatulence
- Intestinal obstruction
- Megacolon
### Investigations
- Increased blood alkaline phosphatase
- Decreased blood bicarbonate
- Increased hepatic enzymes
- Decreased platelet count
### Metabolism and Nutrition Disorders
- Hyperglycemia
- Metabolic acidosis
### Skin and Subcutaneous Tissue Disorders
- Drug eruption
- Pruritus
- Rash
## Postmarketing Experience
Adverse reactions reported in the post marketing setting arise from a population of unknown size and are voluntary in nature. As such, reliability in estimating their frequency or in establishing a causal relationship to drug exposure is not always possible.
Hypersensitivity reactions:
- Dyspnea
- Angioedema
- Rash
- Pruritus
# Drug Interactions
Fidaxomicin and its main metabolite, OP-1118, are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract.
### Cyclosporine
- Cyclosporine is an inhibitor of multiple transporters, including P-gp.
- When cyclosporine was co-administered with fidaxomicin, plasma concentrations of fidaxomicin and OP-1118 were significantly increased but remained in the ng/mL range.
- Concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e., gastrointestinal tract) via P-gp inhibition; however, concomitant P-gp inhibitor use had no attributable effect on safety or treatment outcome of fidaxomicin-treated patients in controlled clinical trials.
- Based on these results, fidaxomicin may be co-administered with P-gp inhibitors and no dose adjustment is recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively.
- The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin.
- There are, however, no adequate and well-controlled studies in pregnant women. *Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fidaxomicin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fidaxomicin during labor and delivery.
### Nursing Mothers
- It is not known whether fidaxomicin is excreted in human milk.
- Because many drugs are excreted in human milk, caution should be exercised when fidaxomicin is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of fidaxomicin in patients <18 years of age have not been established.
### Geriatic Use
- Of the total number of patients in controlled trials of fidaxomicin, 50% were 65 years of age and over, while 31% were 75 and over.
- No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects.
- In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age).
- However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.
### Gender
There is no FDA guidance on the use of Fidaxomicin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fidaxomicin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Fidaxomicin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Fidaxomicin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fidaxomicin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fidaxomicin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Fidaxomicin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Fidaxomicin and IV administrations.
# Overdosage
- No cases of acute overdose have been reported in humans. No drug-related adverse effects were seen in dogs dosed with fidaxomicin tablets at 9600 mg/day (over 100 times the human dose, scaled by weight) for 3 months.
# Pharmacology
## Mechanism of Action
Fidaxomicin is bactericidal against C. difficile in vitro, inhibiting RNA synthesis by RNA polymerases.
## Structure
Fidaxomicin (fidaxomicin) is a macrolide antibacterial drug for oral administration. Its CAS chemical name is Oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-oxy]methyl]-12-oxy]-11-ethyl-8-hydroxy-18--9,13,15-trimethyl-, (3E,5E,8S,9E,11S,12R,13E,15E,18S)-. The structural formula of fidaxomicin is shown in Figure 1.
## Pharmacodynamics
Fidaxomicin acts locally in the gastrointestinal tract on C. difficile. In a dose-ranging trial (N=48) of fidaxomicin using 50 mg, 100 mg, and 200 mg twice daily for 10 days, a dose-response relationship was observed for efficacy.
## Pharmacokinetics
The pharmacokinetic parameters of fidaxomicin and its main metabolite OP-1118 following a single dose of 200 mg in healthy adult males (N=14) are summarized in Table 2.
### Absorption
Fidaxomicin has minimal systemic absorption following oral administration, with plasma concentrations of fidaxomicin and OP-1118 in the ng/mL range at the therapeutic dose. In fidaxomicin-treated patients from controlled trials, plasma concentrations of fidaxomicin and OP-1118 obtained within the Tmax window (1-5 hours) were approximately 2- to 6-fold higher than Cmax values in healthy adults. Following administration of fidaxomicin 200 mg twice daily for 10 days, OP-1118 plasma concentrations within the Tmax window were approximately 50%-80% higher than on Day 1, while concentrations of fidaxomicin were similar on Days 1 and 10.
In a food-effect study involving administration of fidaxomicin to healthy adults (N=28) with a high-fat meal versus under fasting conditions, Cmax of fidaxomicin and OP-1118 decreased by 21.5% and 33.4%, respectively, while AUC0-t remained unchanged. This decrease in Cmax is not considered clinically significant, and thus, fidaxomicin may be administered with or without food.
### Distribution
Fidaxomicin is mainly confined to the gastrointestinal tract following oral administration. In selected patients (N=8) treated with fidaxomicin 200 mg twice daily for 10 days from controlled trials, fecal concentrations of fidaxomicin and OP-1118 obtained within 24 hours of the last dose ranged from 639-2710 μg/g and 213-1210 μg/g, respectively. In contrast, plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) ranged 2-179 ng/mL and 10-829 ng/mL, respectively.
### Metabolism
Fidaxomicin is primarily transformed by hydrolysis at the isobutyryl ester to form its main and microbiologically active metabolite, OP-1118. Metabolism of fidaxomicin and formation of OP-1118 are not dependent on cytochrome P450 (CYP) enzymes.
At the therapeutic dose, OP-1118 was the predominant circulating compound in healthy adults, followed by fidaxomicin.
### Excretion
Fidaxomicin is mainly excreted in feces. In one trial of healthy adults (N=11), more than 92% of the dose was recovered in the stool as fidaxomicin and OP-1118 following single doses of 200 mg and 300 mg. In another trial of healthy adults (N=6), 0.59% of the dose was recovered in urine as OP-1118 only following a single dose of 200 mg.
### Specific Populations
In controlled trials of patients treated with fidaxomicin 200 mg twice daily for 10 days, mean and median values of fidaxomicin and OP-1118 plasma concentrations within the Tmax window (1-5 hours) were approximately 2- to 4-fold higher in elderly patients (≥65 years of age) versus non-elderly patients (<65 years of age). Despite greater exposures in elderly patients, fidaxomicin and OP-1118 plasma concentrations remained in the ng/mL range.
Plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) did not vary by gender in patients treated with fidaxomicin 200 mg twice daily for 10 days from controlled trials. No dose adjustment is recommended based on gender.
In controlled trials of patients treated with fidaxomicin 200 mg twice daily for 10 days, plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) did not vary by severity of renal impairment (based on creatinine clearance) between mild (51-79 mL/min), moderate (31-50 mL/min), and severe (≤30 mL/min) categories. No dose adjustment is recommended based on renal function.
The impact of hepatic impairment on the pharmacokinetics of fidaxomicin has not been evaluated. Because fidaxomicin and OP-1118 do not appear to undergo significant hepatic metabolism, elimination of fidaxomicin and OP-1118 is not expected to be significantly affected by hepatic impairment.
In vivo studies were conducted to evaluate intestinal drug-drug interactions of fidaxomicin as a P-gp substrate, P-gp inhibitor, and inhibitor of major CYP enzymes expressed in the gastrointestinal tract (CYP3A4, CYP2C9, and CYP2C19).
Table 3 summarizes the impact of a co-administered drug (P-gp inhibitor) on the pharmacokinetics of fidaxomicin .
Fidaxomicin had no significant impact on the pharmacokinetics of the following co-administered drugs: digoxin (P-gp substrate), midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). No dose adjustment is warranted when fidaxomicin is co-administered with substrates of P-gp or CYP enzymes.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, and Impairment of Fertility
- Long-term carcinogenicity studies have not been conducted to evaluate the carcinogenic potential of fidaxomicin.
- Neither fidaxomicin nor OP-1118 was mutagenic in the Ames assay. Fidaxomicin was also negative in the rat micronucleus assay. However, fidaxomicin was clastogenic in Chinese hamster ovary cells.
- Fidaxomicin did not affect the fertility of male and female rats at intravenous doses of 6.3 mg/kg. The exposure (AUC0-t) was approximately 100 times that in humans.
# Clinical Studies
In two randomized, double-blinded trials, a non-inferiority design was utilized to demonstrate the efficacy of fidaxomicin (200 mg twice daily for 10 days) compared to vancomycin (125 mg four times daily for 10 days) in adults with Clostridium difficile-associated diarrhea (CDAD).
Enrolled patients were 18 years of age or older, and received no more than 24 hours of pretreatment with vancomycin or metronidazole. CDAD was defined by >3 unformed bowel movements (or >200 mL of unformed stool for subjects having rectal collection devices) in the 24 hours before randomization, and presence of either C. difficile toxin A or B in the stool within 48 hours of randomization. Enrolled patients had either no prior CDAD history or only one prior CDAD episode in the past three months. Subjects with life-threatening/fulminant infection, hypotension, septic shock, peritoneal signs, significant dehydration, or toxic megacolon were excluded.
The demographic profile and baseline CDAD characteristics of enrolled subjects were similar in the two trials. Patients had a median age of 64 years, were mainly white (90%), female (58%), and inpatients (63%). The median number of bowel movements per day was 6, and 37% of subjects had severe CDAD (defined as 10 or more unformed bowel movements per day or WBC ≥15000/mm3). Diarrhea alone was reported in 45% of patients and 84% of subjects had no prior CDAD episode.
The primary efficacy endpoint was the clinical response rate at the end of treatment, based upon improvement in diarrhea or other symptoms such that, in the investigator's judgment, further CDAD treatment was not needed. An additional efficacy endpoint was sustained clinical response 25 days after the end of treatment. Sustained response was evaluated only for patients who were clinical successes at the end of treatment. Sustained response was defined as clinical response at the end of treatment, and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment.
The results for clinical response at the end of treatment in both trials, shown in Table 5, indicate that fidaxomicin is non-inferior to vancomycin based on the 95% confidence interval (CI) lower limit being greater than the non-inferiority margin of -10%.
The results for sustained clinical response at the end of the follow-up period, also shown in Table 5, indicate that fidaxomicin is superior to vancomycin on this endpoint. Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained clinical response were due to lower rates of proven or suspected CDAD during the follow-up period in fidaxomicin patients.
Restriction Endonuclease Analysis (REA) was used to identify C. difficile baseline isolates in the BI group, isolates associated with increasing rates and severity of CDAD in the US in the years prior to the clinical trials. Similar rates of clinical response at the end of treatment and proven or suspected CDAD during the follow-up period were seen in fidaxomicin-treated and vancomycin-treated patients infected with a BI isolate. However, fidaxomicin did not demonstrate superiority in sustained clinical response when compared with vancomycin (Table 6).
# How Supplied
- Fidaxomicin tablets are white to off-white film-coated, oblong tablets containing 200 mg of fidaxomicin; each tablet is debossed with "FDX" on one side and "200" on the other side.
- Fidaxomicin tablets are supplied as bottles of 20 tablets (NDC 52015-080-01).
## Storage
- Storage: 20 °-25°C (68 °-77°F); excursions permitted to 15° - 30°C (59° - 86°F).
- See USP controlled room temperature.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Administration with Food
- Patients should be informed that fidaxomicin tablets may be taken with or without food.
### Antibacterial Resistance
- Patients should be counseled that antibacterial drugs, including fidaxomicin, should only be used to treat bacterial infections. They do not treat viral infections. Patients should be counseled that fidaxomicin only treats Clostridium difficile-associated diarrhea and should not be used to treat any other infection.
- When fidaxomicin tablets are prescribed, patients should be told that, although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by fidaxomicin or other antibacterial drugs in the future.
# Precautions with Alcohol
Alcohol-Fidaxomicin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Dificid
# Look-Alike Drug Names
There is limited information regarding Fidaxomicin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Fidaxomicin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]
# Disclaimer
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# Overview
Fidaxomicin is a Macrolide that is FDA approved for the treatment of Clostridium difficile-Associated Diarrhea. Common adverse reactions include Abdominal pain, nausea, vomiting, anemia, neutropenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Clostridium difficile-Associated Diarrhea
- Dose is one 200 mg fidaxomicin tablet orally twice daily for 10 days with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fidaxomicin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fidaxomicin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Fidaxomicin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fidaxomicin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fidaxomicin in pediatric patients.
# Contraindications
- Hypersensitivity to fidaxomicin.
# Warnings
### Not for Systemic Infections
- Since there is minimal systemic absorption of fidaxomicin, fidaxomicin is not effective for treatment of systemic infections.
### Hypersensitivity Reactions
- Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin.
- If a severe hypersensitivity reaction occurs, fidaxomicin should be discontinued and appropriate therapy should be instituted.
- Some patients with hypersensitivity reactions also reported a history of allergy to other macrolides.
- Physicians prescribing fidaxomicin to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions.
### Development of Drug-Resistant Bacteria
- Prescribing fidaxomicin in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice.
The safety of fidaxomicin 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment.
Thirty-three patients receiving fidaxomicin (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies.
The following adverse reactions were reported in <2% of patients taking fidaxomicin tablets in controlled trials:
### Gastrointestinal Disorders
- Abdominal distension
- Abdominal tenderness
- Dyspepsia
- Dysphagia
- Flatulence
- Intestinal obstruction
- Megacolon
### Investigations
- Increased blood alkaline phosphatase
- Decreased blood bicarbonate
- Increased hepatic enzymes
- Decreased platelet count
### Metabolism and Nutrition Disorders
- Hyperglycemia
- Metabolic acidosis
### Skin and Subcutaneous Tissue Disorders
- Drug eruption
- Pruritus
- Rash
## Postmarketing Experience
Adverse reactions reported in the post marketing setting arise from a population of unknown size and are voluntary in nature. As such, reliability in estimating their frequency or in establishing a causal relationship to drug exposure is not always possible.
Hypersensitivity reactions:
- Dyspnea
- Angioedema
- Rash
- Pruritus
# Drug Interactions
Fidaxomicin and its main metabolite, OP-1118, are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract.
### Cyclosporine
- Cyclosporine is an inhibitor of multiple transporters, including P-gp.
- When cyclosporine was co-administered with fidaxomicin, plasma concentrations of fidaxomicin and OP-1118 were significantly increased but remained in the ng/mL range.
- Concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e., gastrointestinal tract) via P-gp inhibition; however, concomitant P-gp inhibitor use had no attributable effect on safety or treatment outcome of fidaxomicin-treated patients in controlled clinical trials.
- Based on these results, fidaxomicin may be co-administered with P-gp inhibitors and no dose adjustment is recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively.
- The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin.
- There are, however, no adequate and well-controlled studies in pregnant women. *Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fidaxomicin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fidaxomicin during labor and delivery.
### Nursing Mothers
- It is not known whether fidaxomicin is excreted in human milk.
- Because many drugs are excreted in human milk, caution should be exercised when fidaxomicin is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of fidaxomicin in patients <18 years of age have not been established.
### Geriatic Use
- Of the total number of patients in controlled trials of fidaxomicin, 50% were 65 years of age and over, while 31% were 75 and over.
- No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects.
- In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age).
- However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.
### Gender
There is no FDA guidance on the use of Fidaxomicin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fidaxomicin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Fidaxomicin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Fidaxomicin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fidaxomicin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fidaxomicin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Fidaxomicin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Fidaxomicin and IV administrations.
# Overdosage
- No cases of acute overdose have been reported in humans. No drug-related adverse effects were seen in dogs dosed with fidaxomicin tablets at 9600 mg/day (over 100 times the human dose, scaled by weight) for 3 months.
# Pharmacology
## Mechanism of Action
Fidaxomicin is bactericidal against C. difficile in vitro, inhibiting RNA synthesis by RNA polymerases.
## Structure
Fidaxomicin (fidaxomicin) is a macrolide antibacterial drug for oral administration. Its CAS chemical name is Oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl]oxy]methyl]-12-[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl]oxy]-11-ethyl-8-hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-, (3E,5E,8S,9E,11S,12R,13E,15E,18S)-. The structural formula of fidaxomicin is shown in Figure 1.
## Pharmacodynamics
Fidaxomicin acts locally in the gastrointestinal tract on C. difficile. In a dose-ranging trial (N=48) of fidaxomicin using 50 mg, 100 mg, and 200 mg twice daily for 10 days, a dose-response relationship was observed for efficacy.
## Pharmacokinetics
The pharmacokinetic parameters of fidaxomicin and its main metabolite OP-1118 following a single dose of 200 mg in healthy adult males (N=14) are summarized in Table 2.
### Absorption
Fidaxomicin has minimal systemic absorption following oral administration, with plasma concentrations of fidaxomicin and OP-1118 in the ng/mL range at the therapeutic dose. In fidaxomicin-treated patients from controlled trials, plasma concentrations of fidaxomicin and OP-1118 obtained within the Tmax window (1-5 hours) were approximately 2- to 6-fold higher than Cmax values in healthy adults. Following administration of fidaxomicin 200 mg twice daily for 10 days, OP-1118 plasma concentrations within the Tmax window were approximately 50%-80% higher than on Day 1, while concentrations of fidaxomicin were similar on Days 1 and 10.
In a food-effect study involving administration of fidaxomicin to healthy adults (N=28) with a high-fat meal versus under fasting conditions, Cmax of fidaxomicin and OP-1118 decreased by 21.5% and 33.4%, respectively, while AUC0-t remained unchanged. This decrease in Cmax is not considered clinically significant, and thus, fidaxomicin may be administered with or without food.
### Distribution
Fidaxomicin is mainly confined to the gastrointestinal tract following oral administration. In selected patients (N=8) treated with fidaxomicin 200 mg twice daily for 10 days from controlled trials, fecal concentrations of fidaxomicin and OP-1118 obtained within 24 hours of the last dose ranged from 639-2710 μg/g and 213-1210 μg/g, respectively. In contrast, plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) ranged 2-179 ng/mL and 10-829 ng/mL, respectively.
### Metabolism
Fidaxomicin is primarily transformed by hydrolysis at the isobutyryl ester to form its main and microbiologically active metabolite, OP-1118. Metabolism of fidaxomicin and formation of OP-1118 are not dependent on cytochrome P450 (CYP) enzymes.
At the therapeutic dose, OP-1118 was the predominant circulating compound in healthy adults, followed by fidaxomicin.
### Excretion
Fidaxomicin is mainly excreted in feces. In one trial of healthy adults (N=11), more than 92% of the dose was recovered in the stool as fidaxomicin and OP-1118 following single doses of 200 mg and 300 mg. In another trial of healthy adults (N=6), 0.59% of the dose was recovered in urine as OP-1118 only following a single dose of 200 mg.
### Specific Populations
In controlled trials of patients treated with fidaxomicin 200 mg twice daily for 10 days, mean and median values of fidaxomicin and OP-1118 plasma concentrations within the Tmax window (1-5 hours) were approximately 2- to 4-fold higher in elderly patients (≥65 years of age) versus non-elderly patients (<65 years of age). Despite greater exposures in elderly patients, fidaxomicin and OP-1118 plasma concentrations remained in the ng/mL range.
Plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) did not vary by gender in patients treated with fidaxomicin 200 mg twice daily for 10 days from controlled trials. No dose adjustment is recommended based on gender.
In controlled trials of patients treated with fidaxomicin 200 mg twice daily for 10 days, plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) did not vary by severity of renal impairment (based on creatinine clearance) between mild (51-79 mL/min), moderate (31-50 mL/min), and severe (≤30 mL/min) categories. No dose adjustment is recommended based on renal function.
The impact of hepatic impairment on the pharmacokinetics of fidaxomicin has not been evaluated. Because fidaxomicin and OP-1118 do not appear to undergo significant hepatic metabolism, elimination of fidaxomicin and OP-1118 is not expected to be significantly affected by hepatic impairment.
In vivo studies were conducted to evaluate intestinal drug-drug interactions of fidaxomicin as a P-gp substrate, P-gp inhibitor, and inhibitor of major CYP enzymes expressed in the gastrointestinal tract (CYP3A4, CYP2C9, and CYP2C19).
Table 3 summarizes the impact of a co-administered drug (P-gp inhibitor) on the pharmacokinetics of fidaxomicin [see Drug Interactions (7.1)].
Fidaxomicin had no significant impact on the pharmacokinetics of the following co-administered drugs: digoxin (P-gp substrate), midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). No dose adjustment is warranted when fidaxomicin is co-administered with substrates of P-gp or CYP enzymes.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, and Impairment of Fertility
- Long-term carcinogenicity studies have not been conducted to evaluate the carcinogenic potential of fidaxomicin.
- Neither fidaxomicin nor OP-1118 was mutagenic in the Ames assay. Fidaxomicin was also negative in the rat micronucleus assay. However, fidaxomicin was clastogenic in Chinese hamster ovary cells.
- Fidaxomicin did not affect the fertility of male and female rats at intravenous doses of 6.3 mg/kg. The exposure (AUC0-t) was approximately 100 times that in humans.
# Clinical Studies
In two randomized, double-blinded trials, a non-inferiority design was utilized to demonstrate the efficacy of fidaxomicin (200 mg twice daily for 10 days) compared to vancomycin (125 mg four times daily for 10 days) in adults with Clostridium difficile-associated diarrhea (CDAD).
Enrolled patients were 18 years of age or older, and received no more than 24 hours of pretreatment with vancomycin or metronidazole. CDAD was defined by >3 unformed bowel movements (or >200 mL of unformed stool for subjects having rectal collection devices) in the 24 hours before randomization, and presence of either C. difficile toxin A or B in the stool within 48 hours of randomization. Enrolled patients had either no prior CDAD history or only one prior CDAD episode in the past three months. Subjects with life-threatening/fulminant infection, hypotension, septic shock, peritoneal signs, significant dehydration, or toxic megacolon were excluded.
The demographic profile and baseline CDAD characteristics of enrolled subjects were similar in the two trials. Patients had a median age of 64 years, were mainly white (90%), female (58%), and inpatients (63%). The median number of bowel movements per day was 6, and 37% of subjects had severe CDAD (defined as 10 or more unformed bowel movements per day or WBC ≥15000/mm3). Diarrhea alone was reported in 45% of patients and 84% of subjects had no prior CDAD episode.
The primary efficacy endpoint was the clinical response rate at the end of treatment, based upon improvement in diarrhea or other symptoms such that, in the investigator's judgment, further CDAD treatment was not needed. An additional efficacy endpoint was sustained clinical response 25 days after the end of treatment. Sustained response was evaluated only for patients who were clinical successes at the end of treatment. Sustained response was defined as clinical response at the end of treatment, and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment.
The results for clinical response at the end of treatment in both trials, shown in Table 5, indicate that fidaxomicin is non-inferior to vancomycin based on the 95% confidence interval (CI) lower limit being greater than the non-inferiority margin of -10%.
The results for sustained clinical response at the end of the follow-up period, also shown in Table 5, indicate that fidaxomicin is superior to vancomycin on this endpoint. Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained clinical response were due to lower rates of proven or suspected CDAD during the follow-up period in fidaxomicin patients.
Restriction Endonuclease Analysis (REA) was used to identify C. difficile baseline isolates in the BI group, isolates associated with increasing rates and severity of CDAD in the US in the years prior to the clinical trials. Similar rates of clinical response at the end of treatment and proven or suspected CDAD during the follow-up period were seen in fidaxomicin-treated and vancomycin-treated patients infected with a BI isolate. However, fidaxomicin did not demonstrate superiority in sustained clinical response when compared with vancomycin (Table 6).
# How Supplied
- Fidaxomicin tablets are white to off-white film-coated, oblong tablets containing 200 mg of fidaxomicin; each tablet is debossed with "FDX" on one side and "200" on the other side.
- Fidaxomicin tablets are supplied as bottles of 20 tablets (NDC 52015-080-01).
## Storage
- Storage: 20 °-25°C (68 °-77°F); excursions permitted to 15° - 30°C (59° - 86°F).
- See USP controlled room temperature.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Administration with Food
- Patients should be informed that fidaxomicin tablets may be taken with or without food.
### Antibacterial Resistance
- Patients should be counseled that antibacterial drugs, including fidaxomicin, should only be used to treat bacterial infections. They do not treat viral infections. Patients should be counseled that fidaxomicin only treats Clostridium difficile-associated diarrhea and should not be used to treat any other infection.
- When fidaxomicin tablets are prescribed, patients should be told that, although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by fidaxomicin or other antibacterial drugs in the future.
# Precautions with Alcohol
Alcohol-Fidaxomicin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Dificid[2]
# Look-Alike Drug Names
There is limited information regarding Fidaxomicin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Fidaxomicin | |
8a8558e5135e45b550f26fda9d13dac5b4e4754e | wikidoc | Filoviridae | Filoviridae
Filoviruses are viruses belonging to the family Filoviridae, which is in the order Mononegavirales. These viruses are single stranded negative sense RNA viruses that target primates. There are two genera: the Ebola virus (Ebolavirus, with four species) and the Marburg virus (Marburgvirus).
These viruses cause horrific viral hemorrhagic fevers, characterized by bleeding and coagulation abnormalities including diffuse bleeding.
The virions (viral particles) are characteristically shaped as long, cylindrical, filamentous particles which may be straight, curved, coiled, or found in a "6" or "U" shaped configuration. They are occasionally branched and the particles vary greatly in length but the diameter (about 80nm) is consistent.
They are produced by budding from an infected cell, and consist of the viral RNA strand and proteins encapsulated in a lipid membrane formed from the host cell's plasma membrane.
The inability of the immune system to clear these viruses may, at least in part, be due to the complex synthesis of a viral glycoprotein which forms heterotrimeric spikes within the virions plasma membrane. The gene encoding this protein in Ebola virus, but not Marburg virus, contains a stop codon and as a result two forms of the Ebola GP can be produced via a frame shift during translation. The full length GP precursor then undergoes proteolytic cleavage to form GP while a truncated form of GP, secreted GP (sGP), is produced from the non-frame-shifted sequence. This results in a variety of epitopes which may result in a less focused immune response that simply doesn't have the time to clear the infection before the organism succumbs.
Another virally expressed protein recognised by the immune system is VP40 which is normally expressed on the membrane complexed to VP24.
The filoviridae family was discovered in 1967 when 31 people were infected with the Marburg virus in Marburg, Germany after working with tissue from monkeys imported from Uganda . Seven people who caught the disease died. All subsequent outbreaks have occurred in sub-Saharan Africa. The second genus of the filoviridae family, Ebola virus, was discovered in 1976 when outbreaks occurred in northern Zaire and southern Sudan. The Ebola virus is a very potent virus, having a mortality rate of 50% up to 90% reported in some of the Zaire outbreaks.
The natural reservoir of both the Marburg virus and the Ebola virus appears to be zoonotic, which means that the virus is transmitted to humans from other animals. Despite numerous attempts to find the source of both the Marburg and Ebola viruses, neither has been found. Bats though because they can replacate filoviriade-like viruses have been suspected .
The mechanisms through which filoviruses spread are not fully understood. The route of transmission from animals to humans is unknown. Person-to-person transmission occurs primarily through physical contact with infected bodily fluids. | Filoviridae
Filoviruses are viruses belonging to the family Filoviridae, which is in the order Mononegavirales. These viruses are single stranded negative sense RNA viruses that target primates. There are two genera: the Ebola virus (Ebolavirus, with four species) [1] and the Marburg virus (Marburgvirus).
These viruses cause horrific viral hemorrhagic fevers, characterized by bleeding and coagulation abnormalities including diffuse bleeding.
The virions (viral particles) are characteristically shaped as long, cylindrical, filamentous particles which may be straight, curved, coiled, or found in a "6" or "U" shaped configuration. They are occasionally branched and the particles vary greatly in length but the diameter (about 80nm) is consistent.
They are produced by budding from an infected cell, and consist of the viral RNA strand and proteins encapsulated in a lipid membrane formed from the host cell's plasma membrane.
The inability of the immune system to clear these viruses may, at least in part, be due to the complex synthesis of a viral glycoprotein which forms heterotrimeric spikes within the virions plasma membrane. The gene encoding this protein in Ebola virus, but not Marburg virus, contains a stop codon and as a result two forms of the Ebola GP can be produced via a frame shift during translation. The full length GP precursor then undergoes proteolytic cleavage to form GP while a truncated form of GP, secreted GP (sGP), is produced from the non-frame-shifted sequence. This results in a variety of epitopes which may result in a less focused immune response that simply doesn't have the time to clear the infection before the organism succumbs.
Another virally expressed protein recognised by the immune system is VP40 which is normally expressed on the membrane complexed to VP24.
The filoviridae family was discovered in 1967 when 31 people were infected with the Marburg virus in Marburg, Germany after working with tissue from monkeys imported from Uganda [1]. Seven people who caught the disease died. All subsequent outbreaks have occurred in sub-Saharan Africa. The second genus of the filoviridae family, Ebola virus, was discovered in 1976 when outbreaks occurred in northern Zaire and southern Sudan. The Ebola virus is a very potent virus, having a mortality rate of 50% up to 90% reported in some of the Zaire outbreaks.
The natural reservoir of both the Marburg virus and the Ebola virus appears to be zoonotic, which means that the virus is transmitted to humans from other animals. Despite numerous attempts to find the source of both the Marburg and Ebola viruses, neither has been found. Bats though because they can replacate filoviriade-like viruses have been suspected [2].
The mechanisms through which filoviruses spread are not fully understood. The route of transmission from animals to humans is unknown. Person-to-person transmission occurs primarily through physical contact with infected bodily fluids. | https://www.wikidoc.org/index.php/Filoviridae |
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