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1d28b38d61aed62c9067edf0d1a7a23d5c9938eb	wikidoc	Silica gel	Silica gel Silica gel is a granular, porous form of silica made synthetically from sodium silicate. Despite the name, silica gel is a solid. Silica gel is most commonly encountered in everyday life as beads packed in a semi-permeable plastic. In this form, it is used as a desiccant to control local humidity in order to avoid spoilage of some goods. Because of poisonous dopants (see below) and their very high absorption of moisture, silica gel packets usually bear warnings for the user not to eat the contents. If consumed, the pure silica gel is unlikely to cause acute or chronic illness, but would be problematic nonetheless. However, some packaged desiccants may include fungicide and/or pesticide poisons. It is not known whether these would be labelled specifically. Food-grade desiccant should not include any poisons which would cause long-term harm to humans if consumed in the quantities normally included with the items of food. # History Silica gel was patented by chemistry professor Walter A. Patrick at Johns Hopkins University, Baltimore, Maryland in 1919. It was used in World War I for the absorption of vapors and gases in gas mask canisters, as part of his patent. The substance was in existence as early as the 1640s as a scientific curiosity. In World War II, silica gel was indispensable in the war effort for keeping penicillin dry, protecting military equipment from moisture damage, as a fluid cracking catalyst for the production of high octane gasoline, and as a catalyst support for the manufacture of butadiene from ethanol, feedstock for the synthetic rubber program. # Properties Silica gel's high surface area (around 800 m²/g) allows it to absorb water readily, making it useful as a desiccant (drying agent). Once saturated with water, the gel can be regenerated by heating to 120 °C (250 °F) for two hours. Some types of silica gel will "pop" when exposed to enough water. # Applications ## Desiccant In many items from leather to pepperoni, moisture encourages the growth of mold and spoilage. Condensation may also damage other items like electronics and may speed the decomposition of chemicals, such as those in vitamin pills. By adding sachets of silica gel, these items can be preserved longer. Silica gel may also be used to keep the relative humidity inside a high frequency radio or satellite transmission system waveguide as low as possible. Excessive moisture buildup within a waveguide can cause arcing inside the waveguide itself, damaging the power amplifier feeding it. Also, the beads of water that form and condense inside the waveguide change the characteristic impedance and frequency, impeding the signal. It is common for a small compressed air system (similar to a small home aquarium pump) to be employed to circulate the air inside the waveguide over a jar of silica gel. Silica gel is also used to dry the air in industrial compressed air systems. Air from the compressor discharge flows through a bed of silica gel beads. The silica gel adsorbs moisture from the air, preventing damage to the compressed air users due to condensation or moisture. The same system is used to dry the compressed air on railway locomotives, where condensation and ice in the brake air pipes can lead to brake failure. Silica gel is sometimes used as a preservation tool to control relative humidity in museum and library exhibitions and storage. ## Chemistry In chemistry, silica gel is used in chromatography as a stationary phase. In column chromatography the stationary phase is most often composed of silica gel particles of 40-63 μm. In this application, due to silica gel's polarity, non-polar components tend to elute before more polar ones, hence the name normal phase chromatography. However, when hydrophobic groups (such as C18 groups) are attached to the silica gel then polar components elute first and the method is referred to as reverse phase chromatography. Silica gel is also applied to aluminum or plastic sheets for thin layer chromatography. Chelating groups have also been covalently bound to silica gel. These materials have the ability to remove metal ions selectively from aqueous media. Chelating groups can be covalently bound to polyamines that have been grafted onto a silica gel surface producing a material of greater mechanical integrity. Silica gel is also combined with alkali metals to form a M-SG reducing agent. ## Cat litter Silica gel is also used as cat litter, by itself or in combination with more traditional materials, such as clays including bentonite. It is trackless and virtually odorless, albeit expensive. # Hazards Alone, silica gel is non-toxic, non-flammable and chemically unreactive. However, some of the beads may be doped with a moisture indicator, such as cobalt(II) chloride, which is toxic and may be carcinogenic. Cobalt (II) chloride is deep blue when dry (anhydrous) and pink when moist (hydrated). Crystalline silica dust can cause silicosis but synthetic amorphous silica gel is non-friable, and so does not cause silicosis. A chemically similar substance with far greater porosity is aerogel.	Silica gel Silica gel is a granular, porous form of silica made synthetically from sodium silicate. Despite the name, silica gel is a solid. Silica gel is most commonly encountered in everyday life as beads packed in a semi-permeable plastic. In this form, it is used as a desiccant to control local humidity in order to avoid spoilage of some goods. Because of poisonous dopants (see below) and their very high absorption of moisture, silica gel packets usually bear warnings for the user not to eat the contents. If consumed, the pure silica gel is unlikely to cause acute or chronic illness, but would be problematic nonetheless. However, some packaged desiccants may include fungicide and/or pesticide poisons. It is not known whether these would be labelled specifically. Food-grade desiccant should not include any poisons which would cause long-term harm to humans if consumed in the quantities normally included with the items of food. # History Silica gel was patented by chemistry professor Walter A. Patrick at Johns Hopkins University, Baltimore, Maryland in 1919. It was used in World War I for the absorption of vapors and gases in gas mask canisters, as part of his patent. The substance was in existence as early as the 1640s as a scientific curiosity.[1] In World War II, silica gel was indispensable in the war effort for keeping penicillin dry, protecting military equipment from moisture damage, as a fluid cracking catalyst for the production of high octane gasoline, and as a catalyst support for the manufacture of butadiene from ethanol, feedstock for the synthetic rubber program. # Properties Silica gel's high surface area (around 800 m²/g) allows it to absorb water readily, making it useful as a desiccant (drying agent). Once saturated with water, the gel can be regenerated by heating to 120 °C (250 °F) for two hours. Some types of silica gel will "pop" when exposed to enough water. # Applications ## Desiccant In many items from leather to pepperoni, moisture encourages the growth of mold and spoilage. Condensation may also damage other items like electronics and may speed the decomposition of chemicals, such as those in vitamin pills. By adding sachets of silica gel, these items can be preserved longer. Silica gel may also be used to keep the relative humidity inside a high frequency radio or satellite transmission system waveguide as low as possible. Excessive moisture buildup within a waveguide can cause arcing inside the waveguide itself, damaging the power amplifier feeding it. Also, the beads of water that form and condense inside the waveguide change the characteristic impedance and frequency, impeding the signal. It is common for a small compressed air system (similar to a small home aquarium pump) to be employed to circulate the air inside the waveguide over a jar of silica gel. Silica gel is also used to dry the air in industrial compressed air systems. Air from the compressor discharge flows through a bed of silica gel beads. The silica gel adsorbs moisture from the air, preventing damage to the compressed air users due to condensation or moisture. The same system is used to dry the compressed air on railway locomotives, where condensation and ice in the brake air pipes can lead to brake failure. Silica gel is sometimes used as a preservation tool to control relative humidity in museum and library exhibitions and storage. ## Chemistry In chemistry, silica gel is used in chromatography as a stationary phase. In column chromatography the stationary phase is most often composed of silica gel particles of 40-63 μm. In this application, due to silica gel's polarity, non-polar components tend to elute before more polar ones, hence the name normal phase chromatography. However, when hydrophobic groups (such as C18 groups) are attached to the silica gel then polar components elute first and the method is referred to as reverse phase chromatography. Silica gel is also applied to aluminum or plastic sheets for thin layer chromatography. Chelating groups have also been covalently bound to silica gel. These materials have the ability to remove metal ions selectively from aqueous media. Chelating groups can be covalently bound to polyamines that have been grafted onto a silica gel surface producing a material of greater mechanical integrity. Silica gel is also combined with alkali metals to form a M-SG reducing agent. ## Cat litter Silica gel is also used as cat litter[2], by itself or in combination with more traditional materials, such as clays including bentonite. It is trackless and virtually odorless, albeit expensive. # Hazards Alone, silica gel is non-toxic, non-flammable and chemically unreactive. However, some of the beads may be doped with a moisture indicator, such as cobalt(II) chloride, which is toxic and may be carcinogenic. Cobalt (II) chloride is deep blue when dry (anhydrous) and pink when moist (hydrated). Crystalline silica dust can cause silicosis but synthetic amorphous silica gel is non-friable, and so does not cause silicosis. A chemically similar substance with far greater porosity is aerogel.	https://www.wikidoc.org/index.php/Silica_gel
ad28d1b73d6890f866bdd613d1a1f3ce94b4422a	wikidoc	Siltuximab	Siltuximab - Siltuximab 11 mg/kg is given over 1 hour as an intravenous infusion administered every 3 weeks until treatment failure. - Perform hematology laboratory tests prior to each dose of Siltuximab therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in TABLE 1 are not met, consider delaying treatment with Siltuximab. Do not reduce dose. - Do not administer Siltuximab to patients with severe infections until the infection resolves. - Discontinue Siltuximab in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment. # Instructions for Preparation and Administration Use aseptic technique for reconstitution and preparation of dosing solution. - 1.- Calculate the dose (mg), total volume (mL) of reconstituted Siltuximab solution required and the number of vials needed. A 21-gauge 1-½ inch needle is recommended for preparation. Infusion bags (250 mL) must contain Dextrose 5% in Water and must be made of Polyvinyl chloride (PVC) with Di-{2-ethylhexyl}phthalate (DEHP), or Polyolefin (PO). - 2.- Allow the vial(s) of Siltuximab to come to room temperature over approximately 30 minutes. Siltuximab should remain at room temperature for the duration of the preparation. - 3.- Aseptically reconstitute each Siltuximab vial as instructed in TABLE 2. Gently swirl the reconstituted vials to aid the dissolution of the lyophilized powder. DO NOT SHAKE or SWIRL VIGOROUSLY. Do not remove the contents until all of the solids have been completely dissolved. The lyophilized powder should dissolve in less than 60 minutes. Once reconstituted, and prior to further dilution, inspect the vials for particulates and discoloration. Do not use if particles or solution discoloration are present or if visibly opaque. The reconstituted product should be kept for no more than two hours prior to addition into the infusion bag. - 4.- Dilute the reconstituted Siltuximab solution dose to 250 mL with sterile Dextrose 5% in Water by withdrawing a volume equal to the total calculated volume of reconstituted Siltuximab from the Dextrose 5% in Water, 250 mL bag. Slowly add the total calculated volume (mL) of reconstituted Siltuximab solution to the Dextrose 5% in Water infusion bag. Gently invert the bag to mix the solution. - 5.- Administer the diluted Siltuximab solution in 5% Dextrose in Water 250 mL by intravenous infusion over a period of 1 hour using administration sets lined with polyvinyl chloride (PVC) or polyurethane (PU), containing a 0.2-micron inline polyethersulfone (PES) filter. The infusion should be completed within 4 hours of the dilution of the reconstituted solution to the infusion bag. - 6.- Do not infuse Siltuximab concomitantly in the same intravenous line with other agents. - 7.- Do not store any unused portion of the reconstituted product or of the infusion solution. Waste material should be disposed of in accordance with local requirements. - Do not administer Siltuximab to patients with severe infections until the infection resolves. Siltuximab may mask signs and symptoms of acute inflammation including suppression of fever and of acute phase reactants such as C-reactive protein (CRP). Monitor patients receiving Siltuximab closely for infections. Institute prompt anti-infective therapy and do not administer further Siltuximab until the infection resolves. # Vaccinations - Do not administer live vaccines to patients receiving Siltuximab because IL-6 inhibition may interfere with the normal immune response to new antigens. # Infusion Related Reactions and Hypersensitivity - Stop the infusion of Siltuximab if the patient develops signs of anaphylaxis. Discontinue further therapy with Siltuximab. - Stop the infusion if the patient develops a mild to moderate infusion reaction. If the reaction resolves, the Siltuximab infusion may be restarted at a lower infusion rate. Consider medication with antihistamines, acetaminophen, and corticosteroids. Discontinue Siltuximab if the patient does not tolerate the infusion following these interventions. - Administer Siltuximab in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation. # Gastrointestinal Perforation - Gastrointestinal perforation has been reported in clinical trials although not in MCD trials. Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation. - Concurrent active severe infections. - Infusion-related reactions and hypersensitivity. # 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 clinical practice. - The most common adverse reactions (>10% compared to placebo) during treatment with Siltuximab in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection. - The data presented below in TABLE 3 were collected from Study 1. Study 1, in MCD, was an international, multicenter, randomized phase 2 study of every 3 week infusions comparing Siltuximab and best supportive care (BSC) to placebo and BSC. There were 53 patients randomized to the Siltuximab arm at a dose of 11 mg/kg and 26 patients randomized to the placebo arm. Of the 26 placebo-treated patients, 13 patients subsequently crossed-over to receive Siltuximab The median age was 48 years (range 20 to 78), 66% male, 48% Asian, 39% White, 4% Black or African American, 7% other. The patients randomized to Siltuximab received a median of 19 infusions (range 1 to 50) compared to patients randomized to placebo who received a median of 8 infusions (range 2 to 32). To control for disparate exposure between arms, Table 3 reports the per patient incidence of adverse reactions that occurred during the first 8 infusions. Adverse reactions that occurred >3% in the Siltuximab arm are presented. - Siltuximab was also evaluated as a single agent in another hematologic disease in Study 2. Study 2 was an international, multicenter, randomized phase 2 study of every 4 week infusions comparing Siltuximab and BSC to placebo and BSC. There were 50 patients randomized to the Siltuximab arm at a dose of 15 mg/kg (unapproved dose) and 26 patients randomized to the placebo arm. The median age was 72 years (range 50 to 85), 58% male, 96% White, 1% Asian, 1% Black, and 1% other. The median number of infusions in both arms was 3 (range 1 to 4). The study was stopped early due to a lack of efficacy. Adverse reactions that occurred >3% in the Siltuximab arm are presented in Table 4. # Long Term Exposure - The safety of long term administration of Siltuximab to patients with MCD was evaluated in Study 3. Study 3 enrolled patients from the initial dose finding study of Siltuximab with MCD who were benefiting from chronic Siltuximab therapy. Siltuximab was administered at a dose of 11 mg/kg every 3 to 6 weeks. At the time of data cut off 19 patients were enrolled. The median age was 44 years (range 18 – 76), 63% male, 84% Caucasian, 11% Asian, and 5% Black. The median exposure to Siltuximab for these 19 patients was 5.1 years (range 3.4 to 7.2). The most common adverse reaction (>20%) reported by subjects receiving Siltuximab in this study was upper respiratory tract infection (63%); diarrhea (32%); pain in extremities, arthralgia and fatigue (21% each). No patient was removed from therapy for any reason. There were no deaths. There were no cumulative toxicities identified with prolonged treatment with Siltuximab. # Anaphylaxis and Infusion Related Reactions - Approximately 750 patients have been treated with Siltuximab. Of these, one patient experienced an anaphylactic reaction. Data from 249 patients treated with Siltuximab monotherapy forms the basis of the safety evaluation of infusion related reactions. Infusion related reactions were reported in 4.8% of these patients. Symptoms of infusion reactions consisted of back pain, chest pain or discomfort, nausea and vomiting, flushing, erythema, and palpitations. # Immunogenicity - Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to Siltuximab with the incidence of antibodies to other products may be misleading. The clinical significance of anti-siltuximab antibodies following treatment with Siltuximab is not known. - The immunogenicity of siltuximab has been evaluated using antigen-bridging enzyme immunoassay (EIA) and electrochemiluminescence-based immunoassay (ECLIA) methods. A total of 411 patients across the clinical studies were evaluated at multiple time points for anti-therapeutic antibody (ATA) responses to siltuximab after treatment with Siltuximab Following Siltuximab dosing, 0.2% (1/411) of patients tested positive for anti-siltuximab antibodies. Further immunogenicity analyses of the single positive sample revealed a low titer of anti-siltuximab antibodies with non-neutralizing capabilities. - No evidence of altered toxicity profile was identified in the patient who developed antibodies to siltuximab. # Cytochrome P450 Substrates - Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in patients treated with Siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment with Siltuximab. - Upon initiation or discontinuation of Siltuximab, in patients being treated with CYP450 substrates with a narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. The effect of Siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy. Exercise caution when Siltuximab is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin). - There are no adequate or well-controlled studies in pregnant women. In animal reproduction studies, administration of a human antibody to IL-6 to pregnant cynomolgus monkeys caused decreases in globulin levels in pregnant animals and in the offspring. Siltuximab crossed the placenta in monkeys. Infants born to pregnant women treated with Siltuximab may be at increased risk of infection, and caution is advised in the administration of live vaccines to these infants. Siltuximab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Advise patients of childbearing potential to avoid pregnancy. Women of childbearing potential should use contraception during and for 3 months after treatment. # Animal Data - In an embryo-fetal development study, siltuximab doses of 9.2 or 46 mg/kg/week were administered intravenously to pregnant monkeys during gestation days (GD) 20 to 118, which includes the period of organogenesis. Fetuses were evaluated on GD 140, approximately 25 days prior to the natural birth. Exposures at the low and high dose after the 25th administration were approximately 3 and 7 times respectively the exposure in humans at the recommended dose of 11 mg/kg. There was no siltuximab-related maternal or fetal toxicity. However, siltuximab crossed the placenta at both doses and when measured on GD 140, fetal serum concentrations of siltuximab were similar to maternal concentrations. In a combined embryofetal and pre- and post-natal development study, cynomolgus monkeys were intravenously administered doses of 10 or 50 mg/kg/week of a human antibody to IL-6 from GD 20 to natural delivery (GD 167). The offspring was evaluated up to 7 months after birth for developmental effects. No maternal or infant toxicity was observed; however, globulin levels were decreased in pregnant animals (GD 34 through lactation day 30) and in the offspring (lactation days 30–120) at both doses. - Measurement of IL-6 concentrations in serum or plasma during treatment should not be used as pharmacodynamic marker, as siltuximab-neutralized antibody-IL-6 complexes interfere with current immunological-based IL-6 quantification methods. # Distribution - Following Siltuximab administration (11 mg/kg, once every 3 weeks as 1-hour intravenous infusion) in patients with multi centric Castleman's disease, the maximum serum siltuximab concentration (Cmax) occurred close to the end of infusion. At steady state, the serum mean Cmax value for siltuximab is 332 mcg/mL (42% CV), and the serum mean predose trough value is 84 mcg/mL (78% CV). - With the once every 3 week dosing regimen, siltuximab steady state is achieved by the sixth infusion, and siltuximab accumulates approximately 1.7-fold relative to a single dose. Following multiple dosing, siltuximab showed approximately dose proportional pharmacokinetics over the dose range of 2.8 to 11 mg/kg. - Based on population pharmacokinetic analysis, the central volume of distribution in a male subject with body weight of 70 kg is 4.5 L (20% CV). # Elimination - Based on the population pharmacokinetic analysis, the clearance of siltuximab in patients is 0.23 L/day (51% CV). Based on population pharmacokinetic analysis (n=378), body weight was identified as the only statistically significant covariate for siltuximab clearance. Therefore, the body weight based dosing is appropriate. - The mean terminal half-life (t1/2) for siltuximab in patients after the first intravenous infusion of 11 mg/kg is 20.6 days (range: 14.2 to 29.7 days). # Specific Populations - Age and Gender: Based on population pharmacokinetic analysis, age and gender do not affect exposure of siltuximab. - Renal Impairment: A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 377 patients enrolled in clinical trials, including 176 with normal renal function (CLCr ≥90 mL/min), 122 with mild renal impairment (CLCr 60 to <90 mL/min), 75 with moderate renal impairment (CLCr 30 to <60 mL/min), and 3 with severe renal impairment (CLCr 15 to 29 mL/min). The apparent clearance of siltuximab was similar in patients with pre-existing mild, moderate and severe renal impairment (CLCr 15 to <90 mL/min) compared to patients with normal renal function. The potential effect of end stage renal disease on siltuximab pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient. - Hepatic Impairment: A population pharmacokinetic analysis (based on pre-existing hepatic function) was carried out with data from 377 patients enrolled in clinical trials, including 302 with normal hepatic function, 72 with mild hepatic impairment (Child-Pugh A), and 3 with moderate hepatic impairment (Child-Pugh B). The apparent clearance of siltuximab was similar in patients with pre-existing mild and moderate hepatic impairment (Child-Pugh Class A and B) compared to patients with normal hepatic function. The potential effect of severe hepatic impairment on siltuximab pharmacokinetics cannot be determined as clinical and pharmacokinetic data are not available. - No carcinogenicity or genotoxicity studies have been conducted with siltuximab. - Two fertility studies were conducted. In one study, drug-treated male mice were mated with untreated females and in the second study drug-treated female mice were mated with untreated males. A murine analog of siltuximab was administered subcutaneously at doses up to 100 mg/kg/week for a total of 7 doses in both studies. There was no effect on male or female fertility parameters. In addition, siltuximab did not produce any toxicity in the reproductive organs in cynomolgus monkeys in the 6-month repeat-dose toxicology study at doses up to 46 mg/kg (approximately 7 times) the systemic exposure in patients at the recommended dose. - The major efficacy outcome of the study was durable tumor and symptomatic response, defined as tumor response (PR and CR based on modified International Working Group response criteria for malignant lymphoma) assessed by independent review and complete resolution or stabilization of MCD symptoms. Thirty-four MCD related signs and symptoms prospectively identified were collected and graded according to the NCI-CTCAE v 4, by investigators. A durable response was defined as tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. The durable tumor and symptomatic response in the Siltuximab arm was 34% compared to 0% in the placebo arm (95% CI: 11.1, 54.8; p=0.0012). - Other analyses included tumor response, time to treatment failure and an increase in hemoglobin of 1.5 g/dL or more, in patients who were anemic at time of study entry, at week 13. The results are summarized in TABLE 5. - A consistent treatment effect was confirmed on subgroup analysis for all parameters evaluated with the exception of the hyaline vascular histological subtype. There were no patients with hyaline vascular histology who demonstrated a durable tumor and symptomatic response. However, activity was suggested in this subtype based on change in hemoglobin and median time to treatment failure. - At the time of the analysis, overall survival data were not mature. One year survival rate was 100% in the Siltuximab arm and 92% in the placebo arm. - NDC 57894-420-01 contains one 100 mg vial, single use vial - NDC 57894-421-01 contains one 400 mg vial, single use vial - While stored, protect from light. This product contains no preservative. Patients or their caregivers should be advised of the potential benefits and risks of Siltuximab. Physicians should instruct their patients to read the patient labeling before starting Siltuximab therapy and to reread it each time they receive an infusion. It is important that the patient's overall health be assessed at each treatment visit and that any questions resulting from the patient's or their caregiver's reading of the patient labeling be discussed. # Infections - Inform patients that Siltuximab may lower their resistance to infections. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment. # Vaccination - Inform the patient that they should discuss the recommended vaccinations prior to treatment with Siltuximab. # Allergic Reactions - Advise patients to seek immediate medical attention if they experience any symptoms of serious allergic reactions during the infusion. Signs include: difficulty breathing, chest tightness, wheezing, severe dizziness or light-headedness, swelling of the lips or skin rash. # Contraception - Advise patients of childbearing potential to avoid pregnancy which may include use of contraception during treatment and for 3 months after Siltuximab therapy. # Other Medical Conditions - Advise patients to report any signs of new or worsening medical conditions.	Siltuximab - Siltuximab 11 mg/kg is given over 1 hour as an intravenous infusion administered every 3 weeks until treatment failure. - Perform hematology laboratory tests prior to each dose of Siltuximab therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in TABLE 1 are not met, consider delaying treatment with Siltuximab. Do not reduce dose. - Do not administer Siltuximab to patients with severe infections until the infection resolves. - Discontinue Siltuximab in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment. ### Instructions for Preparation and Administration Use aseptic technique for reconstitution and preparation of dosing solution. - 1.- Calculate the dose (mg), total volume (mL) of reconstituted Siltuximab solution required and the number of vials needed. A 21-gauge 1-½ inch needle is recommended for preparation. Infusion bags (250 mL) must contain Dextrose 5% in Water and must be made of Polyvinyl chloride (PVC) with Di-{2-ethylhexyl}phthalate (DEHP), or Polyolefin (PO). - 2.- Allow the vial(s) of Siltuximab to come to room temperature over approximately 30 minutes. Siltuximab should remain at room temperature for the duration of the preparation. - 3.- Aseptically reconstitute each Siltuximab vial as instructed in TABLE 2. Gently swirl the reconstituted vials to aid the dissolution of the lyophilized powder. DO NOT SHAKE or SWIRL VIGOROUSLY. Do not remove the contents until all of the solids have been completely dissolved. The lyophilized powder should dissolve in less than 60 minutes. Once reconstituted, and prior to further dilution, inspect the vials for particulates and discoloration. Do not use if particles or solution discoloration are present or if visibly opaque. The reconstituted product should be kept for no more than two hours prior to addition into the infusion bag. - 4.- Dilute the reconstituted Siltuximab solution dose to 250 mL with sterile Dextrose 5% in Water by withdrawing a volume equal to the total calculated volume of reconstituted Siltuximab from the Dextrose 5% in Water, 250 mL bag. Slowly add the total calculated volume (mL) of reconstituted Siltuximab solution to the Dextrose 5% in Water infusion bag. Gently invert the bag to mix the solution. - 5.- Administer the diluted Siltuximab solution in 5% Dextrose in Water 250 mL by intravenous infusion over a period of 1 hour using administration sets lined with polyvinyl chloride (PVC) or polyurethane (PU), containing a 0.2-micron inline polyethersulfone (PES) filter. The infusion should be completed within 4 hours of the dilution of the reconstituted solution to the infusion bag. - 6.- Do not infuse Siltuximab concomitantly in the same intravenous line with other agents. - 7.- Do not store any unused portion of the reconstituted product or of the infusion solution. Waste material should be disposed of in accordance with local requirements. - Do not administer Siltuximab to patients with severe infections until the infection resolves. Siltuximab may mask signs and symptoms of acute inflammation including suppression of fever and of acute phase reactants such as C-reactive protein (CRP). Monitor patients receiving Siltuximab closely for infections. Institute prompt anti-infective therapy and do not administer further Siltuximab until the infection resolves. ### Vaccinations - Do not administer live vaccines to patients receiving Siltuximab because IL-6 inhibition may interfere with the normal immune response to new antigens. ### Infusion Related Reactions and Hypersensitivity - Stop the infusion of Siltuximab if the patient develops signs of anaphylaxis. Discontinue further therapy with Siltuximab. - Stop the infusion if the patient develops a mild to moderate infusion reaction. If the reaction resolves, the Siltuximab infusion may be restarted at a lower infusion rate. Consider medication with antihistamines, acetaminophen, and corticosteroids. Discontinue Siltuximab if the patient does not tolerate the infusion following these interventions. - Administer Siltuximab in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation. ### Gastrointestinal Perforation - Gastrointestinal perforation has been reported in clinical trials although not in MCD trials. Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation. - Concurrent active severe infections. - Infusion-related reactions and hypersensitivity. ### 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 clinical practice. - The most common adverse reactions (>10% compared to placebo) during treatment with Siltuximab in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection. - The data presented below in TABLE 3 were collected from Study 1. Study 1, in MCD, was an international, multicenter, randomized phase 2 study of every 3 week infusions comparing Siltuximab and best supportive care (BSC) to placebo and BSC. There were 53 patients randomized to the Siltuximab arm at a dose of 11 mg/kg and 26 patients randomized to the placebo arm. Of the 26 placebo-treated patients, 13 patients subsequently crossed-over to receive Siltuximab The median age was 48 years (range 20 to 78), 66% male, 48% Asian, 39% White, 4% Black or African American, 7% other. The patients randomized to Siltuximab received a median of 19 infusions (range 1 to 50) compared to patients randomized to placebo who received a median of 8 infusions (range 2 to 32). To control for disparate exposure between arms, Table 3 reports the per patient incidence of adverse reactions that occurred during the first 8 infusions. Adverse reactions that occurred >3% in the Siltuximab arm are presented. - Siltuximab was also evaluated as a single agent in another hematologic disease in Study 2. Study 2 was an international, multicenter, randomized phase 2 study of every 4 week infusions comparing Siltuximab and BSC to placebo and BSC. There were 50 patients randomized to the Siltuximab arm at a dose of 15 mg/kg (unapproved dose) and 26 patients randomized to the placebo arm. The median age was 72 years (range 50 to 85), 58% male, 96% White, 1% Asian, 1% Black, and 1% other. The median number of infusions in both arms was 3 (range 1 to 4). The study was stopped early due to a lack of efficacy. Adverse reactions that occurred >3% in the Siltuximab arm are presented in Table 4. ### Long Term Exposure - The safety of long term administration of Siltuximab to patients with MCD was evaluated in Study 3. Study 3 enrolled patients from the initial dose finding study of Siltuximab with MCD who were benefiting from chronic Siltuximab therapy. Siltuximab was administered at a dose of 11 mg/kg every 3 to 6 weeks. At the time of data cut off 19 patients were enrolled. The median age was 44 years (range 18 – 76), 63% male, 84% Caucasian, 11% Asian, and 5% Black. The median exposure to Siltuximab for these 19 patients was 5.1 years (range 3.4 to 7.2). The most common adverse reaction (>20%) reported by subjects receiving Siltuximab in this study was upper respiratory tract infection (63%); diarrhea (32%); pain in extremities, arthralgia and fatigue (21% each). No patient was removed from therapy for any reason. There were no deaths. There were no cumulative toxicities identified with prolonged treatment with Siltuximab. ### Anaphylaxis and Infusion Related Reactions - Approximately 750 patients have been treated with Siltuximab. Of these, one patient experienced an anaphylactic reaction. Data from 249 patients treated with Siltuximab monotherapy forms the basis of the safety evaluation of infusion related reactions. Infusion related reactions were reported in 4.8% of these patients. Symptoms of infusion reactions consisted of back pain, chest pain or discomfort, nausea and vomiting, flushing, erythema, and palpitations. ### Immunogenicity - Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to Siltuximab with the incidence of antibodies to other products may be misleading. The clinical significance of anti-siltuximab antibodies following treatment with Siltuximab is not known. - The immunogenicity of siltuximab has been evaluated using antigen-bridging enzyme immunoassay (EIA) and electrochemiluminescence-based immunoassay (ECLIA) methods. A total of 411 patients across the clinical studies were evaluated at multiple time points for anti-therapeutic antibody (ATA) responses to siltuximab after treatment with Siltuximab Following Siltuximab dosing, 0.2% (1/411) of patients tested positive for anti-siltuximab antibodies. Further immunogenicity analyses of the single positive sample revealed a low titer of anti-siltuximab antibodies with non-neutralizing capabilities. - No evidence of altered toxicity profile was identified in the patient who developed antibodies to siltuximab. ### Cytochrome P450 Substrates - Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in patients treated with Siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment with Siltuximab. - Upon initiation or discontinuation of Siltuximab, in patients being treated with CYP450 substrates with a narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. The effect of Siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy. Exercise caution when Siltuximab is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin). - There are no adequate or well-controlled studies in pregnant women. In animal reproduction studies, administration of a human antibody to IL-6 to pregnant cynomolgus monkeys caused decreases in globulin levels in pregnant animals and in the offspring. Siltuximab crossed the placenta in monkeys. Infants born to pregnant women treated with Siltuximab may be at increased risk of infection, and caution is advised in the administration of live vaccines to these infants. Siltuximab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Advise patients of childbearing potential to avoid pregnancy. Women of childbearing potential should use contraception during and for 3 months after treatment. ### Animal Data - In an embryo-fetal development study, siltuximab doses of 9.2 or 46 mg/kg/week were administered intravenously to pregnant monkeys during gestation days (GD) 20 to 118, which includes the period of organogenesis. Fetuses were evaluated on GD 140, approximately 25 days prior to the natural birth. Exposures at the low and high dose after the 25th administration were approximately 3 and 7 times respectively the exposure in humans at the recommended dose of 11 mg/kg. There was no siltuximab-related maternal or fetal toxicity. However, siltuximab crossed the placenta at both doses and when measured on GD 140, fetal serum concentrations of siltuximab were similar to maternal concentrations. In a combined embryofetal and pre- and post-natal development study, cynomolgus monkeys were intravenously administered doses of 10 or 50 mg/kg/week of a human antibody to IL-6 from GD 20 to natural delivery (GD 167). The offspring was evaluated up to 7 months after birth for developmental effects. No maternal or infant toxicity was observed; however, globulin levels were decreased in pregnant animals (GD 34 through lactation day 30) and in the offspring (lactation days 30–120) at both doses. - Measurement of IL-6 concentrations in serum or plasma during treatment should not be used as pharmacodynamic marker, as siltuximab-neutralized antibody-IL-6 complexes interfere with current immunological-based IL-6 quantification methods. ### Distribution - Following Siltuximab administration (11 mg/kg, once every 3 weeks as 1-hour intravenous infusion) in patients with multi centric Castleman's disease, the maximum serum siltuximab concentration (Cmax) occurred close to the end of infusion. At steady state, the serum mean Cmax value for siltuximab is 332 mcg/mL (42% CV), and the serum mean predose trough value is 84 mcg/mL (78% CV). - With the once every 3 week dosing regimen, siltuximab steady state is achieved by the sixth infusion, and siltuximab accumulates approximately 1.7-fold relative to a single dose. Following multiple dosing, siltuximab showed approximately dose proportional pharmacokinetics over the dose range of 2.8 to 11 mg/kg. - Based on population pharmacokinetic analysis, the central volume of distribution in a male subject with body weight of 70 kg is 4.5 L (20% CV). ### Elimination - Based on the population pharmacokinetic analysis, the clearance of siltuximab in patients is 0.23 L/day (51% CV). Based on population pharmacokinetic analysis (n=378), body weight was identified as the only statistically significant covariate for siltuximab clearance. Therefore, the body weight based dosing is appropriate. - The mean terminal half-life (t1/2) for siltuximab in patients after the first intravenous infusion of 11 mg/kg is 20.6 days (range: 14.2 to 29.7 days). ### Specific Populations - Age and Gender: Based on population pharmacokinetic analysis, age [range: 18 to 85 years (n=378)] and gender [female (n=175), male (n=203)] do not affect exposure of siltuximab. - Renal Impairment: A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 377 patients enrolled in clinical trials, including 176 with normal renal function (CLCr ≥90 mL/min), 122 with mild renal impairment (CLCr 60 to <90 mL/min), 75 with moderate renal impairment (CLCr 30 to <60 mL/min), and 3 with severe renal impairment (CLCr 15 to 29 mL/min). The apparent clearance of siltuximab was similar in patients with pre-existing mild, moderate and severe renal impairment (CLCr 15 to <90 mL/min) compared to patients with normal renal function. The potential effect of end stage renal disease on siltuximab pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient. - Hepatic Impairment: A population pharmacokinetic analysis (based on pre-existing hepatic function) was carried out with data from 377 patients enrolled in clinical trials, including 302 with normal hepatic function, 72 with mild hepatic impairment (Child-Pugh A), and 3 with moderate hepatic impairment (Child-Pugh B). The apparent clearance of siltuximab was similar in patients with pre-existing mild and moderate hepatic impairment (Child-Pugh Class A and B) compared to patients with normal hepatic function. The potential effect of severe hepatic impairment on siltuximab pharmacokinetics cannot be determined as clinical and pharmacokinetic data are not available. - No carcinogenicity or genotoxicity studies have been conducted with siltuximab. - Two fertility studies were conducted. In one study, drug-treated male mice were mated with untreated females and in the second study drug-treated female mice were mated with untreated males. A murine analog of siltuximab was administered subcutaneously at doses up to 100 mg/kg/week for a total of 7 doses in both studies. There was no effect on male or female fertility parameters. In addition, siltuximab did not produce any toxicity in the reproductive organs in cynomolgus monkeys in the 6-month repeat-dose toxicology study at doses up to 46 mg/kg (approximately 7 times) the systemic exposure in patients at the recommended dose. - The major efficacy outcome of the study was durable tumor and symptomatic response, defined as tumor response (PR and CR based on modified International Working Group response criteria for malignant lymphoma) assessed by independent review and complete resolution or stabilization of MCD symptoms. Thirty-four MCD related signs and symptoms prospectively identified were collected and graded according to the NCI-CTCAE v 4, by investigators. A durable response was defined as tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. The durable tumor and symptomatic response in the Siltuximab arm was 34% compared to 0% in the placebo arm (95% CI: 11.1, 54.8; p=0.0012). - Other analyses included tumor response, time to treatment failure and an increase in hemoglobin of 1.5 g/dL or more, in patients who were anemic at time of study entry, at week 13. The results are summarized in TABLE 5. - A consistent treatment effect was confirmed on subgroup analysis for all parameters evaluated with the exception of the hyaline vascular histological subtype. There were no patients with hyaline vascular histology who demonstrated a durable tumor and symptomatic response. However, activity was suggested in this subtype based on change in hemoglobin and median time to treatment failure. - At the time of the analysis, overall survival data were not mature. One year survival rate was 100% in the Siltuximab arm and 92% in the placebo arm. - NDC 57894-420-01 contains one 100 mg vial, single use vial - NDC 57894-421-01 contains one 400 mg vial, single use vial - While stored, protect from light. This product contains no preservative. Patients or their caregivers should be advised of the potential benefits and risks of Siltuximab. Physicians should instruct their patients to read the patient labeling before starting Siltuximab therapy and to reread it each time they receive an infusion. It is important that the patient's overall health be assessed at each treatment visit and that any questions resulting from the patient's or their caregiver's reading of the patient labeling be discussed. ### Infections - Inform patients that Siltuximab may lower their resistance to infections. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment. ### Vaccination - Inform the patient that they should discuss the recommended vaccinations prior to treatment with Siltuximab. ### Allergic Reactions - Advise patients to seek immediate medical attention if they experience any symptoms of serious allergic reactions during the infusion. Signs include: difficulty breathing, chest tightness, wheezing, severe dizziness or light-headedness, swelling of the lips or skin rash. ### Contraception - Advise patients of childbearing potential to avoid pregnancy which may include use of contraception during treatment and for 3 months after Siltuximab therapy. ### Other Medical Conditions - Advise patients to report any signs of new or worsening medical conditions.	https://www.wikidoc.org/index.php/Siltuximab
08cd485cbb477a635f340abcbda490d7b4786deb	wikidoc	Simeprevir	Simeprevir # 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 Simeprevir is a hepatitis C virus NS3/4A protease inhibitor that is FDA approved for the treatment of chronic hepatitis C (CHC) genotype 1 infection as a component of a combination antiviral treatment regimen. Common adverse reactions include pruritus, rash, nausea, hyperbilirubinemia, headache, insomnia, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Indications Simeprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection as a component of a combination antiviral treatment regimen. - Simeprevir mono therapy is not recommended. - Simeprevir efficacy in combination with peg interferon alfa and ribavirin (RBV) is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with hepatitis C virus (HCV) genotype 1a without the Q80K polymorphism. Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism. - Simeprevir is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) due to substantial increases in simeprevir exposures, which have been associated with increased frequency of adverse reactions. - Simeprevir is not recommended in patients who have previously failed therapy with a treatment regimen that included simeprevir or other HCV protease inhibitors. ### Dosage Administer simeprevir in combination with other antiviral drugs for the treatment of CHC infection. For specific dosing recommendations for the antiviral drugs used in combination with simeprevir, refer to their respective prescribing information. Simeprevir monotherapy is not recommended. Administer simeprevir in combination with either: - Peg-IFN-alfa and RBV: Table 1 displays the recommended dosage regimen and treatment duration of simeprevir in combination with Peg-IFN-alfa and RBV. Refer to Table 3 for treatment stopping rules for simeprevir combination therapy with Peg-IFN-alfa and RBV; or - Sofosbuvir: Table 2 displays the recommended dosage regimen and treatment duration of simeprevir in combination with sofosbuvir. The recommended dosage of simeprevir is one capsule taken orally once daily with food. The capsule should be swallowed as a whole. Prior to initiation of treatment with simeprevir with Peg-IFN-alfa and RBV, screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism is strongly recommended and alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism. Prior to initiation of treatment with simeprevir with sofosbuvir, screening patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism is not strongly recommended but may be considered. Use with Peg-IFN-Alfa and RBV During treatment, HCV RNA levels should be monitored as clinically indicated using a sensitive assay with a lower limit of quantification of at least 25 IU/mL. Because patients with an inadequate on-treatment virologic response (i.e., HCV RNA ≥ 25 IU/mL) are not likely to achieve a sustained virologic response (SVR), discontinuation of treatment is recommended in these patients. Table 3 presents treatment stopping rules for patients who experience an inadequate on-treatment virology response at Weeks 4, 12, and 24. To prevent treatment failure, avoid reducing the dosage of simeprevir or interrupting treatment. If treatment with simeprevir is discontinued because of adverse reactions or inadequate on-treatment virologic response, simeprevir treatment must not be reinitiated. If adverse reactions potentially related to the antiviral drug(s) used in combination with simeprevir occur, refer to the instructions outlined in their respective prescribing information for recommendations on dosage adjustment or interruption. If any of the other antiviral drugs used in combination with simeprevir for the treatment of CHC infection are permanently discontinued for any reason, simeprevir should also be discontinued. No dosage recommendation can be made for patients with moderate hepatic impairment (Child-Pugh Class B) due to modest increases in simeprevir exposures. Simeprevir is not recommended for patients with severe hepatic impairment (Child-Pugh Class C) due to substantially higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. The safety and efficacy of simeprevir have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). Do not administer simeprevir in combination with Peg-IFN-alfa and RBV in patients with decompensated cirrhosis (moderate or severe hepatic impairment). The potential risks and benefits of simeprevir should be carefully considered prior to use in patients with moderate hepatic impairment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Simeprevir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Simeprevir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and efficacy of simeprevir 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 simeprevir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Simeprevir in pediatric patients. # Contraindications There are no specific contraindications to simeprevir. However, as simeprevir should always be administered in combination with other antiviral drugs for the treatment of chronic hepatitis C infection, prescribers should consult the complete prescribing information for these drugs for a description of contraindications. # Warnings ## Risk of Serious Adverse Reactions Associated With Combination Treatment Simeprevir should be used in combination with other antiviral drugs for the treatment of CHC infection. Therefore, consult the prescribing information for these drugs before starting therapy with simeprevir. Warnings and Precautions related to these drugs also apply to their use in simeprevir combination treatment. ### Photosensitivity Photosensitivity reactions have been observed with simeprevir combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with simeprevir in combination with Peg-IFN-alfa and ribavirin. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema. Use sun protective measures and limit sun exposure during treatment with simeprevir. Avoid use of tanning devices during treatment with simeprevir. Discontinuation of simeprevir should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue simeprevir in the setting of a photosensitivity reaction, expert consultation is advised. ### Rash Rash has been observed with simeprevir combination therapy. Rash occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of simeprevir have been reported in subjects receiving simeprevir in combination with Peg-IFN-alfa and RBV. Most of the rash events in Simeprevir-treated patients were of mild or moderate severity. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, simeprevir should be discontinued. Patients should be monitored until the rash has resolved. ### Sulfa Allergy Simeprevir contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of simeprevir. ### Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions Co-administration of simeprevir with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions # Adverse Reactions ## Clinical Trials Experience Simeprevir should be administered in combination with other antiviral drugs. Refer to the prescribing information of the antiviral drugs used in combination with simeprevir for a description of adverse reactions associated with their use. The following serious and otherwise important adverse drug reactions (ADRs) are discussed in detail in another section of the labeling: - Photosensitivity - Rash ### Clinical Trials Experience 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 clinical practice. Adverse Reactions when Used in Combination with Peg-IFN-Alfa and RBV The safety profile of simeprevir in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection who were treatment-naïve or who had previously relapsed following interferon therapy with or without RBV is based on pooled data from three Phase 3 trials. These trials included a total of 1178 subjects who received simeprevir or placebo in combination with 24 or 48 weeks of Peg-IFN-alfa and RBV. Of the 1178 subjects, 781 subjects were randomized to receive simeprevir 150 mg once daily for 12 weeks and 397 subjects were randomized to receive placebo once daily for 12 weeks. In the pooled Phase 3 safety data, the majority of the adverse reactions reported during 12 weeks treatment with simeprevir in combination with Peg-IFN-alfa and RBV were Grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 23% of subjects receiving simeprevir in combination with Peg-IFN-alfa and RBV versus 25% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Serious adverse reactions were reported in 2% of subjects receiving simeprevir in combination with Peg-IFN-alfa and RBV and in 3% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Discontinuation of simeprevir or placebo due to adverse reactions occurred in 2% and 1% of subjects receiving simeprevir with Peg-IFN-alfa and RBV and subjects receiving placebo with Peg-IFN-alfa and RBV, respectively. The following table lists adverse reactions (all Grades) that occurred with at least 3% higher frequency among subjects receiving simeprevir 150 mg once daily in combination with Peg-IFN-alfa and RBV, compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, during the first 12 weeks of treatment in the pooled Phase 3 trials in subjects who were treatment-naïve or who had previously relapsed after Peg-IFN-alfa and RBV therapy (see TABLE 4). In the Phase 3 clinical trials, rash (including photosensitivity reactions) was observed in 28% of Simeprevir-treated subjects compared to 20% of placebo-treated subjects during the 12 weeks of treatment with simeprevir or placebo in combination with Peg-IFN-alfa and RBV. Fifty-six percent (56%) of rash events in the simeprevir group occurred in the first 4 weeks, with 42% of cases occurring in the first 2 weeks. Most of the rash events in Simeprevir-treated subjects were of mild or moderate severity (Grade 1 or Grade 2). Severe (Grade 3) rash occurred in 1% of Simeprevir-treated subjects and in none of the placebo-treated subjects. There were no reports of life-threatening (Grade 4) rash. Discontinuation of simeprevir or placebo due to rash occurred in 1% of Simeprevir-treated subjects, compared to less than 1% of placebo-treated subjects. The frequencies of rash and photosensitivity reactions were higher in subjects with higher simeprevir exposures. All subjects enrolled in the Phase 3 trials were directed to use sun protection measures. In these trials, adverse reactions under the specific category of photosensitivity were reported in 5% of Simeprevir-treated subjects compared to 1% of placebo-treated subjects during the 12 weeks of treatment with simeprevir or placebo in combination with Peg-IFN-alfa and RBV. Most photosensitivity reactions in Simeprevir-treated subjects were of mild or moderate severity (Grade 1 or 2). Two Simeprevir-treated subjects experienced photosensitivity reactions which resulted in hospitalization. No life-threatening photosensitivity reactions were reported. ### Dyspnea During the 12 weeks of treatment with Simeprevir, dyspnea was reported in 12% of Simeprevir-treated subjects compared to 8% of placebo-treated subjects (all grades; pooled Phase 3 trials). All dyspnea events reported in Simeprevir-treated subjects were of mild or moderate severity (Grade 1 or 2). There were no Grade 3 or 4 dyspnea events reported and no subjects discontinued treatment with simeprevir due to dyspnea. Sixty-one percent (61%) of dyspnea events occurred in the first 4 weeks of treatment with simeprevir. ### Laboratory abnormalities There were no differences between treatment groups for the following laboratory parameters: hemoglobin, neutrophils, platelets, aspartate aminotransferase, alanine aminotransferase, amylase, or serum creatinine. Laboratory abnormalities that were observed at a higher incidence in Simeprevir-treated subjects than in placebo-treated subjects are listed in Table 5. Elevations in bilirubin were predominately mild to moderate (Grade 1 or 2) in severity, and included elevation of both direct and indirect bilirubin. Elevations in bilirubin occurred early after treatment initiation, peaking by study Week 2, and were rapidly reversible upon cessation of simeprevir. Bilirubin elevations were generally not associated with elevations in liver transaminases. ### Adverse Reactions when Used with Sofosbuvir In the COSMOS trial, the most common (> 10%) adverse reactions reported during 12 weeks treatment with simeprevir in combination with sofosbuvir without RBV were fatigue (25%), headache (21%), nausea (21%), insomnia (14%) and pruritus (11%). Rash and photosensitivity were reported in 11% and 7% of subjects, respectively. During 24 weeks treatment with simeprevir in combination with sofosbuvir, dizziness (16%), and diarrhea (16%) were also commonly reported. ## Postmarketing Experience There is limited information regarding Simeprevir Postmarketing Experience in the drug label. # Drug Interactions ## Potential for simeprevir to Affect Other Drugs Simeprevir mildly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but does not affect hepatic CYP3A4 activity. Co-administration of simeprevir with drugs that are primarily metabolized by CYP3A4 may result in increased plasma concentrations of such drugs (see TABLE 6). Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo. Simeprevir inhibits OATP1B1/3 and P-glycoprotein (P-gp) transporters. Co-administration of simeprevir with drugs that are substrates for OATP1B1/3 and P-gp transport may result in increased plasma concentrations of such drugs (see TABLE 6). ### Potential for Other Drugs to Affect Simeprevir The primary enzyme involved in the biotransformation of simeprevir is CYP3A. Clinically relevant effects of other drugs on simeprevir pharmacokinetics via CYP3A may occur. Co-administration of simeprevir with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir. Co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy (see TABLE 6). Therefore, co-administration of simeprevir with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended. ### Established and Other Potentially Significant Drug Interactions Table 6 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of simeprevir and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with simeprevir are also included in Table 6. For information regarding the magnitude of interaction, see TABLES 7 and 8. ### Drugs without Clinically Significant Interactions with Simeprevir In addition to the drugs included in Table 6, the interaction between simeprevir and the following drugs were evaluated in clinical studies and no dose adjustments are needed for either drug caffeine, dextromethorphan, escitalopram, ethinyl estradiol/norethindrone, methadone, midazolam (intravenous administration), omeprazole, raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir, disoproxil fumarate, and warfarin. No clinically relevant drug-drug interaction is expected when simeprevir is co-administered with antacids, the corticosteroids budesonide, fluticasone, methylprednisolone, and prednisone, fluvastatin, H2-receptor antagonists, the narcotic analgesics buprenorphine and naloxone, NRTIs (such as abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine), maraviroc, methylphenidate, and proton pump inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C ## Pregnancy Simeprevir must be administered in combination with other antiviral drugs. Refer to prescribing information of the drugs used in combination with simeprevir for information regarding use in pregnancy. Pregnancy Category C ### Risk Summary Adequate and well-controlled trials with simeprevir have not been conducted in pregnant women. In animal reproduction studies with simeprevir, embryofetal developmental toxicity was observed at drug exposures higher than human exposure at the recommended clinical dose. Simeprevir should be used during pregnancy only if the potential benefit justifies the potential risk. Female patients of childbearing potential should use an effective contraceptive method. If simeprevir is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on use in pregnancy. ### Animal Data Simeprevir showed no teratogenicity in rats and mice at exposures 0.5 times (in rats) and 6 times (in mice) the mean area under the plasma concentration time curve (AUC) in humans at the recommended dose of 150 mg once daily. In a mouse embryofetal study at doses up to 1000 mg/kg, simeprevir resulted in early and late in utero fetal losses and early maternal deaths at an exposure approximately 6 times higher than the mean AUC in humans at the recommended 150 mg daily dose. Significantly decreased fetal weights and an increase in fetal skeletal variations were seen at exposures approximately 4 times higher than the mean AUC in humans at the recommended daily dose. In a rat pre- and postnatal study, maternal animals were exposed to simeprevir during gestation and lactation at doses up to 1000 mg/kg/day. In pregnant rats, simeprevir resulted in early deaths at 1000 mg/kg/day corresponding to exposures similar to the mean AUC in humans at the recommended 150 mg once daily dose. Significant reduction in body weight gain was seen at an exposure 0.7 times the mean AUC in humans at the recommended 150 mg once daily dose. The developing rat offspring exhibited significantly decreased body weight and negative effects on physical growth (delay and small size) and development (decreased motor activity) following simeprevir exposure in utero (via maternal dosing) and during lactation (via maternal milk to nursing pups) at a maternal exposure similar to the mean AUC in humans at the recommended 150 mg once daily dose. Subsequent survival, behavior and reproductive capacity were not affected. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Simeprevir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Simeprevir during labor and delivery. ### Nursing Mothers ## Nursing Mothers It is not known whether simeprevir or its metabolites are present in human breast milk. When administered to lactating rats, simeprevir was detected in plasma of suckling rats likely due to excretion of simeprevir via milk. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with Simeprevir, taking into account the importance of the therapy to the mother. If simeprevir is administered in a regimen containing RBV, the information for RBV with regard to nursing mothers also applies to this combination regimen. ### Pediatric Use The safety and efficacy of simeprevir in pediatric patients have not been established. ### Geriatic Use Clinical studies of simeprevir did not include sufficient numbers of patients older than 65 years to determine whether they respond differently from younger patients. No dose adjustment of simeprevir is required in geriatric patients. ### Gender There is no FDA guidance on the use of Simeprevir with respect to specific gender populations. ### Race Patients of East Asian ancestry exhibit higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. There are insufficient safety data to recommend an appropriate dose for patients of East Asian ancestry. The potential risks and benefits of simeprevir should be carefully considered prior to use in patients of East Asian ancestry. ### Renal Impairment No dose adjustment of simeprevir is required in patients with mild, moderate or severe renal impairment. The safety and efficacy of simeprevir have not been studied in HCV-infected patients with severe renal impairment (creatinine clearance below 30 mL/min) or end-stage renal disease, including patients requiring dialysis. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir. Refer to the prescribing information for the other antiviral drug(s) used in combination with simeprevir regarding their use in patients with renal impairment. ### Hepatic Impairment No dose adjustment of simeprevir is required in patients with mild hepatic impairment (Child-Pugh Class A). The safety and efficacy of simeprevir have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). No dosage recommendation can be given for patients with moderate hepatic impairment (Child-Pugh Class B) due to modest increases in simeprevir exposures. Simeprevir is not recommended for patients with severe hepatic impairment (Child-Pugh Class C) due to substantially higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. The potential risks and benefits of simeprevir should be carefully considered prior to use in patients with moderate hepatic impairment. Refer to the prescribing information for the antiviral drug(s) used in combination with simeprevir regarding their use in patients with hepatic impairment. The combination of simeprevir with Peg-IFN-alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Simeprevir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Simeprevir in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - During treatment, HCV RNA levels should be monitored as clinically indicated using a sensitive assay with a lower limit of quantification of at least 25 IU/mL. Because patients with an inadequate on-treatment virology response (i.e., HCV RNA ≥ 25 IU/mL) are not likely to achieve a sustained virology response (SVR), discontinuation of treatment is recommended in these patients. - Discontinuation of simeprevir should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue simeprevir in the setting of a photosensitivity reaction, expert consultation is advised. - Discontinuation of simeprevir should be considered if the rash becomes severePatients should be monitored until the rash has resolved. - Concomitant use of simeprevir with digoxin resulted in increased concentrations of digoxin due to inhibition of P-gp by simeprevir. Routine therapeutic drug monitoring of digoxin concentrations is acceptable. - Concomitant use of simeprevir with these antiarrhythmics when given orally may result in mild increases in concentrations of these antiarrhythmics due to intestinal CYP3A4 inhibition by simeprevir. Therapeutic drug monitoring for these antiarrhythmics, if available, is recommended when co-administered with simeprevir. - Clinical monitoring of patients is recommended when simeprevir is co-administered with orally administered calcium channel blockers. - Concomitant use of simeprevir with simvastatin resulted in increased plasma concentrations of simvastatin. Titrate the simvastatin dose carefully and use the lowest necessary dose of simvastatin while monitoring for safety when co-administered with simeprevir. - Concomitant use of simeprevir with pitavastatin, pravastatin or lovastatin has not been studied. The dose of pitavastatin, pravastatin or lovastatin should be titrated carefully and the lowest necessary dose should be used while monitoring for safety when co-administered with simeprevir. - Concomitant use of simeprevir and sirolimus may result in mildly increased or decreased plasma concentrations of sirolimus. Routine monitoring of blood concentrations of sirolimus is acceptable. - Dose adjustment of the PDE-5 inhibitor may be required when simeprevir is co-administered with sildenafil or tadalafil administered chronically at doses used for the treatment of pulmonary arterial hypertension. Consider starting with the lowest dose of the PDE-5 inhibitor and increase as needed, with clinical monitoring as appropriate. # IV Compatibility There is limited information regarding the compatibility of Simeprevir and IV administrations. # Overdosage Human experience of overdose with simeprevir is limited. There is no specific antidote for overdose with simeprevir. In the event of an overdose, the patient's clinical status should be observed and the usual supportive measures employed. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir. # Pharmacology ## Mechanism of Action Simeprevir is a direct-acting antiviral (DAA) agent against the hepatitis C virus. ## Structure OLYSIO (simeprevir) is an inhibitor of the HCV NS3/4A protease. The chemical name for simeprevir is (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2-2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxy-8-methyl-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopentacyclopropadiazacyclotetradecine-12a(1H)-carboxamide. Its molecular formula is C38H47N5O7S2 and its molecular weight is 749.94. Simeprevir has the following structural formula: ### Chemical Structure Simeprevir drug substance is a white to almost white powder. Simeprevir is practically insoluble in water over a wide pH range. It is practically insoluble in propylene glycol, very slightly soluble in ethanol, and slightly soluble in acetone. It is soluble in dichloromethane and freely soluble in some organic solvents (e.g., tetrahydrofuran and N,N-dimethylformamide). OLYSIO (simeprevir) for oral administration is available as 150 mg strength hard gelatin capsules. Each capsule contains 154.4 mg of simeprevir sodium salt, which is equivalent to 150 mg of simeprevir. OLYSIO (simeprevir) capsules contain the following inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate and sodium lauryl sulphate. The white capsule contains gelatin and titanium dioxide (E171) and is printed with ink containing iron oxide black (E172) and shellac (E904). ## Pharmacodynamics ### Cardiac Electrophysiology The effect of simeprevir at the recommended dose of 150 mg once daily and 350 mg (at 2.3 times the recommended dosage) once daily for 7 days on the QT interval was evaluated in a randomized, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg once daily), 4-way cross-over study in 60 healthy subjects. No meaningful changes in QTc interval were observed at either the recommended dose of 150 mg once daily or the dose of 350 mg (2.3 times the recommended dosage) once daily. ## Pharmacokinetics The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in adult HCV-infected subjects. Plasma Cmax and AUC increased more than dose-proportionally after multiple doses between 75 mg and 200 mg once daily, with accumulation occurring following repeated dosing. Steady-state was reached after 7 days of once daily dosing. Plasma exposure (AUC) of simeprevir in HCV-infected subjects was about 2- to 3-fold higher compared to that observed in HCV-uninfected subjects. Plasma Cmax and AUC of simeprevir were similar during co-administration of simeprevir with Peg-IFN-alfa and RBV compared with administration of simeprevir alone. In HCV-infected subjects, the mean steady-state predose plasma concentration was 1936 ng/mL (standard deviation: 2640) and the mean steady-state AUC24 was 57469 ng.h/mL (standard deviation: 63571). ### Absorption Simeprevir is orally bioavailable. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours post dose. In vitro studies with human Caco-2 cells indicated that simeprevir is a substrate of P-gp. Effects of Food on Oral Absorption Administration of simeprevir with food to healthy subjects increased the relative bioavailability (AUC) by 61% and 69% after a high-fat, high-caloric (928 kcal) and normal-caloric (533 kcal) breakfast, respectively, and delayed the absorption by 1 hour and 1.5 hours, respectively. Due to increased bioavailability, simeprevir should be administered with food. The type of food does not affect exposure to simeprevir. ### Distribution Simeprevir is extensively bound to plasma proteins (greater than 99.9%), primarily to albumin and, to a lesser extent, alfa 1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. In animals, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues. In vitro data and physiologically-based pharmacokinetic modeling and simulations indicate that hepatic uptake in humans is mediated by OATP1B1/3. ### Metabolism Simeprevir is metabolized in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Co-administration of simeprevir with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir, and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir. Following a single oral administration of 200 mg (1.3 times the recommended dosage) 14C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (mean: 83%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in feces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O-demethylation followed by oxidation. ### Elimination Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its elimination. Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in feces. Less than 1% of the administered dose was recovered in urine. Unchanged simeprevir in feces accounted for on average 31% of the administered dose. The terminal elimination half-life of simeprevir was 10 to 13 hours in HCV-uninfected subjects and 41 hours in HCV-infected subjects receiving 200 mg (1.3 times the recommended dosage) of simeprevir. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility ### Carcinogenesis and Mutagenesis Simeprevir was not genotoxic in a series of in vitro and in vivo tests including the Ames test, the mammalian forward mutation assay in mouse lymphoma cells or the in vivo mammalian micronucleus test. Carcinogenicity studies with simeprevir have not been conducted. If Simeprevir is administered in a combination regimen containing RBV, refer to the prescribing information for RBV for information on carcinogenesis and mutagenesis. ### Impairment of Fertility In a rat fertility study at doses up to 500 mg/kg/day, 3 male rats treated with simeprevir (2/24 rats at 50 mg/kg/day and 1/24 rats at 500 mg/kg/day) showed no motile sperm, small testes and epididymides, and resulted in infertility in 2 out of 3 of the male rats at approximately 0.2 times the mean AUC in humans. If Simeprevir is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on impairment of fertility. ## Animal Toxicology and/or Pharmacology Cardiovascular toxicity consisting of acute endocardial and myocardial necrosis restricted to the left ventricular subendocardial area was seen in 2 out of 6 animals in a 2-week oral dog toxicity study at an exposure approximately 28 times the mean AUC in humans at the recommended daily dose of 150 mg. No cardiac findings were observed in a 6-month and a 9-month oral toxicity study at exposures, respectively, of 11 and 4 times the mean AUC in humans at the recommended daily dose of 150 mg. If Simeprevir is administered in a combination regimen containing sofosbuvir, refer to the prescribing information for sofosbuvir for information on animal toxicology. # Clinical Studies ## Overview of Clinical Trials The efficacy of Simeprevir in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection was evaluated in two Phase 3 trials in treatment-naïve subjects (trials QUEST 1 and QUEST 2), one Phase 3 trial in subjects who relapsed after prior interferon-based therapy (PROMISE) and one Phase 2 trial in subjects who failed prior therapy with Peg-IFN and RBV (including prior relapsers, partial and null responders) (ASPIRE). Prior relapsers were subjects who had HCV RNA not detected at the end of prior IFN-based therapy and HCV RNA detected during follow-up; prior partial responders were subjects with prior on-treatment greater than or equal to 2 log10 reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at the end of prior therapy with Peg-IFN and RBV; and null responders were subjects with prior on-treatment less than 2 log10 reduction in HCV RNA from baseline at Week 12 during prior therapy with Peg-IFN and RBV. Subjects in these trials had compensated liver disease (including cirrhosis), HCV RNA of at least 10000 IU/mL, and liver histopathology consistent with CHC infection. In subjects who were treatment-naïve and prior relapsers, the overall duration of treatment with Peg-IFN-alfa and RBV in the Phase 3 trials was response-guided. In these subjects, the planned total duration of HCV treatment was 24 weeks if the following on-treatment protocol-defined response-guided therapy (RGT) criteria were met: HCV RNA lower than 25 IU/mL (detected or not detected) at Week 4 AND HCV RNA not detected at Week 12. Plasma HCV RNA levels were measured using the Roche COBAS® TaqMan® HCV test (version 2.0), for use with the High Pure System (25 IU/mL lower limit of quantification and 15 IU/mL limit of detection). Treatment stopping rules for HCV therapy were used to ensure that subjects with inadequate on-treatment virologic response discontinued treatment in a timely manner. The efficacy of Simeprevir in combination with sofosbuvir without or with RBV was evaluated in a Phase 2 trial (COSMOS) in HCV genotype 1 infected prior null responders with METAVIR fibrosis score F0–F4 or treatment-naïve subjects with METAVIR fibrosis score F3–F4 and compensated liver disease. SVR was defined as HCV RNA not detected 24 weeks after planned end of treatment (SVR24) in the ASPIRE trial and was defined as HCV RNA lower than 25 IU/mL detected or not detected 12 weeks after the planned end of treatment (SVR12) in the COSMOS and Phase 3 trials. ## Treatment with Simeprevir in Combination with Peg-IFN-alfa and RBV Treatment-Naïve Adult Subjects with HCV Genotype 1 Infection The efficacy of Simeprevir in treatment-naïve patients with HCV genotype 1 infection was demonstrated in two randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trials (QUEST 1 and QUEST 2). The designs of both trials were similar. All subjects received 12 weeks of once daily treatment with 150 mg Simeprevir or placebo, plus Peg-IFN-alfa-2a (QUEST 1 and QUEST 2) or Peg-IFN-alfa-2b (QUEST 2) and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa and RBV in accordance with the on-treatment protocol-defined RGT criteria. Subjects in the control groups received 48 weeks of Peg-IFN-alfa-2a or -2b and RBV. In the pooled analysis for QUEST 1 and QUEST 2, demographics and baseline characteristics were balanced between both trials and between the Simeprevir and placebo treatment groups. In the pooled analysis of trials (QUEST 1 and QUEST 2), the 785 enrolled subjects had a median age of 47 years (range: 18 to 73 years); 56% were male; 91% were White, 7% Black or African American, 1% Asian, and 17% Hispanic; 23% had a body mass index (BMI) greater than or equal to 30 kg/m2; 78% had HCV RNA levels greater than 800000 IU/mL; 74% had METAVIR fibrosis score F0, F1 or F2, 16% METAVIR fibrosis score F3, and 10% METAVIR fibrosis score F4 (cirrhosis); 48% had HCV genotype 1a, and 51% HCV genotype 1b; 29% had IL28B CC genotype, 56% IL28B CT genotype, and 15% IL28B TT genotype; 17% of the overall population and 34% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. In QUEST 1, all subjects received Peg-IFN-alfa-2a; in QUEST 2, 69% of the subjects received Peg-IFN-alfa-2a and 31% received Peg-IFN-alfa-2b. Table 11 shows the response rates in treatment-naïve adult subjects with HCV genotype 1 infection. In the Simeprevir treatment group, SVR12 rates were lower in subjects with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism. In the pooled analysis of QUEST 1 and QUEST 2, 88% (459/521) of Simeprevir-treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 88% (405/459). Seventy-eight percent (78%; 404/521) of Simeprevir-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 90% (362/404), while 8% (32/392) with HCV RNA not detected at end of treatment had viral relapse. SVR12 rates were higher for the Simeprevir treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), METAVIR fibrosis score, and IL28B genotype. Table 12 shows the SVR rates by METAVIR fibrosis score. SVR12 rates were higher for subjects receiving Simeprevir with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (88% and 78%, respectively) compared to subjects receiving placebo with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (62% and 42%, respectively) (QUEST 2). Adult Subjects with HCV Genotype 1 Infection who Failed Prior Peg-IFN-alfa and RBV Therapy The PROMISE trial was a randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trial in subjects with HCV genotype 1 infection who relapsed after prior IFN-based therapy. All subjects received 12 weeks of once daily treatment with 150 mg Simeprevir or placebo, plus Peg-IFN-alfa-2a and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa-2a and RBV in accordance with the protocol-defined RGT criteria. Subjects in the control group received 48 weeks of Peg-IFN-alfa-2a and RBV. Demographics and baseline characteristics were balanced between the Simeprevir and placebo treatment groups. The 393 subjects enrolled in the PROMISE trial had a median age of 52 years (range: 20 to 71 years); 66% were male; 94% were White, 3% Black or African American, 2% Asian, and 7% Hispanic; 26% had a BMI greater than or equal to 30 kg/m2; 84% had HCV RNA levels greater than 800000 IU/mL; 69% had METAVIR fibrosis score F0, F1 or F2, 15% METAVIR fibrosis score F3, and 15% METAVIR fibrosis score F4 (cirrhosis); 42% had HCV genotype 1a, and 58% HCV genotype 1b; 24% had IL28B CC genotype, 64% IL28B CT genotype, and 12% IL28B TT genotype; 13% of the overall population and 31% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. The prior IFN-based HCV therapy was Peg-IFN-alfa-2a/RBV (68%) or Peg-IFN-alfa-2b/RBV (27%). Table 13 shows the response rates for the Simeprevir and placebo treatment groups in adult subjects with HCV genotype 1 infection who relapsed after prior interferon-based therapy. In the Simeprevir treatment group, SVR12 rates were lower in subjects infected with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism. In PROMISE, 93% (241/260) of Simeprevir-treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 83% (200/241). Seventy-seven percent (77%; 200/260) of Simeprevir-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 87% (173/200), while 13% (25/196) with HCV RNA not detected at end of treatment had viral relapse. SVR12 rates were higher for the Simeprevir treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), prior HCV therapy, METAVIR fibrosis score, and IL28B genotype. Table 14 shows the SVR rates by METAVIR fibrosis score. The ASPIRE trial was a randomized, double-blind, placebo-controlled, 7-arm, Phase 2 trial in subjects with HCV genotype 1 infection, who failed prior therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders). Subjects received 12, 24 or 48 weeks of 100 mg or 150 mg Simeprevir in combination with 48 weeks of Peg-IFN-alfa-2a and RBV, or 48 weeks of placebo in combination with 48 weeks of Peg-IFN-alfa-2a and RBV. Demographics and baseline characteristics were balanced between the Simeprevir and placebo treatment groups. The 462 subjects enrolled in the ASPIRE trial had a median age of 50 years (range: 20 to 69 years); 67% were male; 93% were White, 5% Black or African American, and 2% Asian; 25% had a BMI greater than or equal to 30 kg/m2; 86% had HCV RNA levels greater than 800000 IU/mL; 63% had METAVIR fibrosis score F0, F1, or F2, 19% METAVIR fibrosis score F3, and 18% METAVIR fibrosis score F4 (cirrhosis); 41% had HCV genotype 1a, and 58% HCV genotype 1b; 18% had IL28B CC genotype, 65% IL28B CT genotype, and 18% IL28B TT genotype (information available for 328 subjects); 12% of the overall population and 27% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. Forty percent (40%) of subjects were prior relapsers, 35% prior partial responders, and 25% prior null responders following prior therapy with Peg-IFN-alfa and RBV. One hundred ninety-nine subjects received Simeprevir 150 mg once daily (pooled analysis) of which 66 subjects received Simeprevir for 12 weeks and 66 subjects received placebo in combination with Peg-IFN-alfa and RBV. Table 15 shows the response rates for the OLYSIO and placebo treatment groups in prior relapsers, prior partial responders and prior null responders. In prior partial responders, SVR24 rates in subjects receiving Simeprevir with Peg-IFN-alfa and RBV were 47% and 77% in subjects with HCV genotype 1a and 1b, respectively, compared to 13% and 7%, respectively, in subjects receiving placebo with Peg-IFN-alfa and RBV. In prior null responders, SVR24 rates in subjects receiving Simeprevir with Peg-IFN-alfa and RBV were 41% and 47% in subjects with HCV genotype 1a and 1b, respectively, compared to 0% and 33%, respectively, in subjects receiving placebo with Peg-IFN-alfa and RBV. SVR24 rates were higher in the Simeprevir-treated subjects compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, regardless of HCV geno/subtype, METAVIR fibrosis score, and IL28B genotype. ## Simeprevir in Combination with Sofosbuvir Adult Subjects with HCV Genotype 1 Infection The COSMOS trial was an open-label, randomized Phase 2 trial to investigate the efficacy and safety of 12 or 24 weeks of Simeprevir (150 mg once daily) in combination with sofosbuvir (400 mg once daily) without or with RBV in HCV genotype 1-infected prior null responders with METAVIR fibrosis score F0–F2 (Cohort 1), or treatment-naïve subjects and prior null responders with METAVIR fibrosis score F3–F4 and compensated liver disease (Cohort 2). The 80 enrolled subjects without advanced hepatic fibrosis in Cohort 1 had a median age of 56 years (range 27 to 70 years; with 8% above 65 years); 61% were male; 71% were White, 29% Black or African American, and 25% were Hispanic; 30% had a BMI greater than or equal to 30 kg/m2; 98% had HCV RNA levels greater than 800,000 IU/mL; 41% had METAVIR fibrosis score F0 or F1 and 59% had METAVIR fibrosis score F2; 78% had HCV genotype 1a, and the remaining patients had HCV genotype 1b; 39% of the overall population and 50% of the subjects with genotype 1a had the NS3 Q80K polymorphism at baseline; 6% had IL28B CC genotype, 70% IL28B CT genotype, and 24% IL28B TT genotype. All subjects were prior null responders to Peg-IFN-alfa and RBV. The 87 enrolled subjects with advanced hepatic fibrosis in Cohort 2 had a median age of 58 years (range 28 to 70 years; with 3% above 65 years); 67% were male; 91% were White, 9% Black or African American, and 17% were Hispanic; 44% had a BMI greater than or equal to 30 kg/m2; 84% had HCV RNA levels greater than 800,000 IU/mL; 53% had METAVIR fibrosis score F3 and 47% had METAVIR fibrosis score F4 (cirrhosis); 78% had HCV genotype 1a, and 22% HCV genotype 1b; 31% of the overall population and 40% of the subjects with genotype 1a had the NS3 Q80K polymorphism at baseline; 21% had IL28B CC genotype, 56% IL28B CT genotype, and 23% IL28B TT genotype. Fifty-four percent of subjects were prior null responders to Peg-IFN-alfa and RBV and 46% were treatment-naïve. Table 16 shows the response rates by combining prior null responders in Cohort 1 and treatment-naïve subjects and prior null responders in Cohort 2. When treatment arms with and without ribavirin were combined, the overall SVR12 rate was 95% (61/64) in subjects with METAVIR fibrosis score F0-F3 who received 12 weeks treatment of Simeprevir in combination with sofosbuvir with/without RBV when pooling both cohorts. The overall SVR12 rate was 96% (22/23) in subjects with METAVIR fibrosis score F4 who received 24 weeks treatment of Simeprevir in combination with sofosbuvir with/without RBV when pooling both cohorts. Addition of RBV did not increase response rates in comparison with Simeprevir in combination with sofosbuvir alone; and therefore these data are not shown in Table 16. # How Supplied OLYSIO 150 mg capsules are white, marked with "TMC435 150" in black ink. The capsules are packaged into a bottle containing 28 capsules (NDC 59676-225-28) or a bottle of 7 capsules (emergency supply; NDC 59676-225-07). ## Storage Store simeprevir capsules in the original bottle in order to protect from light at room temperature below 30°C (86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information OLYSIO (oh li see oh) (simeprevir) Capsules Read this Patient Information before you start taking simeprevir 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 your treatment. Simeprevir is used in combination with other antiviral medicines for treating chronic hepatitis C infection. When taking simeprevir in combination with peginterferon alfa and ribavirin you should also read those Medication Guides. When taking simeprevir in combination with sofosbuvir, you should also read its Patient Information leaflet. ## What is the most important information I should know about Simeprevir? If you are pregnant, or plan to become pregnant, talk with your healthcare provider before taking simeprevir. It is not known if simeprevir will harm your unborn baby. Also read the Medication Guides for peginterferon alfa and ribavirin if your healthcare provider prescribes these medications for you in combination with simeprevir. Females must use an effective form of birth control during treatment with simeprevir. Talk with your healthcare provider about birth control methods that you may use during treatment with simeprevir. Simeprevir combination treatment may cause rashes and skin reactions to sunlight. These rashes and skin reactions to sunlight can be severe and you may need to be treated in a hospital. Rashes and skin reactions to sunlight are most common during the first 4 weeks of treatment, but can happen at any time during combination treatment with simeprevir. Use sunscreen, and wear a hat, sunglasses, and protective clothing when you will be exposed to sunlight during treatment with simeprevir. Limit sunlight exposure during treatment with simeprevir. Avoid use of tanning beds, sunlamps, or other types of light therapy during treatment with simeprevir. Call your healthcare provider right away if you get any of the following symptoms: burning, redness, swelling or blisters on your skin mouth sores or ulcers red or inflamed eyes, like "pink eye" (conjunctivitis) You should not take simeprevir alone. Simeprevir should be used together with other medicines to treat chronic hepatitis C infection. ## What is OLYSIO? OLYSIO is a prescription medicine used with other antiviral medicines to treat chronic (lasting a long time) hepatitis C infection in adults. OLYSIO should not be taken alone. It is not known if simeprevir is safe and effective in children under 18 years of age. ## Who should not take OLYSIO? "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT OLYSIO?" What should I tell my healthcare provider before taking OLYSIO? Before taking OLYSIO, tell your healthcare provider if you: have liver problems other than hepatitis C virus infection have ever taken any medicine to treat hepatitis C virus infection had a liver transplant are receiving phototherapy have any other medical condition are of East Asian descent are breastfeeding. It is not known if simeprevir passes into your breast milk. You and your healthcare provider should decide if you will take simeprevir or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. OLYSIO and other medicines may affect each other. This can cause you to have too much or not enough simeprevir or other medicines in your body, which may affect the way simeprevir or your other medicines work, or may cause side effects. Do not start taking a new medicine without telling your healthcare provider or pharmacist. ## Especially tell your healthcare provider if you take any of the following medicines: amiodarone (Cordarone, Pacerone), when taken by mouth amlodipine (Norvasc), when taken by mouth atazanavir (Reyataz) atorvastatin (Lipitor, Caduet) carbamazepine (Carbatrol, Epitol, Equetro, Tegretol) cisapride (Propulsid, Propulsid Quicksolv) clarithromycin (Biaxin, Prevpac) cobicistat-containing medicine (Stribild) cyclosporine (Gengraf, Neoral, Sandimmune) darunavir (Prezista) delavirdine mesylate (Rescriptor) dexamethasone, when taken by mouth or given by injection digoxin (Lanoxin) diltiazem (Cardizem, Dilacor XR, Tiazac), when taken by mouth disopyramide (Norpace), when taken by mouth efavirenz (Sustiva, Atripla) erythromycin (E.E.S., Eryc, Ery-Tab, Erythrocin, Erythrocin Stearate), when taken by mouth or when given by injection etravirine (Intelence) felodipine (Plendil), when taken by mouth flecainide (Tambocor), when taken by mouth fluconazole (Diflucan), when taken by mouth or when given by injection fosamprenavir (Lexiva) indinavir (Crixivan) itraconazole (Sporanox, Onmel), when taken by mouth ketoconazole (Nizoral), when taken by mouth lopinavir (Kaletra) lovastatin (Advicor, Altoprev, Mevacor) mexiletine (Mexitil), when taken by mouth midazolam, when taken by mouth milk thistle (Silybum marianum) or products containing milk thistle nelfinavir (Viracept) nevirapine (Viramune, Viramune XR) nicardipine (Cardene), when taken by mouth nifedipine (Adalat CC, Afeditab CR, Procardia), when taken by mouth nisoldipine (Sular), when taken by mouth -xcarbazepine (Oxtellar XR™, Trileptal) phenobarbital (Luminal) phenytoin (Dilantin, Phenytek) pitavastatin (Livalo) posaconazole (Noxafil), when taken by mouth pravastatin (Pravachol) propafenone (Rythmol SR), when taken by mouth quinidine (Nuedexta, Duraquin, Quinaglute), when taken by mouth rifabutin (Mycobutin) rifampin (Rifadin, Rifamate, Rifater, Rimactane) rifapentine (Priftin) ritonavir (Norvir) rosuvastatin (Crestor) saquinavir mesylate (Invirase) sildenafil (Revatio, Viagra) simvastatin (Zocor, Vytorin, Simcor) sirolimus (Rapamune) St. John's wort (Hypericum perforatum) or products containing St. John's wort tadalafil (Adcirca, Cialis) telithromycin (Ketek) tipranavir (Aptivus) triazolam (Halcion), when taken by mouth verapamil (Calan, Covera-HS, Isoptin, Tarka), when taken by mouth voriconazole (Vfend), when taken by mouth or when given by injection This is not a complete list of medicines that could interact with simeprevir. Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. ## How should I take OLYSIO? Take simeprevir exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to. Do not stop taking simeprevir unless your healthcare provider tells you to. If you think there is a reason to stop taking OLYSIO, talk to your healthcare provider before doing so. Take 1 simeprevir capsule each day with food. Swallow simeprevir capsules whole. If you miss a dose of simeprevir and it is more than 12 hours until your next dose, take the missed dose as soon as possible with food. Take the next dose of simeprevir at your regular time. If you miss a dose of simeprevir and it is less than 12 hours until your next dose, skip the missed dose. Take the next dose of simeprevir at your regular time. Do not take two doses of simeprevir at the same time to make up for a missed dose. If you take too much OLYSIO, call your healthcare provider right away or go to the nearest hospital emergency room. ## What are the possible side effects of OLYSIO? See "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT OLYSIO?" The most common side effects of simeprevir when used in combination with peginterferon alfa and ribavirin include: skin rash. See "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT OLYSIO?" section of this leaflet. itching nausea The most common side effects of simeprevir when used in combination with sofosbuvir include: tiredness headache nausea Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of simeprevir. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. ## How should I store OLYSIO? Store simeprevir at room temperature below 86°F (30°C). Store simeprevir in the original bottle to protect it from light. Keep simeprevir and all medicines out of the reach of children. General information about the safe and effective use of OLYSIO It is not known if treatment with simeprevir will prevent you from infecting another person with the hepatitis C virus during your treatment. Talk with your healthcare provider about ways to prevent spreading the hepatitis C virus. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use simeprevir for a condition for which it was not prescribed. Do not give your simeprevir to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about OLYSIO, talk with your pharmacist or healthcare provider. You can ask your pharmacist or healthcare provider for information about simeprevir that is written for health professionals. For more information about OLYSIO, go to www.simeprevir.com or call 1-800-526-7736. ## What are the ingredients in OLYSIO? Active ingredient: simeprevir Inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate, sodium lauryl sulphate. The white capsule contains gelatin and titanium dioxide (E171) and is printed with ink containing iron oxide black (E172) and shellac (E904). This Patient Information has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol Alcohol-Simeprevir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names OLYSIO,Galexos, Galexos, and Sovriad # Look-Alike Drug Names There is limited information about the look alike drug names. # Drug Shortage Status # Price	Simeprevir Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Turky Alkathery, 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 Simeprevir is a hepatitis C virus NS3/4A protease inhibitor that is FDA approved for the treatment of chronic hepatitis C (CHC) genotype 1 infection as a component of a combination antiviral treatment regimen. Common adverse reactions include pruritus, rash, nausea, hyperbilirubinemia, headache, insomnia, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Indications Simeprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection as a component of a combination antiviral treatment regimen. - Simeprevir mono therapy is not recommended. - Simeprevir efficacy in combination with peg interferon alfa and ribavirin (RBV) is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with hepatitis C virus (HCV) genotype 1a without the Q80K polymorphism. Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism. - Simeprevir is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) due to substantial increases in simeprevir exposures, which have been associated with increased frequency of adverse reactions. - Simeprevir is not recommended in patients who have previously failed therapy with a treatment regimen that included simeprevir or other HCV protease inhibitors. ### Dosage Administer simeprevir in combination with other antiviral drugs for the treatment of CHC infection. For specific dosing recommendations for the antiviral drugs used in combination with simeprevir, refer to their respective prescribing information. Simeprevir monotherapy is not recommended. Administer simeprevir in combination with either: - Peg-IFN-alfa and RBV: Table 1 displays the recommended dosage regimen and treatment duration of simeprevir in combination with Peg-IFN-alfa and RBV. Refer to Table 3 for treatment stopping rules for simeprevir combination therapy with Peg-IFN-alfa and RBV; or - Sofosbuvir: Table 2 displays the recommended dosage regimen and treatment duration of simeprevir in combination with sofosbuvir. The recommended dosage of simeprevir is one capsule taken orally once daily with food. The capsule should be swallowed as a whole. Prior to initiation of treatment with simeprevir with Peg-IFN-alfa and RBV, screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism is strongly recommended and alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism. Prior to initiation of treatment with simeprevir with sofosbuvir, screening patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism is not strongly recommended but may be considered. Use with Peg-IFN-Alfa and RBV During treatment, HCV RNA levels should be monitored as clinically indicated using a sensitive assay with a lower limit of quantification of at least 25 IU/mL. Because patients with an inadequate on-treatment virologic response (i.e., HCV RNA ≥ 25 IU/mL) are not likely to achieve a sustained virologic response (SVR), discontinuation of treatment is recommended in these patients. Table 3 presents treatment stopping rules for patients who experience an inadequate on-treatment virology response at Weeks 4, 12, and 24. To prevent treatment failure, avoid reducing the dosage of simeprevir or interrupting treatment. If treatment with simeprevir is discontinued because of adverse reactions or inadequate on-treatment virologic response, simeprevir treatment must not be reinitiated. If adverse reactions potentially related to the antiviral drug(s) used in combination with simeprevir occur, refer to the instructions outlined in their respective prescribing information for recommendations on dosage adjustment or interruption. If any of the other antiviral drugs used in combination with simeprevir for the treatment of CHC infection are permanently discontinued for any reason, simeprevir should also be discontinued. No dosage recommendation can be made for patients with moderate hepatic impairment (Child-Pugh Class B) due to modest increases in simeprevir exposures. Simeprevir is not recommended for patients with severe hepatic impairment (Child-Pugh Class C) due to substantially higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. The safety and efficacy of simeprevir have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). Do not administer simeprevir in combination with Peg-IFN-alfa and RBV in patients with decompensated cirrhosis (moderate or severe hepatic impairment). The potential risks and benefits of simeprevir should be carefully considered prior to use in patients with moderate hepatic impairment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Simeprevir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Simeprevir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and efficacy of simeprevir 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 simeprevir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Simeprevir in pediatric patients. # Contraindications There are no specific contraindications to simeprevir. However, as simeprevir should always be administered in combination with other antiviral drugs for the treatment of chronic hepatitis C infection, prescribers should consult the complete prescribing information for these drugs for a description of contraindications. # Warnings ## Risk of Serious Adverse Reactions Associated With Combination Treatment Simeprevir should be used in combination with other antiviral drugs for the treatment of CHC infection. Therefore, consult the prescribing information for these drugs before starting therapy with simeprevir. Warnings and Precautions related to these drugs also apply to their use in simeprevir combination treatment. ### Photosensitivity Photosensitivity reactions have been observed with simeprevir combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with simeprevir in combination with Peg-IFN-alfa and ribavirin. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema. Use sun protective measures and limit sun exposure during treatment with simeprevir. Avoid use of tanning devices during treatment with simeprevir. Discontinuation of simeprevir should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue simeprevir in the setting of a photosensitivity reaction, expert consultation is advised. ### Rash Rash has been observed with simeprevir combination therapy. Rash occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of simeprevir have been reported in subjects receiving simeprevir in combination with Peg-IFN-alfa and RBV. Most of the rash events in Simeprevir-treated patients were of mild or moderate severity. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, simeprevir should be discontinued. Patients should be monitored until the rash has resolved. ### Sulfa Allergy Simeprevir contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of simeprevir. ### Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions Co-administration of simeprevir with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions # Adverse Reactions ## Clinical Trials Experience Simeprevir should be administered in combination with other antiviral drugs. Refer to the prescribing information of the antiviral drugs used in combination with simeprevir for a description of adverse reactions associated with their use. The following serious and otherwise important adverse drug reactions (ADRs) are discussed in detail in another section of the labeling: - Photosensitivity - Rash ### Clinical Trials Experience 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 clinical practice. Adverse Reactions when Used in Combination with Peg-IFN-Alfa and RBV The safety profile of simeprevir in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection who were treatment-naïve or who had previously relapsed following interferon therapy with or without RBV is based on pooled data from three Phase 3 trials. These trials included a total of 1178 subjects who received simeprevir or placebo in combination with 24 or 48 weeks of Peg-IFN-alfa and RBV. Of the 1178 subjects, 781 subjects were randomized to receive simeprevir 150 mg once daily for 12 weeks and 397 subjects were randomized to receive placebo once daily for 12 weeks. In the pooled Phase 3 safety data, the majority of the adverse reactions reported during 12 weeks treatment with simeprevir in combination with Peg-IFN-alfa and RBV were Grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 23% of subjects receiving simeprevir in combination with Peg-IFN-alfa and RBV versus 25% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Serious adverse reactions were reported in 2% of subjects receiving simeprevir in combination with Peg-IFN-alfa and RBV and in 3% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Discontinuation of simeprevir or placebo due to adverse reactions occurred in 2% and 1% of subjects receiving simeprevir with Peg-IFN-alfa and RBV and subjects receiving placebo with Peg-IFN-alfa and RBV, respectively. The following table lists adverse reactions (all Grades) that occurred with at least 3% higher frequency among subjects receiving simeprevir 150 mg once daily in combination with Peg-IFN-alfa and RBV, compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, during the first 12 weeks of treatment in the pooled Phase 3 trials in subjects who were treatment-naïve or who had previously relapsed after Peg-IFN-alfa and RBV therapy (see TABLE 4). In the Phase 3 clinical trials, rash (including photosensitivity reactions) was observed in 28% of Simeprevir-treated subjects compared to 20% of placebo-treated subjects during the 12 weeks of treatment with simeprevir or placebo in combination with Peg-IFN-alfa and RBV. Fifty-six percent (56%) of rash events in the simeprevir group occurred in the first 4 weeks, with 42% of cases occurring in the first 2 weeks. Most of the rash events in Simeprevir-treated subjects were of mild or moderate severity (Grade 1 or Grade 2). Severe (Grade 3) rash occurred in 1% of Simeprevir-treated subjects and in none of the placebo-treated subjects. There were no reports of life-threatening (Grade 4) rash. Discontinuation of simeprevir or placebo due to rash occurred in 1% of Simeprevir-treated subjects, compared to less than 1% of placebo-treated subjects. The frequencies of rash and photosensitivity reactions were higher in subjects with higher simeprevir exposures. All subjects enrolled in the Phase 3 trials were directed to use sun protection measures. In these trials, adverse reactions under the specific category of photosensitivity were reported in 5% of Simeprevir-treated subjects compared to 1% of placebo-treated subjects during the 12 weeks of treatment with simeprevir or placebo in combination with Peg-IFN-alfa and RBV. Most photosensitivity reactions in Simeprevir-treated subjects were of mild or moderate severity (Grade 1 or 2). Two Simeprevir-treated subjects experienced photosensitivity reactions which resulted in hospitalization. No life-threatening photosensitivity reactions were reported. ### Dyspnea During the 12 weeks of treatment with Simeprevir, dyspnea was reported in 12% of Simeprevir-treated subjects compared to 8% of placebo-treated subjects (all grades; pooled Phase 3 trials). All dyspnea events reported in Simeprevir-treated subjects were of mild or moderate severity (Grade 1 or 2). There were no Grade 3 or 4 dyspnea events reported and no subjects discontinued treatment with simeprevir due to dyspnea. Sixty-one percent (61%) of dyspnea events occurred in the first 4 weeks of treatment with simeprevir. ### Laboratory abnormalities There were no differences between treatment groups for the following laboratory parameters: hemoglobin, neutrophils, platelets, aspartate aminotransferase, alanine aminotransferase, amylase, or serum creatinine. Laboratory abnormalities that were observed at a higher incidence in Simeprevir-treated subjects than in placebo-treated subjects are listed in Table 5. Elevations in bilirubin were predominately mild to moderate (Grade 1 or 2) in severity, and included elevation of both direct and indirect bilirubin. Elevations in bilirubin occurred early after treatment initiation, peaking by study Week 2, and were rapidly reversible upon cessation of simeprevir. Bilirubin elevations were generally not associated with elevations in liver transaminases. ### Adverse Reactions when Used with Sofosbuvir In the COSMOS trial, the most common (> 10%) adverse reactions reported during 12 weeks treatment with simeprevir in combination with sofosbuvir without RBV were fatigue (25%), headache (21%), nausea (21%), insomnia (14%) and pruritus (11%). Rash and photosensitivity were reported in 11% and 7% of subjects, respectively. During 24 weeks treatment with simeprevir in combination with sofosbuvir, dizziness (16%), and diarrhea (16%) were also commonly reported. ## Postmarketing Experience There is limited information regarding Simeprevir Postmarketing Experience in the drug label. # Drug Interactions ## Potential for simeprevir to Affect Other Drugs Simeprevir mildly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but does not affect hepatic CYP3A4 activity. Co-administration of simeprevir with drugs that are primarily metabolized by CYP3A4 may result in increased plasma concentrations of such drugs (see TABLE 6). Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo. Simeprevir inhibits OATP1B1/3 and P-glycoprotein (P-gp) transporters. Co-administration of simeprevir with drugs that are substrates for OATP1B1/3 and P-gp transport may result in increased plasma concentrations of such drugs (see TABLE 6). ### Potential for Other Drugs to Affect Simeprevir The primary enzyme involved in the biotransformation of simeprevir is CYP3A. Clinically relevant effects of other drugs on simeprevir pharmacokinetics via CYP3A may occur. Co-administration of simeprevir with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir. Co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy (see TABLE 6). Therefore, co-administration of simeprevir with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended. ### Established and Other Potentially Significant Drug Interactions Table 6 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of simeprevir and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with simeprevir are also included in Table 6. For information regarding the magnitude of interaction, see TABLES 7 and 8. ### Drugs without Clinically Significant Interactions with Simeprevir In addition to the drugs included in Table 6, the interaction between simeprevir and the following drugs were evaluated in clinical studies and no dose adjustments are needed for either drug caffeine, dextromethorphan, escitalopram, ethinyl estradiol/norethindrone, methadone, midazolam (intravenous administration), omeprazole, raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir, disoproxil fumarate, and warfarin. No clinically relevant drug-drug interaction is expected when simeprevir is co-administered with antacids, the corticosteroids budesonide, fluticasone, methylprednisolone, and prednisone, fluvastatin, H2-receptor antagonists, the narcotic analgesics buprenorphine and naloxone, NRTIs (such as abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine), maraviroc, methylphenidate, and proton pump inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C ## Pregnancy Simeprevir must be administered in combination with other antiviral drugs. Refer to prescribing information of the drugs used in combination with simeprevir for information regarding use in pregnancy. Pregnancy Category C ### Risk Summary Adequate and well-controlled trials with simeprevir have not been conducted in pregnant women. In animal reproduction studies with simeprevir, embryofetal developmental toxicity was observed at drug exposures higher than human exposure at the recommended clinical dose. Simeprevir should be used during pregnancy only if the potential benefit justifies the potential risk. Female patients of childbearing potential should use an effective contraceptive method. If simeprevir is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on use in pregnancy. ### Animal Data Simeprevir showed no teratogenicity in rats and mice at exposures 0.5 times (in rats) and 6 times (in mice) the mean area under the plasma concentration time curve (AUC) in humans at the recommended dose of 150 mg once daily. In a mouse embryofetal study at doses up to 1000 mg/kg, simeprevir resulted in early and late in utero fetal losses and early maternal deaths at an exposure approximately 6 times higher than the mean AUC in humans at the recommended 150 mg daily dose. Significantly decreased fetal weights and an increase in fetal skeletal variations were seen at exposures approximately 4 times higher than the mean AUC in humans at the recommended daily dose. In a rat pre- and postnatal study, maternal animals were exposed to simeprevir during gestation and lactation at doses up to 1000 mg/kg/day. In pregnant rats, simeprevir resulted in early deaths at 1000 mg/kg/day corresponding to exposures similar to the mean AUC in humans at the recommended 150 mg once daily dose. Significant reduction in body weight gain was seen at an exposure 0.7 times the mean AUC in humans at the recommended 150 mg once daily dose. The developing rat offspring exhibited significantly decreased body weight and negative effects on physical growth (delay and small size) and development (decreased motor activity) following simeprevir exposure in utero (via maternal dosing) and during lactation (via maternal milk to nursing pups) at a maternal exposure similar to the mean AUC in humans at the recommended 150 mg once daily dose. Subsequent survival, behavior and reproductive capacity were not affected. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Simeprevir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Simeprevir during labor and delivery. ### Nursing Mothers ## Nursing Mothers It is not known whether simeprevir or its metabolites are present in human breast milk. When administered to lactating rats, simeprevir was detected in plasma of suckling rats likely due to excretion of simeprevir via milk. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with Simeprevir, taking into account the importance of the therapy to the mother. If simeprevir is administered in a regimen containing RBV, the information for RBV with regard to nursing mothers also applies to this combination regimen. ### Pediatric Use The safety and efficacy of simeprevir in pediatric patients have not been established. ### Geriatic Use Clinical studies of simeprevir did not include sufficient numbers of patients older than 65 years to determine whether they respond differently from younger patients. No dose adjustment of simeprevir is required in geriatric patients. ### Gender There is no FDA guidance on the use of Simeprevir with respect to specific gender populations. ### Race Patients of East Asian ancestry exhibit higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. There are insufficient safety data to recommend an appropriate dose for patients of East Asian ancestry. The potential risks and benefits of simeprevir should be carefully considered prior to use in patients of East Asian ancestry. ### Renal Impairment No dose adjustment of simeprevir is required in patients with mild, moderate or severe renal impairment. The safety and efficacy of simeprevir have not been studied in HCV-infected patients with severe renal impairment (creatinine clearance below 30 mL/min) or end-stage renal disease, including patients requiring dialysis. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir. Refer to the prescribing information for the other antiviral drug(s) used in combination with simeprevir regarding their use in patients with renal impairment. ### Hepatic Impairment No dose adjustment of simeprevir is required in patients with mild hepatic impairment (Child-Pugh Class A). The safety and efficacy of simeprevir have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). No dosage recommendation can be given for patients with moderate hepatic impairment (Child-Pugh Class B) due to modest increases in simeprevir exposures. Simeprevir is not recommended for patients with severe hepatic impairment (Child-Pugh Class C) due to substantially higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. The potential risks and benefits of simeprevir should be carefully considered prior to use in patients with moderate hepatic impairment. Refer to the prescribing information for the antiviral drug(s) used in combination with simeprevir regarding their use in patients with hepatic impairment. The combination of simeprevir with Peg-IFN-alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Simeprevir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Simeprevir in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - During treatment, HCV RNA levels should be monitored as clinically indicated using a sensitive assay with a lower limit of quantification of at least 25 IU/mL. Because patients with an inadequate on-treatment virology response (i.e., HCV RNA ≥ 25 IU/mL) are not likely to achieve a sustained virology response (SVR), discontinuation of treatment is recommended in these patients. - Discontinuation of simeprevir should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue simeprevir in the setting of a photosensitivity reaction, expert consultation is advised. - Discontinuation of simeprevir should be considered if the rash becomes severePatients should be monitored until the rash has resolved. - Concomitant use of simeprevir with digoxin resulted in increased concentrations of digoxin due to inhibition of P-gp by simeprevir. Routine therapeutic drug monitoring of digoxin concentrations is acceptable. - Concomitant use of simeprevir with these antiarrhythmics when given orally may result in mild increases in concentrations of these antiarrhythmics due to intestinal CYP3A4 inhibition by simeprevir. Therapeutic drug monitoring for these antiarrhythmics, if available, is recommended when co-administered with simeprevir. - Clinical monitoring of patients is recommended when simeprevir is co-administered with orally administered calcium channel blockers. - Concomitant use of simeprevir with simvastatin resulted in increased plasma concentrations of simvastatin. Titrate the simvastatin dose carefully and use the lowest necessary dose of simvastatin while monitoring for safety when co-administered with simeprevir. - Concomitant use of simeprevir with pitavastatin, pravastatin or lovastatin has not been studied. The dose of pitavastatin, pravastatin or lovastatin should be titrated carefully and the lowest necessary dose should be used while monitoring for safety when co-administered with simeprevir. - Concomitant use of simeprevir and sirolimus may result in mildly increased or decreased plasma concentrations of sirolimus. Routine monitoring of blood concentrations of sirolimus is acceptable. - Dose adjustment of the PDE-5 inhibitor may be required when simeprevir is co-administered with sildenafil or tadalafil administered chronically at doses used for the treatment of pulmonary arterial hypertension. Consider starting with the lowest dose of the PDE-5 inhibitor and increase as needed, with clinical monitoring as appropriate. # IV Compatibility There is limited information regarding the compatibility of Simeprevir and IV administrations. # Overdosage Human experience of overdose with simeprevir is limited. There is no specific antidote for overdose with simeprevir. In the event of an overdose, the patient's clinical status should be observed and the usual supportive measures employed. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir. # Pharmacology ## Mechanism of Action Simeprevir is a direct-acting antiviral (DAA) agent against the hepatitis C virus. ## Structure OLYSIO (simeprevir) is an inhibitor of the HCV NS3/4A protease. The chemical name for simeprevir is (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2-2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxy-8-methyl-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide. Its molecular formula is C38H47N5O7S2 and its molecular weight is 749.94. Simeprevir has the following structural formula: ### Chemical Structure Simeprevir drug substance is a white to almost white powder. Simeprevir is practically insoluble in water over a wide pH range. It is practically insoluble in propylene glycol, very slightly soluble in ethanol, and slightly soluble in acetone. It is soluble in dichloromethane and freely soluble in some organic solvents (e.g., tetrahydrofuran and N,N-dimethylformamide). OLYSIO (simeprevir) for oral administration is available as 150 mg strength hard gelatin capsules. Each capsule contains 154.4 mg of simeprevir sodium salt, which is equivalent to 150 mg of simeprevir. OLYSIO (simeprevir) capsules contain the following inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate and sodium lauryl sulphate. The white capsule contains gelatin and titanium dioxide (E171) and is printed with ink containing iron oxide black (E172) and shellac (E904). ## Pharmacodynamics ### Cardiac Electrophysiology The effect of simeprevir at the recommended dose of 150 mg once daily and 350 mg (at 2.3 times the recommended dosage) once daily for 7 days on the QT interval was evaluated in a randomized, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg once daily), 4-way cross-over study in 60 healthy subjects. No meaningful changes in QTc interval were observed at either the recommended dose of 150 mg once daily or the dose of 350 mg (2.3 times the recommended dosage) once daily. ## Pharmacokinetics The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in adult HCV-infected subjects. Plasma Cmax and AUC increased more than dose-proportionally after multiple doses between 75 mg and 200 mg once daily, with accumulation occurring following repeated dosing. Steady-state was reached after 7 days of once daily dosing. Plasma exposure (AUC) of simeprevir in HCV-infected subjects was about 2- to 3-fold higher compared to that observed in HCV-uninfected subjects. Plasma Cmax and AUC of simeprevir were similar during co-administration of simeprevir with Peg-IFN-alfa and RBV compared with administration of simeprevir alone. In HCV-infected subjects, the mean steady-state predose plasma concentration was 1936 ng/mL (standard deviation: 2640) and the mean steady-state AUC24 was 57469 ng.h/mL (standard deviation: 63571). ### Absorption Simeprevir is orally bioavailable. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours post dose. In vitro studies with human Caco-2 cells indicated that simeprevir is a substrate of P-gp. Effects of Food on Oral Absorption Administration of simeprevir with food to healthy subjects increased the relative bioavailability (AUC) by 61% and 69% after a high-fat, high-caloric (928 kcal) and normal-caloric (533 kcal) breakfast, respectively, and delayed the absorption by 1 hour and 1.5 hours, respectively. Due to increased bioavailability, simeprevir should be administered with food. The type of food does not affect exposure to simeprevir. ### Distribution Simeprevir is extensively bound to plasma proteins (greater than 99.9%), primarily to albumin and, to a lesser extent, alfa 1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. In animals, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues. In vitro data and physiologically-based pharmacokinetic modeling and simulations indicate that hepatic uptake in humans is mediated by OATP1B1/3. ### Metabolism Simeprevir is metabolized in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Co-administration of simeprevir with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir, and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir. Following a single oral administration of 200 mg (1.3 times the recommended dosage) 14C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (mean: 83%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in feces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O-demethylation followed by oxidation. ### Elimination Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its elimination. Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in feces. Less than 1% of the administered dose was recovered in urine. Unchanged simeprevir in feces accounted for on average 31% of the administered dose. The terminal elimination half-life of simeprevir was 10 to 13 hours in HCV-uninfected subjects and 41 hours in HCV-infected subjects receiving 200 mg (1.3 times the recommended dosage) of simeprevir. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility ### Carcinogenesis and Mutagenesis Simeprevir was not genotoxic in a series of in vitro and in vivo tests including the Ames test, the mammalian forward mutation assay in mouse lymphoma cells or the in vivo mammalian micronucleus test. Carcinogenicity studies with simeprevir have not been conducted. If Simeprevir is administered in a combination regimen containing RBV, refer to the prescribing information for RBV for information on carcinogenesis and mutagenesis. ### Impairment of Fertility In a rat fertility study at doses up to 500 mg/kg/day, 3 male rats treated with simeprevir (2/24 rats at 50 mg/kg/day and 1/24 rats at 500 mg/kg/day) showed no motile sperm, small testes and epididymides, and resulted in infertility in 2 out of 3 of the male rats at approximately 0.2 times the mean AUC in humans. If Simeprevir is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on impairment of fertility. ## Animal Toxicology and/or Pharmacology Cardiovascular toxicity consisting of acute endocardial and myocardial necrosis restricted to the left ventricular subendocardial area was seen in 2 out of 6 animals in a 2-week oral dog toxicity study at an exposure approximately 28 times the mean AUC in humans at the recommended daily dose of 150 mg. No cardiac findings were observed in a 6-month and a 9-month oral toxicity study at exposures, respectively, of 11 and 4 times the mean AUC in humans at the recommended daily dose of 150 mg. If Simeprevir is administered in a combination regimen containing sofosbuvir, refer to the prescribing information for sofosbuvir for information on animal toxicology. # Clinical Studies ## Overview of Clinical Trials The efficacy of Simeprevir in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection was evaluated in two Phase 3 trials in treatment-naïve subjects (trials QUEST 1 and QUEST 2), one Phase 3 trial in subjects who relapsed after prior interferon-based therapy (PROMISE) and one Phase 2 trial in subjects who failed prior therapy with Peg-IFN and RBV (including prior relapsers, partial and null responders) (ASPIRE). Prior relapsers were subjects who had HCV RNA not detected at the end of prior IFN-based therapy and HCV RNA detected during follow-up; prior partial responders were subjects with prior on-treatment greater than or equal to 2 log10 reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at the end of prior therapy with Peg-IFN and RBV; and null responders were subjects with prior on-treatment less than 2 log10 reduction in HCV RNA from baseline at Week 12 during prior therapy with Peg-IFN and RBV. Subjects in these trials had compensated liver disease (including cirrhosis), HCV RNA of at least 10000 IU/mL, and liver histopathology consistent with CHC infection. In subjects who were treatment-naïve and prior relapsers, the overall duration of treatment with Peg-IFN-alfa and RBV in the Phase 3 trials was response-guided. In these subjects, the planned total duration of HCV treatment was 24 weeks if the following on-treatment protocol-defined response-guided therapy (RGT) criteria were met: HCV RNA lower than 25 IU/mL (detected or not detected) at Week 4 AND HCV RNA not detected at Week 12. Plasma HCV RNA levels were measured using the Roche COBAS® TaqMan® HCV test (version 2.0), for use with the High Pure System (25 IU/mL lower limit of quantification and 15 IU/mL limit of detection). Treatment stopping rules for HCV therapy were used to ensure that subjects with inadequate on-treatment virologic response discontinued treatment in a timely manner. The efficacy of Simeprevir in combination with sofosbuvir without or with RBV was evaluated in a Phase 2 trial (COSMOS) in HCV genotype 1 infected prior null responders with METAVIR fibrosis score F0–F4 or treatment-naïve subjects with METAVIR fibrosis score F3–F4 and compensated liver disease. SVR was defined as HCV RNA not detected 24 weeks after planned end of treatment (SVR24) in the ASPIRE trial and was defined as HCV RNA lower than 25 IU/mL detected or not detected 12 weeks after the planned end of treatment (SVR12) in the COSMOS and Phase 3 trials. ## Treatment with Simeprevir in Combination with Peg-IFN-alfa and RBV Treatment-Naïve Adult Subjects with HCV Genotype 1 Infection The efficacy of Simeprevir in treatment-naïve patients with HCV genotype 1 infection was demonstrated in two randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trials (QUEST 1 and QUEST 2). The designs of both trials were similar. All subjects received 12 weeks of once daily treatment with 150 mg Simeprevir or placebo, plus Peg-IFN-alfa-2a (QUEST 1 and QUEST 2) or Peg-IFN-alfa-2b (QUEST 2) and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa and RBV in accordance with the on-treatment protocol-defined RGT criteria. Subjects in the control groups received 48 weeks of Peg-IFN-alfa-2a or -2b and RBV. In the pooled analysis for QUEST 1 and QUEST 2, demographics and baseline characteristics were balanced between both trials and between the Simeprevir and placebo treatment groups. In the pooled analysis of trials (QUEST 1 and QUEST 2), the 785 enrolled subjects had a median age of 47 years (range: 18 to 73 years); 56% were male; 91% were White, 7% Black or African American, 1% Asian, and 17% Hispanic; 23% had a body mass index (BMI) greater than or equal to 30 kg/m2; 78% had HCV RNA levels greater than 800000 IU/mL; 74% had METAVIR fibrosis score F0, F1 or F2, 16% METAVIR fibrosis score F3, and 10% METAVIR fibrosis score F4 (cirrhosis); 48% had HCV genotype 1a, and 51% HCV genotype 1b; 29% had IL28B CC genotype, 56% IL28B CT genotype, and 15% IL28B TT genotype; 17% of the overall population and 34% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. In QUEST 1, all subjects received Peg-IFN-alfa-2a; in QUEST 2, 69% of the subjects received Peg-IFN-alfa-2a and 31% received Peg-IFN-alfa-2b. Table 11 shows the response rates in treatment-naïve adult subjects with HCV genotype 1 infection. In the Simeprevir treatment group, SVR12 rates were lower in subjects with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism. In the pooled analysis of QUEST 1 and QUEST 2, 88% (459/521) of Simeprevir-treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 88% (405/459). Seventy-eight percent (78%; 404/521) of Simeprevir-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 90% (362/404), while 8% (32/392) with HCV RNA not detected at end of treatment had viral relapse. SVR12 rates were higher for the Simeprevir treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), METAVIR fibrosis score, and IL28B genotype. Table 12 shows the SVR rates by METAVIR fibrosis score. SVR12 rates were higher for subjects receiving Simeprevir with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (88% and 78%, respectively) compared to subjects receiving placebo with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (62% and 42%, respectively) (QUEST 2). Adult Subjects with HCV Genotype 1 Infection who Failed Prior Peg-IFN-alfa and RBV Therapy The PROMISE trial was a randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trial in subjects with HCV genotype 1 infection who relapsed after prior IFN-based therapy. All subjects received 12 weeks of once daily treatment with 150 mg Simeprevir or placebo, plus Peg-IFN-alfa-2a and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa-2a and RBV in accordance with the protocol-defined RGT criteria. Subjects in the control group received 48 weeks of Peg-IFN-alfa-2a and RBV. Demographics and baseline characteristics were balanced between the Simeprevir and placebo treatment groups. The 393 subjects enrolled in the PROMISE trial had a median age of 52 years (range: 20 to 71 years); 66% were male; 94% were White, 3% Black or African American, 2% Asian, and 7% Hispanic; 26% had a BMI greater than or equal to 30 kg/m2; 84% had HCV RNA levels greater than 800000 IU/mL; 69% had METAVIR fibrosis score F0, F1 or F2, 15% METAVIR fibrosis score F3, and 15% METAVIR fibrosis score F4 (cirrhosis); 42% had HCV genotype 1a, and 58% HCV genotype 1b; 24% had IL28B CC genotype, 64% IL28B CT genotype, and 12% IL28B TT genotype; 13% of the overall population and 31% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. The prior IFN-based HCV therapy was Peg-IFN-alfa-2a/RBV (68%) or Peg-IFN-alfa-2b/RBV (27%). Table 13 shows the response rates for the Simeprevir and placebo treatment groups in adult subjects with HCV genotype 1 infection who relapsed after prior interferon-based therapy. In the Simeprevir treatment group, SVR12 rates were lower in subjects infected with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism. In PROMISE, 93% (241/260) of Simeprevir-treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 83% (200/241). Seventy-seven percent (77%; 200/260) of Simeprevir-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 87% (173/200), while 13% (25/196) with HCV RNA not detected at end of treatment had viral relapse. SVR12 rates were higher for the Simeprevir treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), prior HCV therapy, METAVIR fibrosis score, and IL28B genotype. Table 14 shows the SVR rates by METAVIR fibrosis score. The ASPIRE trial was a randomized, double-blind, placebo-controlled, 7-arm, Phase 2 trial in subjects with HCV genotype 1 infection, who failed prior therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders). Subjects received 12, 24 or 48 weeks of 100 mg or 150 mg Simeprevir in combination with 48 weeks of Peg-IFN-alfa-2a and RBV, or 48 weeks of placebo in combination with 48 weeks of Peg-IFN-alfa-2a and RBV. Demographics and baseline characteristics were balanced between the Simeprevir and placebo treatment groups. The 462 subjects enrolled in the ASPIRE trial had a median age of 50 years (range: 20 to 69 years); 67% were male; 93% were White, 5% Black or African American, and 2% Asian; 25% had a BMI greater than or equal to 30 kg/m2; 86% had HCV RNA levels greater than 800000 IU/mL; 63% had METAVIR fibrosis score F0, F1, or F2, 19% METAVIR fibrosis score F3, and 18% METAVIR fibrosis score F4 (cirrhosis); 41% had HCV genotype 1a, and 58% HCV genotype 1b; 18% had IL28B CC genotype, 65% IL28B CT genotype, and 18% IL28B TT genotype (information available for 328 subjects); 12% of the overall population and 27% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. Forty percent (40%) of subjects were prior relapsers, 35% prior partial responders, and 25% prior null responders following prior therapy with Peg-IFN-alfa and RBV. One hundred ninety-nine subjects received Simeprevir 150 mg once daily (pooled analysis) of which 66 subjects received Simeprevir for 12 weeks and 66 subjects received placebo in combination with Peg-IFN-alfa and RBV. Table 15 shows the response rates for the OLYSIO and placebo treatment groups in prior relapsers, prior partial responders and prior null responders. In prior partial responders, SVR24 rates in subjects receiving Simeprevir with Peg-IFN-alfa and RBV were 47% and 77% in subjects with HCV genotype 1a and 1b, respectively, compared to 13% and 7%, respectively, in subjects receiving placebo with Peg-IFN-alfa and RBV. In prior null responders, SVR24 rates in subjects receiving Simeprevir with Peg-IFN-alfa and RBV were 41% and 47% in subjects with HCV genotype 1a and 1b, respectively, compared to 0% and 33%, respectively, in subjects receiving placebo with Peg-IFN-alfa and RBV. SVR24 rates were higher in the Simeprevir-treated subjects compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, regardless of HCV geno/subtype, METAVIR fibrosis score, and IL28B genotype. ## Simeprevir in Combination with Sofosbuvir Adult Subjects with HCV Genotype 1 Infection The COSMOS trial was an open-label, randomized Phase 2 trial to investigate the efficacy and safety of 12 or 24 weeks of Simeprevir (150 mg once daily) in combination with sofosbuvir (400 mg once daily) without or with RBV in HCV genotype 1-infected prior null responders with METAVIR fibrosis score F0–F2 (Cohort 1), or treatment-naïve subjects and prior null responders with METAVIR fibrosis score F3–F4 and compensated liver disease (Cohort 2). The 80 enrolled subjects without advanced hepatic fibrosis in Cohort 1 had a median age of 56 years (range 27 to 70 years; with 8% above 65 years); 61% were male; 71% were White, 29% Black or African American, and 25% were Hispanic; 30% had a BMI greater than or equal to 30 kg/m2; 98% had HCV RNA levels greater than 800,000 IU/mL; 41% had METAVIR fibrosis score F0 or F1 and 59% had METAVIR fibrosis score F2; 78% had HCV genotype 1a, and the remaining patients had HCV genotype 1b; 39% of the overall population and 50% of the subjects with genotype 1a had the NS3 Q80K polymorphism at baseline; 6% had IL28B CC genotype, 70% IL28B CT genotype, and 24% IL28B TT genotype. All subjects were prior null responders to Peg-IFN-alfa and RBV. The 87 enrolled subjects with advanced hepatic fibrosis in Cohort 2 had a median age of 58 years (range 28 to 70 years; with 3% above 65 years); 67% were male; 91% were White, 9% Black or African American, and 17% were Hispanic; 44% had a BMI greater than or equal to 30 kg/m2; 84% had HCV RNA levels greater than 800,000 IU/mL; 53% had METAVIR fibrosis score F3 and 47% had METAVIR fibrosis score F4 (cirrhosis); 78% had HCV genotype 1a, and 22% HCV genotype 1b; 31% of the overall population and 40% of the subjects with genotype 1a had the NS3 Q80K polymorphism at baseline; 21% had IL28B CC genotype, 56% IL28B CT genotype, and 23% IL28B TT genotype. Fifty-four percent of subjects were prior null responders to Peg-IFN-alfa and RBV and 46% were treatment-naïve. Table 16 shows the response rates by combining prior null responders in Cohort 1 and treatment-naïve subjects and prior null responders in Cohort 2. When treatment arms with and without ribavirin were combined, the overall SVR12 rate was 95% (61/64) in subjects with METAVIR fibrosis score F0-F3 who received 12 weeks treatment of Simeprevir in combination with sofosbuvir with/without RBV when pooling both cohorts. The overall SVR12 rate was 96% (22/23) in subjects with METAVIR fibrosis score F4 who received 24 weeks treatment of Simeprevir in combination with sofosbuvir with/without RBV when pooling both cohorts. Addition of RBV did not increase response rates in comparison with Simeprevir in combination with sofosbuvir alone; and therefore these data are not shown in Table 16. # How Supplied OLYSIO 150 mg capsules are white, marked with "TMC435 150" in black ink. The capsules are packaged into a bottle containing 28 capsules (NDC 59676-225-28) or a bottle of 7 capsules (emergency supply; NDC 59676-225-07). ## Storage Store simeprevir capsules in the original bottle in order to protect from light at room temperature below 30°C (86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information OLYSIO (oh li see oh) (simeprevir) Capsules Read this Patient Information before you start taking simeprevir 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 your treatment. Simeprevir is used in combination with other antiviral medicines for treating chronic hepatitis C infection. When taking simeprevir in combination with peginterferon alfa and ribavirin you should also read those Medication Guides. When taking simeprevir in combination with sofosbuvir, you should also read its Patient Information leaflet. ## What is the most important information I should know about Simeprevir? If you are pregnant, or plan to become pregnant, talk with your healthcare provider before taking simeprevir. It is not known if simeprevir will harm your unborn baby. Also read the Medication Guides for peginterferon alfa and ribavirin if your healthcare provider prescribes these medications for you in combination with simeprevir. Females must use an effective form of birth control during treatment with simeprevir. Talk with your healthcare provider about birth control methods that you may use during treatment with simeprevir. Simeprevir combination treatment may cause rashes and skin reactions to sunlight. These rashes and skin reactions to sunlight can be severe and you may need to be treated in a hospital. Rashes and skin reactions to sunlight are most common during the first 4 weeks of treatment, but can happen at any time during combination treatment with simeprevir. Use sunscreen, and wear a hat, sunglasses, and protective clothing when you will be exposed to sunlight during treatment with simeprevir. Limit sunlight exposure during treatment with simeprevir. Avoid use of tanning beds, sunlamps, or other types of light therapy during treatment with simeprevir. Call your healthcare provider right away if you get any of the following symptoms: burning, redness, swelling or blisters on your skin mouth sores or ulcers red or inflamed eyes, like "pink eye" (conjunctivitis) You should not take simeprevir alone. Simeprevir should be used together with other medicines to treat chronic hepatitis C infection. ## What is OLYSIO? OLYSIO is a prescription medicine used with other antiviral medicines to treat chronic (lasting a long time) hepatitis C infection in adults. OLYSIO should not be taken alone. It is not known if simeprevir is safe and effective in children under 18 years of age. ## Who should not take OLYSIO? "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT OLYSIO?" What should I tell my healthcare provider before taking OLYSIO? Before taking OLYSIO, tell your healthcare provider if you: have liver problems other than hepatitis C virus infection have ever taken any medicine to treat hepatitis C virus infection had a liver transplant are receiving phototherapy have any other medical condition are of East Asian descent are breastfeeding. It is not known if simeprevir passes into your breast milk. You and your healthcare provider should decide if you will take simeprevir or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. OLYSIO and other medicines may affect each other. This can cause you to have too much or not enough simeprevir or other medicines in your body, which may affect the way simeprevir or your other medicines work, or may cause side effects. Do not start taking a new medicine without telling your healthcare provider or pharmacist. ## Especially tell your healthcare provider if you take any of the following medicines: amiodarone (Cordarone, Pacerone), when taken by mouth amlodipine (Norvasc), when taken by mouth atazanavir (Reyataz) atorvastatin (Lipitor, Caduet) carbamazepine (Carbatrol, Epitol, Equetro, Tegretol) cisapride (Propulsid, Propulsid Quicksolv) clarithromycin (Biaxin, Prevpac) cobicistat-containing medicine (Stribild) cyclosporine (Gengraf, Neoral, Sandimmune) darunavir (Prezista) delavirdine mesylate (Rescriptor) dexamethasone, when taken by mouth or given by injection digoxin (Lanoxin) diltiazem (Cardizem, Dilacor XR, Tiazac), when taken by mouth disopyramide (Norpace), when taken by mouth efavirenz (Sustiva, Atripla) erythromycin (E.E.S., Eryc, Ery-Tab, Erythrocin, Erythrocin Stearate), when taken by mouth or when given by injection etravirine (Intelence) felodipine (Plendil), when taken by mouth flecainide (Tambocor), when taken by mouth fluconazole (Diflucan), when taken by mouth or when given by injection fosamprenavir (Lexiva) indinavir (Crixivan) itraconazole (Sporanox, Onmel), when taken by mouth ketoconazole (Nizoral), when taken by mouth lopinavir (Kaletra) lovastatin (Advicor, Altoprev, Mevacor) mexiletine (Mexitil), when taken by mouth midazolam, when taken by mouth milk thistle (Silybum marianum) or products containing milk thistle nelfinavir (Viracept) nevirapine (Viramune, Viramune XR) nicardipine (Cardene), when taken by mouth nifedipine (Adalat CC, Afeditab CR, Procardia), when taken by mouth nisoldipine (Sular), when taken by mouth oxcarbazepine (Oxtellar XR™, Trileptal) phenobarbital (Luminal) phenytoin (Dilantin, Phenytek) pitavastatin (Livalo) posaconazole (Noxafil), when taken by mouth pravastatin (Pravachol) propafenone (Rythmol SR), when taken by mouth quinidine (Nuedexta, Duraquin, Quinaglute), when taken by mouth rifabutin (Mycobutin) rifampin (Rifadin, Rifamate, Rifater, Rimactane) rifapentine (Priftin) ritonavir (Norvir) rosuvastatin (Crestor) saquinavir mesylate (Invirase) sildenafil (Revatio, Viagra) simvastatin (Zocor, Vytorin, Simcor) sirolimus (Rapamune) St. John's wort (Hypericum perforatum) or products containing St. John's wort tadalafil (Adcirca, Cialis) telithromycin (Ketek) tipranavir (Aptivus) triazolam (Halcion), when taken by mouth verapamil (Calan, Covera-HS, Isoptin, Tarka), when taken by mouth voriconazole (Vfend), when taken by mouth or when given by injection This is not a complete list of medicines that could interact with simeprevir. Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. ## How should I take OLYSIO? Take simeprevir exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to. Do not stop taking simeprevir unless your healthcare provider tells you to. If you think there is a reason to stop taking OLYSIO, talk to your healthcare provider before doing so. Take 1 simeprevir capsule each day with food. Swallow simeprevir capsules whole. If you miss a dose of simeprevir and it is more than 12 hours until your next dose, take the missed dose as soon as possible with food. Take the next dose of simeprevir at your regular time. If you miss a dose of simeprevir and it is less than 12 hours until your next dose, skip the missed dose. Take the next dose of simeprevir at your regular time. Do not take two doses of simeprevir at the same time to make up for a missed dose. If you take too much OLYSIO, call your healthcare provider right away or go to the nearest hospital emergency room. ## What are the possible side effects of OLYSIO? See "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT OLYSIO?" The most common side effects of simeprevir when used in combination with peginterferon alfa and ribavirin include: skin rash. See "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT OLYSIO?" section of this leaflet. itching nausea The most common side effects of simeprevir when used in combination with sofosbuvir include: tiredness headache nausea Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of simeprevir. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. ## How should I store OLYSIO? Store simeprevir at room temperature below 86°F (30°C). Store simeprevir in the original bottle to protect it from light. Keep simeprevir and all medicines out of the reach of children. General information about the safe and effective use of OLYSIO It is not known if treatment with simeprevir will prevent you from infecting another person with the hepatitis C virus during your treatment. Talk with your healthcare provider about ways to prevent spreading the hepatitis C virus. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use simeprevir for a condition for which it was not prescribed. Do not give your simeprevir to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about OLYSIO, talk with your pharmacist or healthcare provider. You can ask your pharmacist or healthcare provider for information about simeprevir that is written for health professionals. For more information about OLYSIO, go to www.simeprevir.com or call 1-800-526-7736. ## What are the ingredients in OLYSIO? Active ingredient: simeprevir Inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate, sodium lauryl sulphate. The white capsule contains gelatin and titanium dioxide (E171) and is printed with ink containing iron oxide black (E172) and shellac (E904). This Patient Information has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol Alcohol-Simeprevir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names OLYSIO,Galexos, Galexos, and Sovriad # Look-Alike Drug Names There is limited information about the look alike drug names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Simeprevir
d206c957c09a7458036049d7b528cb2e69bd5d6e	wikidoc	Sinicuichi	Sinicuichi Sinicuichi (Heimia), also known as sun opener or shrubby yellowcrest, is a genus of two or three species of shrubs in the family Lythraceae, native to the Americas, from northern Argentina north to the southernmost United States (southern Texas). The leaves are 2-5 cm long and 1 cm broad, entire, and variably arranged alternate, opposite or whorled on the stems. # Species - Heimia myrtifolia is a shrub growing to 1 m tall. The yellow flowers are 5 petaled and 1 cm in diameter. The leaves are approximately 5 mm wide by 2-3 cm long. - Heimia salicifolia is a shrub growing to 3 m tall. The yellow flowers are 5 petaled and 2-3 cm in diameter. The leaves are approximately 1 cm wide and 3-5 cm long. # Secondary metabolites Both Heimia species contain the following secondary metabolites: - Cryogenine, psychoactive - Sinicuichine - Heimidine - Lyfoline - Nesodine - Abresoline - Anelisine - Dehydrodecadine - Sinine # History & Uses Heimia myrtifolia and Heimia salicifolia are psychoactive and is reputed to produce auditory and / or visual hallucinations. The term 'sun opener' refers to the effects of the plant relating to vision. A brightening or 'opening' of the sun occurs when this plant is consumed. Botanists are actually uncertain as to whether or not the plant now known as 'sinicuichi' is the 'sun opener' that the indigenous peoples of South America used medicinally. Early writings about the plant are unclear, and there is much speculation that the original 'sun opener' was actually cannabis. # Cultivation The species make attractive ornamental plants, flowering in late summer. Although only growing as a shrub in subtropical climates, it can also be grown as a herbaceous perennial in colder areas where the above-ground growth is killed by winter cold. The plants produce very many tiny seeds which are easily cultivated. The seeds should be sown thinly across the top of fine, packed soil. Both species perfer well-drained soil with a good supply of water. The seedlings should be watered by a fine mist or with bottom watering to avoid washing them off to the side of the pot. They should be kept out of intense sunlight until they form the first real leaves. It may be necessary to spread the seedlings out in their initial pots to avoid over-crowding. The seedlings should be moved to at least an inch apart once they are large enough to handle. Be aware that small seedlings of this species often have relatively large root structures. A plant less than a quarter-inch tall may have roots up to two inches deep.	Sinicuichi Sinicuichi (Heimia), also known as sun opener or shrubby yellowcrest, is a genus of two or three species of shrubs in the family Lythraceae, native to the Americas, from northern Argentina north to the southernmost United States (southern Texas). The leaves are 2-5 cm long and 1 cm broad, entire, and variably arranged alternate, opposite or whorled on the stems. # Species - Heimia myrtifolia is a shrub growing to 1 m tall. The yellow flowers are 5 petaled and 1 cm in diameter. The leaves are approximately 5 mm wide by 2-3 cm long. - Heimia salicifolia is a shrub growing to 3 m tall. The yellow flowers are 5 petaled and 2-3 cm in diameter. The leaves are approximately 1 cm wide and 3-5 cm long. # Secondary metabolites Both Heimia species contain the following secondary metabolites: - Cryogenine, psychoactive - Sinicuichine - Heimidine - Lyfoline - Nesodine - Abresoline - Anelisine - Dehydrodecadine - Sinine # History & Uses Heimia myrtifolia and Heimia salicifolia are psychoactive[1] and is reputed to produce auditory and / or visual hallucinations. The term 'sun opener' refers to the effects of the plant relating to vision. A brightening or 'opening' of the sun occurs when this plant is consumed. Botanists are actually uncertain as to whether or not the plant now known as 'sinicuichi' is the 'sun opener' that the indigenous peoples of South America used medicinally. Early writings about the plant are unclear, and there is much speculation that the original 'sun opener' was actually cannabis.[2] # Cultivation The species make attractive ornamental plants, flowering in late summer. Although only growing as a shrub in subtropical climates, it can also be grown as a herbaceous perennial in colder areas where the above-ground growth is killed by winter cold. The plants produce very many tiny seeds which are easily cultivated. The seeds should be sown thinly across the top of fine, packed soil. Both species perfer well-drained soil with a good supply of water. The seedlings should be watered by a fine mist or with bottom watering to avoid washing them off to the side of the pot. They should be kept out of intense sunlight until they form the first real leaves. It may be necessary to spread the seedlings out in their initial pots to avoid over-crowding. The seedlings should be moved to at least an inch apart once they are large enough to handle. Be aware that small seedlings of this species often have relatively large root structures. A plant less than a quarter-inch tall may have roots up to two inches deep.[1]	https://www.wikidoc.org/index.php/Sinicuichi
580a90f6bee0592b2491bb14d5b3ea6e1c08f5bc	wikidoc	Sitaxentan	Sitaxentan # Overview Sitaxentan sodium (TBC-11251) is a medication for the treatment of pulmonary arterial hypertension (PAH). It was marketed as Thelin by Encysive Pharmaceuticals until Pfizer purchased Encysive in February 2008. In 2010, Pfizer voluntarily removed sitaxentan from the market due to concerns about liver toxicity. # Mechanism of Action Sitaxentan is a small molecule that blocks the action of endothelin (ET) on the endothelin-A (ETA) receptor selectively (by a factor of 6000 compared to the ETB). It is a sulfonamide class endothelin receptor antagonist (ERA) and is undergoing Food and Drug Administration (FDA) review for treating pulmonary hypertension. The rationale for benefit compared to bosentan, a nonselective ET blocker, is negligible inhibition of the beneficial effects of ETB stimulation, such as nitric oxide production and clearance of ET from circulation. In clinical trials, the efficacy of sitaxentan has been much the same as bosentan, but the hepatotoxicity of sitaxentan outweighs its benefits. Dosing is once daily, as opposed to twice daily for bosentan. # Regulatory Status On December 10, 2010 Pfizer announced it would be withdrawing sitaxentan worldwide (both from marketing and from all clinical study use), citing that it is a cause of fatal liver damage. Sitaxentan was approved for marketing in the European Union in 2006, in Canada in 2006 and in Australia in 2007. By February 2008 it had been launched commercially in Germany, Austria, The Netherlands, the United Kingdom, Ireland, France, Spain and Italy. In March 2006, the FDA recommended an approvable status to sitaxentan but said it would not yet approve the product. In July 2006, sitaxentan received a second approvable letter stating that efficacy outcome issues raised in the context of the STRIDE-2 study were still unresolved. In July 2007, Encysive commenced a formal dispute resolution process in a preliminary meeting with the FDA. In September 2007 the company announced that it was making preparations for another phase III clinical trial (intended to be named STRIDE-5) to overcome the FDA's concerns. The takeover by Pfizer resulted in a reconfiguration and extension of these plans, to include combination therapy with sildenafil. The Sitaxentan Efficacy and Safety Trial With a Randomized Prospective Assessment of Adding Sildenafil (SR-PAAS) was an ongoing program of three clinical trials conducted in the United States (ClinicalTtrials.gov identifiers: NCT00795639, NCT00796666 and NCT00796510) with anticipated completion dates between June 2010 and January 2014. # Adverse Effects Adverse effects observed with sitaxentan are class effects of endothelin receptor antagonists, and include : - liver enzyme abnormalities (increased ALT and AST) - headache - edema - constipation - nasal congestion - upper respiratory tract infection - dizziness - insomnia - flushing Because sitaxentan inhibits metabolism of warfarin, a decreased dose of warfarin is needed when co-administered with sitaxentan. This is because warfarin acts to prevent blood from clotting, and if it remains unmetabolized, it can continue to thin the blood.	Sitaxentan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Sitaxentan sodium (TBC-11251) is a medication for the treatment of pulmonary arterial hypertension (PAH).[1] It was marketed as Thelin by Encysive Pharmaceuticals until Pfizer purchased Encysive in February 2008. In 2010, Pfizer voluntarily removed sitaxentan from the market due to concerns about liver toxicity.[2] # Mechanism of Action Sitaxentan is a small molecule that blocks the action of endothelin (ET) on the endothelin-A (ETA) receptor selectively (by a factor of 6000 compared to the ETB).[3] It is a sulfonamide class endothelin receptor antagonist (ERA) and is undergoing Food and Drug Administration (FDA) review for treating pulmonary hypertension. The rationale for benefit compared to bosentan, a nonselective ET blocker, is negligible inhibition of the beneficial effects of ETB stimulation, such as nitric oxide production and clearance of ET from circulation. In clinical trials, the efficacy of sitaxentan has been much the same as bosentan, but the hepatotoxicity of sitaxentan outweighs its benefits. Dosing is once daily, as opposed to twice daily for bosentan. # Regulatory Status On December 10, 2010 Pfizer announced it would be withdrawing sitaxentan worldwide (both from marketing and from all clinical study use), citing that it is a cause of fatal liver damage.[2] Sitaxentan was approved for marketing in the European Union in 2006, in Canada in 2006[4] and in Australia in 2007. By February 2008 it had been launched commercially in Germany, Austria, The Netherlands, the United Kingdom, Ireland, France, Spain and Italy. In March 2006, the FDA recommended an approvable status to sitaxentan but said it would not yet approve the product. In July 2006, sitaxentan received a second approvable letter stating that efficacy outcome issues raised in the context of the STRIDE-2 study were still unresolved. In July 2007, Encysive commenced a formal dispute resolution process in a preliminary meeting with the FDA. In September 2007 the company announced that it was making preparations for another phase III clinical trial (intended to be named STRIDE-5) to overcome the FDA's concerns.[5] The takeover by Pfizer resulted in a reconfiguration and extension of these plans, to include combination therapy with sildenafil. The Sitaxentan Efficacy and Safety Trial With a Randomized Prospective Assessment of Adding Sildenafil (SR-PAAS) was an ongoing program of three clinical trials conducted in the United States (ClinicalTtrials.gov identifiers: NCT00795639, NCT00796666 and NCT00796510) with anticipated completion dates between June 2010 and January 2014. # Adverse Effects Adverse effects observed with sitaxentan are class effects of endothelin receptor antagonists, and include : - liver enzyme abnormalities (increased ALT and AST) - headache - edema - constipation - nasal congestion - upper respiratory tract infection - dizziness - insomnia - flushing Because sitaxentan inhibits metabolism of warfarin, a decreased dose of warfarin is needed when co-administered with sitaxentan. This is because warfarin acts to prevent blood from clotting, and if it remains unmetabolized, it can continue to thin the blood.	https://www.wikidoc.org/index.php/Sitaxentan
ba8055835b2bfb2a7d5d7e2fa7c0b10416465351	wikidoc	Skepticism	Skepticism In ordinary usage, skepticism or scepticism (Greek: skeptomai, to look about, to consider; see also spelling differences) refers to - an attitude of doubt or a disposition to incredulity either in general or toward a particular object, - the doctrine that true knowledge or knowledge in a particular area is uncertain, or - the method of suspended judgment, systematic doubt, or criticism that is characteristic of skeptics (Merriam–Webster). In philosophy, skepticism refers more specifically to any one of several propositions. These include propositions about - the limitations of knowledge, - a method of obtaining knowledge through systematic doubt and continual testing, - the arbitrariness, relativity, or subjectivity of moral values, - a method of intellectual caution and suspended judgment, - a lack of confidence in positive motives for human conduct or positive outcomes for human enterprises, that is, cynicism and pessimism (Keeton, 1962). In classical philosophy, skepticism refers to the teachings and the traits of the Skeptikoi, a school of philosophers of whom it was said that they "asserted nothing but only opined" (Liddell and Scott). In this sense, philosophical skepticism, or pyrrhonism, is the philosophical position that one should avoid the postulation of final truths. Turned on itself, skepticism would question that skepticism is a valid perspective at all. In religion, skepticism refers to "doubt concerning basic religious principles (as immortality, providence, and revelation)" (Merriam–Webster). The word skepticism can characterize a position on a single claim, but in scholastic circles more frequently describes a lasting mindset and an approach to accepting or rejecting new information. Individuals who proclaim to have a skeptical outlook are frequently called skeptics, often without regard to whether it is philosophical skepticism or empirical skepticism that they profess. # Philosophical skepticism In philosophical skepticism, pyrrhonism is a position that refrains from making truth claims. A philosophical skeptic does not claim that truth is impossible (which would be a truth claim). The label is commonly used to describe other philosophies which appear similar to philosophical skepticism, such as "academic" skepticism, an ancient variant of Platonism that claimed knowledge of truth was impossible. Empiricism is a closely related, but not identical, position to philosophical skepticism. Empiricists see empiricism as a pragmatic compromise between philosophical skepticism and nomothetic science; philosophical skepticism is in turn sometimes referred to as "radical empiricism." Philosophical skepticism originated in ancient Greek philosophy. One of its first proponents was Pyrrho of Elis (c. 360-275 B.C.), who traveled and studied as far as India, and propounded the adoption of 'practical' skepticism. Subsequently, in the 'New Academy' Arcesilaus (c. 315-241 B.C.) and Carneades (c. 213-129 B.C.) developed more theoretical perspectives, by which conceptions of absolute truth and falsity were refuted as uncertain. Carneades criticized the views of the Dogmatists, especially supporters of Stoicism, asserting that absolute certainty of knowledge is impossible. Sextus Empiricus (c. A.D. 200), the main authority for Greek skepticism, developed the position further, incorporating aspects of empiricism into the basis for asserting knowledge. Greek skeptics criticized the Stoics, accusing them of dogmatism. For the skeptics, the logical mode of argument was untenable, as it relied on propositions which could not be said to be either true or false without relying on further propositions. This was the regress argument, whereby every proposition must rely on other propositions in order to maintain its validity. In addition, the skeptics argued that two propositions could not rely on each other, as this would create a circular argument (as p implies q and q implies p). For the skeptics such logic was thus an inadequate measure of truth which could create as many problems as it claimed to have solved. Truth was not, however, necessarily unobtainable, but rather an idea which did not yet exist in a pure form. Although skepticism was accused of denying the possibility of truth, in actual fact it appears to have mainly been a critical school which merely claimed that logicians had not discovered truth. René Descartes is credited for developing a global skepticism, as a thought experiment in his attempt to find absolute certainty on which to base as the foundation of his philosophy. David Hume has also been described as a global skeptic. However, Descartes was not himself a skeptic and developed his theory of an absolute certainty to disprove other skeptics who argued that there is no certainty. # Scientific skepticism A scientific (or empirical) skeptic is one who questions the reliability of certain kinds of claims by subjecting them to a systematic investigation. The scientific method details the specific process by which this investigation of reality is conducted. Considering the rigor of the scientific method, science itself may simply be thought of as an organized form of skepticism. This does not mean that the scientific skeptic is necessarily a scientist who conducts live experiments (though this may be the case), but that the skeptic generally accepts claims that are in his/her view likely to be true based on testable hypotheses and critical thinking. Common topics that scientifically-skeptical literature questions include health claims surrounding certain foods, procedures, and medicines, such as homeopathy, Reiki, Thought Field Therapy (TFT), vertebral subluxations; the plausibility of supernatural entities (such as ghosts, poltergeists, angels, and gods); as well as the existence of ESP/telekinesis, psychic powers, and telepathy (and thus the credibility of parapsychology); topics in cryptozoology, Bigfoot, the Loch Ness monster, alien visitations, UFOs, crop circles, astrology, repressed memories, creationism, intelligent design, dowsing, conspiracy theories, and other claims the skeptic sees as unlikely to be true on scientific grounds. Most empirical or scientific skeptics do not profess philosophical skepticism. Whereas a philosophical skeptic may deny the very existence of knowledge, an empirical skeptic merely seeks likely proof before accepting that knowledge. ## Activist skepticism Activist skeptics, self-described "debunkers" are a subset of scientific skeptics who aim to expose in public what they see as the truth behind specific extraordinary claims. Debunkers may publish books, air TV programs, create websites, or use other means to advocate their message. In some cases they may challenge claimants outright or even stage elaborate hoaxes to prove their point, such as Project Alpha. Because debunkers often challenge popular ideas, many are not strangers to controversy. Critics of debunkers sometimes accuse them of robbing others of hope. Debunkers frequently reply that it is the claimant, whom they many times accuse of exploiting public gullibility, who is guilty of abuse.Template:Facts Habitual debunkers are sometimes called pseudoskeptics or pathological skeptics and accused of intentionally relying on pseudoscience masquerading as empirical skepticism. # Religious skepticism Religious skepticism is skepticism regarding faith-based claims. Religious skeptics may focus on the core tenets of religions, such as the existence of divine beings, or reports of earthly miracles. A religious skeptic is not necessarily an atheist or agnostic. # Notes and references - A Greek-English Lexicon, Henry George Liddell and Robert Scott, revised and augmented throughout by Sir Henry Stuart Jones, with the assistance of Roderick McKenzie, Clarendon Press, Oxford, UK, 1940. Online. - Webster's New International Dictionary of the English Language, Second Edition, Unabridged, W.A. Neilson, T.A. Knott, P.W. Carhart (eds.), G. & C. Merriam Company, Springfield, MA, 1950. - Butchvarov, Panayot, Skepticism About the External World (Oxford University Press, 1998). - Keeton, Morris T., "skepticism", pp. 277–278 in Dagobert D. Runes (ed.), Dictionary of Philosophy, Littlefield, Adams, and Company, Totowa, NJ, 1962. - Runes, D.D. (ed.), Dictionary of Philosophy, Littlefield, Adams, and Company, Totowa, NJ, 1962. # Further reading - Sextus Empiricus, Outlines of Pyrrhonism, R.G. Bury (trans.), Prometheus Books, Buffalo, NY, 1990.	Skepticism Template:Inline Template:Certainty Template:Otheruses4 In ordinary usage, skepticism or scepticism (Greek: skeptomai, to look about, to consider; see also spelling differences) refers to - an attitude of doubt or a disposition to incredulity either in general or toward a particular object, - the doctrine that true knowledge or knowledge in a particular area is uncertain, or - the method of suspended judgment, systematic doubt, or criticism that is characteristic of skeptics (Merriam–Webster). In philosophy, skepticism refers more specifically to any one of several propositions. These include propositions about - the limitations of knowledge, - a method of obtaining knowledge through systematic doubt and continual testing, - the arbitrariness, relativity, or subjectivity of moral values, - a method of intellectual caution and suspended judgment, - a lack of confidence in positive motives for human conduct or positive outcomes for human enterprises, that is, cynicism and pessimism (Keeton, 1962). In classical philosophy, skepticism refers to the teachings and the traits of the Skeptikoi, a school of philosophers of whom it was said that they "asserted nothing but only opined" (Liddell and Scott). In this sense, philosophical skepticism, or pyrrhonism, is the philosophical position that one should avoid the postulation of final truths. Turned on itself, skepticism would question that skepticism is a valid perspective at all. In religion, skepticism refers to "doubt concerning basic religious principles (as immortality, providence, and revelation)" (Merriam–Webster). The word skepticism can characterize a position on a single claim, but in scholastic circles more frequently describes a lasting mindset and an approach to accepting or rejecting new information. Individuals who proclaim to have a skeptical outlook are frequently called skeptics, often without regard to whether it is philosophical skepticism or empirical skepticism that they profess. # Philosophical skepticism In philosophical skepticism, pyrrhonism is a position that refrains from making truth claims. A philosophical skeptic does not claim that truth is impossible (which would be a truth claim). The label is commonly used to describe other philosophies which appear similar to philosophical skepticism, such as "academic" skepticism, an ancient variant of Platonism that claimed knowledge of truth was impossible. Empiricism is a closely related, but not identical, position to philosophical skepticism. Empiricists see empiricism as a pragmatic compromise between philosophical skepticism and nomothetic science; philosophical skepticism is in turn sometimes referred to as "radical empiricism." Philosophical skepticism originated in ancient Greek philosophy. One of its first proponents was Pyrrho of Elis (c. 360-275 B.C.), who traveled and studied as far as India, and propounded the adoption of 'practical' skepticism. Subsequently, in the 'New Academy' Arcesilaus (c. 315-241 B.C.) and Carneades (c. 213-129 B.C.) developed more theoretical perspectives, by which conceptions of absolute truth and falsity were refuted as uncertain. Carneades criticized the views of the Dogmatists, especially supporters of Stoicism, asserting that absolute certainty of knowledge is impossible. Sextus Empiricus (c. A.D. 200), the main authority for Greek skepticism, developed the position further, incorporating aspects of empiricism into the basis for asserting knowledge. Greek skeptics criticized the Stoics, accusing them of dogmatism. For the skeptics, the logical mode of argument was untenable, as it relied on propositions which could not be said to be either true or false without relying on further propositions. This was the regress argument, whereby every proposition must rely on other propositions in order to maintain its validity. In addition, the skeptics argued that two propositions could not rely on each other, as this would create a circular argument (as p implies q and q implies p). For the skeptics such logic was thus an inadequate measure of truth which could create as many problems as it claimed to have solved. Truth was not, however, necessarily unobtainable, but rather an idea which did not yet exist in a pure form. Although skepticism was accused of denying the possibility of truth, in actual fact it appears to have mainly been a critical school which merely claimed that logicians had not discovered truth. René Descartes is credited for developing a global skepticism, as a thought experiment in his attempt to find absolute certainty on which to base as the foundation of his philosophy. David Hume has also been described as a global skeptic. However, Descartes was not himself a skeptic and developed his theory of an absolute certainty to disprove other skeptics who argued that there is no certainty. # Scientific skepticism A scientific (or empirical) skeptic is one who questions the reliability of certain kinds of claims by subjecting them to a systematic investigation. The scientific method details the specific process by which this investigation of reality is conducted. Considering the rigor of the scientific method, science itself may simply be thought of as an organized form of skepticism. This does not mean that the scientific skeptic is necessarily a scientist who conducts live experiments (though this may be the case), but that the skeptic generally accepts claims that are in his/her view likely to be true based on testable hypotheses and critical thinking. Common topics that scientifically-skeptical literature questions include health claims surrounding certain foods, procedures, and medicines, such as homeopathy, Reiki, Thought Field Therapy (TFT), vertebral subluxations; the plausibility of supernatural entities (such as ghosts, poltergeists, angels, and gods); as well as the existence of ESP/telekinesis, psychic powers, and telepathy (and thus the credibility of parapsychology); topics in cryptozoology, Bigfoot, the Loch Ness monster, alien visitations, UFOs, crop circles, astrology, repressed memories, creationism, intelligent design, dowsing, conspiracy theories, and other claims the skeptic sees as unlikely to be true on scientific grounds. Most empirical or scientific skeptics do not profess philosophical skepticism. Whereas a philosophical skeptic may deny the very existence of knowledge, an empirical skeptic merely seeks likely proof before accepting that knowledge. ## Activist skepticism Activist skeptics, self-described "debunkers" are a subset of scientific skeptics who aim to expose in public what they see as the truth behind specific extraordinary claims. Debunkers may publish books, air TV programs, create websites, or use other means to advocate their message. In some cases they may challenge claimants outright or even stage elaborate hoaxes to prove their point, such as Project Alpha. Because debunkers often challenge popular ideas, many are not strangers to controversy. Critics of debunkers sometimes accuse them of robbing others of hope. Debunkers frequently reply that it is the claimant, whom they many times accuse of exploiting public gullibility, who is guilty of abuse.Template:Facts Habitual debunkers are sometimes called pseudoskeptics or pathological skeptics and accused of intentionally relying on pseudoscience masquerading as empirical skepticism.[citation needed] # Religious skepticism Religious skepticism is skepticism regarding faith-based claims. Religious skeptics may focus on the core tenets of religions, such as the existence of divine beings, or reports of earthly miracles. A religious skeptic is not necessarily an atheist or agnostic. # Notes and references - A Greek-English Lexicon, Henry George Liddell and Robert Scott, revised and augmented throughout by Sir Henry Stuart Jones, with the assistance of Roderick McKenzie, Clarendon Press, Oxford, UK, 1940. Online. - Webster's New International Dictionary of the English Language, Second Edition, Unabridged, W.A. Neilson, T.A. Knott, P.W. Carhart (eds.), G. & C. Merriam Company, Springfield, MA, 1950. - Butchvarov, Panayot, Skepticism About the External World (Oxford University Press, 1998). - Keeton, Morris T., "skepticism", pp. 277–278 in Dagobert D. Runes (ed.), Dictionary of Philosophy, Littlefield, Adams, and Company, Totowa, NJ, 1962. - Runes, D.D. (ed.), Dictionary of Philosophy, Littlefield, Adams, and Company, Totowa, NJ, 1962. # Further reading - Sextus Empiricus, Outlines of Pyrrhonism, R.G. Bury (trans.), Prometheus Books, Buffalo, NY, 1990.	https://www.wikidoc.org/index.php/Skepticism
a262521c7570ada014ab71d4005146d023fbde60	wikidoc	Sleep debt	Sleep debt # Overview Sleep debt is the cumulative effect of not getting enough sleep. A large sleep debt, for example, would suggest that a person is mentally or physically fatigued due to insufficient sleep. There is debate in the scientific community over the specifics of sleep debt. # Scientific skepticism of sleep debt There is debate among researchers as to whether there is such a thing as sleep debt. The Sept 2004 issue of the journal Sleep contained dueling editorials from two of the world's leading sleep researchers: David F. Dinges and Jim Horne. The popular understanding within the journal that sleep debt can be accumulated indefinitely has however been disproven and is no longer considered plausible. A 1997 experiment conducted by psychiatrists at the University of Pennyslvania School of Medicine suggested that cumulative nocturnal sleep debt affects daytime sleepiness, particularly on the first and second, and the sixth and seventh days of sleep restriction. # Evaluating sleep debt Sleep debt has been tested/experimented in a number of studies, most notably by Klerman and Dijk through the use of a sleep latency test. This test attempts to measure how easily someone can fall asleep. When this test is done several times during the day, it is called a multiple sleep latency test (MSLT). However, one does not have to go to a sleep clinic to try this experiment; a home process has been considered: it involves relaxing quietly and alone for a short amount of time. If the feeling of sleep comes fairly easily, one is considered to have sleep debt. Some also suggest that the quality of sleep can have an effect on the level of one's sleep debt. The Epworth Sleepiness Scale (ESS) has also been used to measure potential sleep debt along with a variety of other evaluations. Specifically, the ESS; created by Australian researchers, is a simple eight item questionnaire with scores ranging 0-24. A January 2007 study suggests that saliva tests of the enzyme amylase could be used to indicate sleep debt, as the enzyme increases its activity in correlation with the length of time a subject has been deprived of sleep. # Society-wide sleep debt The National Geographic Magazine reported that the demands of work, social activities, and the availability of 24-hour home entertainment and internet access have caused people to sleep less now than in premodern times. The research behind this article has led some organizations, including the National Sleep Foundation, to create educational campaigns to draw attention to sleep debt. However, Jim Horne of Loughborough University, a Sleep Researcher, questions such claims. In a 2004 editorial in the journal Sleep, he notes that available data suggests that the average number of hours of sleep in a 24-hour period has not changed significantly in recent decades. Comparing data collected from the Bureau of Labor Statistics' American Time Use Survey from 1965-1985 and 1998-2001, shows that the median amount of sleep, napping, and resting done by the average American has changed by less than 0.7%, from a median of 482 minutes per day from 1965 through 1985, to 479 minutes per day from 1998 through 2001. Furthermore, the editorial suggests that there is a range of normal sleep time required by healthy adults, and many indicators used to suggest chronic sleepiness among the population as a whole do not stand up to scientific scrutiny.	Sleep debt Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3] # Overview Sleep debt is the cumulative effect of not getting enough sleep. A large sleep debt, for example, would suggest that a person is mentally or physically fatigued due to insufficient sleep. There is debate in the scientific community over the specifics of sleep debt. # Scientific skepticism of sleep debt There is debate among researchers as to whether there is such a thing as sleep debt. The Sept 2004 issue of the journal Sleep contained dueling editorials from two of the world's leading sleep researchers: David F. Dinges and Jim Horne. The popular understanding within the journal that sleep debt can be accumulated indefinitely has however been disproven and is no longer considered plausible. A 1997 experiment conducted by psychiatrists at the University of Pennyslvania School of Medicine [1] suggested that cumulative nocturnal sleep debt affects daytime sleepiness, particularly on the first and second, and the sixth and seventh days of sleep restriction. # Evaluating sleep debt Sleep debt has been tested/experimented in a number of studies, most notably by Klerman and Dijk through the use of a sleep latency test[2]. This test attempts to measure how easily someone can fall asleep. When this test is done several times during the day, it is called a multiple sleep latency test (MSLT). However, one does not have to go to a sleep clinic to try this experiment; a home process has been considered: it involves relaxing quietly and alone for a short amount of time. If the feeling of sleep comes fairly easily, one is considered to have sleep debt. Some also suggest that the quality of sleep can have an effect on the level of one's sleep debt. The Epworth Sleepiness Scale (ESS) has also been used to measure potential sleep debt along with a variety of other evaluations. Specifically, the ESS; created by Australian researchers, is a simple eight item questionnaire with scores ranging 0-24. [3] A January 2007 study[4] suggests that saliva tests of the enzyme amylase could be used to indicate sleep debt, as the enzyme increases its activity in correlation with the length of time a subject has been deprived of sleep. # Society-wide sleep debt Template:Globalize The National Geographic Magazine reported that the demands of work, social activities, and the availability of 24-hour home entertainment and internet access have caused people to sleep less now than in premodern times.[5] The research behind this article has led some organizations, including the National Sleep Foundation,[6] to create educational campaigns to draw attention to sleep debt. However, Jim Horne of Loughborough University, a Sleep Researcher, questions such claims. In a 2004 editorial in the journal Sleep, he notes that available data suggests that the average number of hours of sleep in a 24-hour period has not changed significantly in recent decades. Comparing data collected from the Bureau of Labor Statistics' American Time Use Survey[7] from 1965-1985[8] and 1998-2001,[9] shows that the median amount of sleep, napping, and resting done by the average American has changed by less than 0.7%, from a median of 482 minutes per day from 1965 through 1985, to 479 minutes per day from 1998 through 2001. Furthermore, the editorial suggests that there is a range of normal sleep time required by healthy adults, and many indicators used to suggest chronic sleepiness among the population as a whole do not stand up to scientific scrutiny.	https://www.wikidoc.org/index.php/Sleep_debt
fcdfd3e9e24ce5614a262f288fe6cd12208e73fe	wikidoc	Somniloquy	Somniloquy # Overview Somniloquy or sleep-talking is a parasomnia that refers to talking aloud in one's sleep. It can be quite loud, ranging from simple sounds to long speeches, and can occur many times during sleep. Listeners may or may not be able to understand what the person is saying. Sleep-talking usually occurs during transitory arousals from REM sleep. It can also occur during NREM sleep at which time it represents a motor breakthrough (see sleep paralysis) of dream speech, words spoken in a dream are spoken out loud. Sleep-talking can occur by itself or as a feature of another sleep disorder such as: - REM sleep behavior disorder (RBD) - loud, emotional or profane sleep talking - Sleepwalking - Night terrors - intense fear, screaming, shouting - Sleep-related eating disorder (SRED) Sleep-talking is very common and is reported in 50% of young children, with most of them outgrowing it by puberty, although it may persist into adulthood (about 5% of adults are reported to talk in their sleep). It appears to run in families. Sleep-talking by itself is harmless and the content should be taken lightly, however it can wake up others and cause them consternation—especially when misinterpreted as conscious speech by an observer. If the sleep-talking is dramatic, emotional, or profane it may be a sign of another sleep disorder (see above). Sleep-talking can be monitored by a partner or by using an audio recording device; devices which remain idle until detecting a soundwave are ideal for this purpose. In order to prevent sleep-talking a mouthguard may be worn. One famous sleep talker is Dion McGregor, a man who became something of an underground celebrity when his roommate Michael Barr recorded his nightly soliloquies (which were often hilariously detailed), which were then released as a series of albums in the 60's.	Somniloquy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Somniloquy or sleep-talking is a parasomnia that refers to talking aloud in one's sleep. It can be quite loud, ranging from simple sounds to long speeches, and can occur many times during sleep. Listeners may or may not be able to understand what the person is saying. Sleep-talking usually occurs during transitory arousals from REM sleep. It can also occur during NREM sleep at which time it represents a motor breakthrough (see sleep paralysis) of dream speech, words spoken in a dream are spoken out loud. Sleep-talking can occur by itself or as a feature of another sleep disorder such as: - REM sleep behavior disorder (RBD) - loud, emotional or profane sleep talking - Sleepwalking - Night terrors - intense fear, screaming, shouting - Sleep-related eating disorder (SRED) Sleep-talking is very common and is reported in 50% of young children, with most of them outgrowing it by puberty, although it may persist into adulthood (about 5% of adults are reported to talk in their sleep). It appears to run in families. Sleep-talking by itself is harmless and the content should be taken lightly, however it can wake up others and cause them consternation—especially when misinterpreted as conscious speech by an observer. If the sleep-talking is dramatic, emotional, or profane it may be a sign of another sleep disorder (see above). Sleep-talking can be monitored by a partner or by using an audio recording device; devices which remain idle until detecting a soundwave are ideal for this purpose. In order to prevent sleep-talking a mouthguard may be worn. One famous sleep talker is Dion McGregor, a man who became something of an underground celebrity when his roommate Michael Barr recorded his nightly soliloquies (which were often hilariously detailed), which were then released as a series of albums in the 60's. Template:WH Template:WS	https://www.wikidoc.org/index.php/Sleep_talking
b2bf4023b38dc78989632d08fda3e65b0fc4de06	wikidoc	SmartMatch	SmartMatch SmartMatch is a proprietary intelligent search engine that searches résumés and other information about job applicants and matches that information with job descriptions . It was developed at Guru.com between 2001 and 2003 and was acquired by Unicru in 2004. During development it was referred to by its codename Convex. SmartMatch uses a variety of techniques from artificial intelligence research to produce high-quality search results. Its three major components are: - A resume parser that can locate the principle structure of English-language résumés. - A domain-specific ontology that allows the extraction of concepts from parsed resumes - A set of machine learning tools that automatically extend and enhance the ontology	SmartMatch SmartMatch is a proprietary intelligent search engine that searches résumés and other information about job applicants and matches that information with job descriptions [1]. It was developed at Guru.com between 2001 and 2003 and was acquired by Unicru in 2004. During development it was referred to by its codename Convex. SmartMatch uses a variety of techniques from artificial intelligence research to produce high-quality search results[2]. Its three major components are: - A resume parser that can locate the principle structure of English-language résumés. - A domain-specific ontology that allows the extraction of concepts from parsed resumes - A set of machine learning tools that automatically extend and enhance the ontology	https://www.wikidoc.org/index.php/SmartMatch
ef1ce890eba501fe8d990ccd5c6e17351c223778	wikidoc	Smoothened	Smoothened Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecular target of the natural teratogen cyclopamine. It also is the target of Vismodegib, the first hedgehog pathway inhibitor to be approved by the U.S. Food and Drug Administration (FDA). # Function Cellular localization plays an essential role in the function of SMO, which anchors to the cell membrane as a 7-pass transmembrane protein. Stimulation of the patched 12-pass transmembrane receptor by the sonic hedgehog ligand leads to translocation of SMO to the primary cilium in vertebrates in a process that involves the exit of patched from the primary cilium, where it normally localizes in its unstimulated state. Vertebrate SMO that is mutated in the domain required for ciliary localisation often cannot contribute to hedgehog pathway activation. Conversely, SMO can become constitutively localized to the primary cilium and potentially activate pathway signaling constitutively as a result of a tryptophan to leucine mutation in the aforementioned domain. SMO has been shown to move during patched stimulation from the plasma membrane near the primary cilium to the ciliary membrane itself via a lateral transport pathway along the membrane, as opposed to via directed transport by vesicles. The cAMP-PKA pathway is known to promote the lateral movement of SMO and hedgehog signal transduction in general. In invertebrates like Drosophila, SMO does not organize at cilia and instead is generally translocated to the plasma membrane following hedgehog binding to patched. After cellular localization, SMO must additionally be activated by a distinct mechanism in order to stimulate hedgehog signal transduction, but that mechanism is unknown. There is evidence for the existence of an unidentified endogenous ligand that binds SMO and activates it. It is believed that mutations in SMO can mimic the ligand-induced conformation of SMO and activate constitutive signal transduction. SMO plays a key role in transcriptional repression and activation by the zinc-finger transcription factor Cubitus interruptus (Ci; known as Gli in vertebrates). When the hedgehog pathway is inactive, a complex of Fused (Fu), Supressor of Fused (Sufu), and the kinesin motor protein Costal-2 (Cos2) tether Ci to microtubules. In this complex, Cos2 promotes proteolytic cleavage of Ci by activating hyperphosphorylation of Ci and subsequent recruitment of ubiquitin ligase; the cleaved Ci goes on to act as a repressor of hedgehog-activated transcription. However, when hedgehog signaling is active, Ci remains intact and acts as a transcriptional activator of the same genes that its cleaved form suppresses. SMO has been shown to bind Costal-2 and play a role in the localization of the Ci complex and prevention of Ci cleavage. Additionally, it is known that vertebrate SMO contributes to the activation of Gli as a transcription factor via association with ciliary structures such as Evc2, but these mechanisms are not fully understood. # Role in disease SMO can function as an oncogene. Activating SMO mutations can lead to unregulated activation of the hedgehog pathway and serve as driving mutations for cancers such as medulloblastoma, basal-cell carcinoma, pancreatic cancer, and prostate cancer. As such, SMO is an attractive cancer drug target, along with the many hedgehog pathway agonists and antagonists that are known to directly target SMO. Cholesterol is known to be crucial in regulating the overall hedgehog pathway, and congenital mutations in cholesterol synthesis pathways can inactivate SMO specifically, leading to developmental disorders. For example, oxysterol 20(S)-OHC is known to activate vertebrate SMO by binding the cysteine rich domain near its extracellular amino-terminal region. In the context of cancer, 20(S)-OHC is the target of a proposed anti-cancer oxysterol binding inhibitor. # Agonists - Smoothened agonist (SAG) - Purmorphamine - Oxysterols including 20(S)-OHC and 20(S)-yne # Antagonists - Cyclopamine - Itraconazole - Vismodegib (Erivedge), a smoothened receptor inhibitor for the treatment of basal-cell carcinoma, being investigated for the treatment of other types of cancer - SANT-1 - Sonidegib - Patidegib	Smoothened Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor[1][2] that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecular target of the natural teratogen cyclopamine.[3] It also is the target of Vismodegib, the first hedgehog pathway inhibitor to be approved by the U.S. Food and Drug Administration (FDA).[4] # Function Cellular localization plays an essential role in the function of SMO, which anchors to the cell membrane as a 7-pass transmembrane protein. Stimulation of the patched 12-pass transmembrane receptor by the sonic hedgehog ligand leads to translocation of SMO to the primary cilium in vertebrates in a process that involves the exit of patched from the primary cilium, where it normally localizes in its unstimulated state.[5] Vertebrate SMO that is mutated in the domain required for ciliary localisation often cannot contribute to hedgehog pathway activation.[6] Conversely, SMO can become constitutively localized to the primary cilium and potentially activate pathway signaling constitutively as a result of a tryptophan to leucine mutation in the aforementioned domain.[7] SMO has been shown to move during patched stimulation from the plasma membrane near the primary cilium to the ciliary membrane itself via a lateral transport pathway along the membrane, as opposed to via directed transport by vesicles. The cAMP-PKA pathway is known to promote the lateral movement of SMO and hedgehog signal transduction in general.[8] In invertebrates like Drosophila, SMO does not organize at cilia and instead is generally translocated to the plasma membrane following hedgehog binding to patched.[9] After cellular localization, SMO must additionally be activated by a distinct mechanism in order to stimulate hedgehog signal transduction, but that mechanism is unknown.[10] There is evidence for the existence of an unidentified endogenous ligand that binds SMO and activates it. It is believed that mutations in SMO can mimic the ligand-induced conformation of SMO and activate constitutive signal transduction.[9] SMO plays a key role in transcriptional repression and activation by the zinc-finger transcription factor Cubitus interruptus (Ci; known as Gli in vertebrates). When the hedgehog pathway is inactive, a complex of Fused (Fu), Supressor of Fused (Sufu), and the kinesin motor protein Costal-2 (Cos2) tether Ci to microtubules. In this complex, Cos2 promotes proteolytic cleavage of Ci by activating hyperphosphorylation of Ci and subsequent recruitment of ubiquitin ligase; the cleaved Ci goes on to act as a repressor of hedgehog-activated transcription. However, when hedgehog signaling is active, Ci remains intact and acts as a transcriptional activator of the same genes that its cleaved form suppresses.[11][12] SMO has been shown to bind Costal-2 and play a role in the localization of the Ci complex and prevention of Ci cleavage.[13][14] Additionally, it is known that vertebrate SMO contributes to the activation of Gli as a transcription factor via association with ciliary structures such as Evc2, but these mechanisms are not fully understood.[9] # Role in disease SMO can function as an oncogene. Activating SMO mutations can lead to unregulated activation of the hedgehog pathway and serve as driving mutations for cancers such as medulloblastoma, basal-cell carcinoma, pancreatic cancer, and prostate cancer.[7][15] As such, SMO is an attractive cancer drug target, along with the many hedgehog pathway agonists and antagonists that are known to directly target SMO.[7] Cholesterol is known to be crucial in regulating the overall hedgehog pathway, and congenital mutations in cholesterol synthesis pathways can inactivate SMO specifically, leading to developmental disorders.[16] For example, oxysterol 20(S)-OHC is known to activate vertebrate SMO by binding the cysteine rich domain near its extracellular amino-terminal region. In the context of cancer, 20(S)-OHC is the target of a proposed anti-cancer oxysterol binding inhibitor.[9] # Agonists - Smoothened agonist (SAG) - Purmorphamine - Oxysterols including 20(S)-OHC and 20(S)-yne # Antagonists - Cyclopamine - Itraconazole - Vismodegib (Erivedge), a smoothened receptor inhibitor for the treatment of basal-cell carcinoma, being investigated for the treatment of other types of cancer - SANT-1 - Sonidegib - Patidegib	https://www.wikidoc.org/index.php/Smoothened
d18c4369c6c37db42c272b5f1e816184a29af7a9	wikidoc	Sodastream	Sodastream SodaStream is the name of a brand of home carbonation systems that was invented by Guy Gilbey in 1903. Later versions allowed the addition of concentrates to create carbonated flavored beverages. It was popular in the 1970s and 1980s when there were a number of brand name syrups available, and, after the company merged with Soda-Club in 1998, it was relaunched with an emphasis on healthier drinks. In the UK (where it was first sold) the SodaStream machine is strongly associated with late-1970s/early-1980s childhood nostalgia. # Product The SodaStream drinksmaker is a device which can force carbon dioxide gas (stored under pressure in a cylinder) into water, making it fizzy. The product includes a machine, a carbon dioxide canister, and one or more reusable beverage bottles (suitable for pressurizing). The bottle, filled with water, is threaded onto the machine, and with a button push, compressed CO2 from the canister is injected, creating sparkling water (also known as seltzer). Varieties of concentrated syrups are available, in order to create regular or diet soft drinks by adding a small amount of concentrate to the water bottle after carbonation. Once a canister is empty, it is returned to a supplier and a new canister is purchased for a fee. By using the appropriate variety of concentrate, different flavours of soft drink can be created. During its heyday, several famous brands were available in SodaStream concentrate form including Tizer, Fanta, Sunkist and Irn-Bru. Milkstream was a variation on the SodaStream for making milkshakes, created by the same company. The ingredients (milk, ice cream and Crusha syrup) were mixed in a tall glass and inserted into the machine, so that the wand extended into the glass to froth up the shake. # History The forerunner of the machine, the "Apparatus for aerating liquids", was created in 1903 by Guy Hugh Gilbey of the London gin distillers, W & A Gilbey Ltd., and was sold to the upper classes (including the royal household). Flavored concentrates such as cherry ciderette and sarsaparilla, were introduced in the 1920s, along with commercial carbonation machines, and the first machine for home carbonation of drinks was produced in 1955. The SodaStream was originally sold in the UK, but later spread to other countries, including Australia, New Zealand, and Germany. SodaStream machines were popular during the 1970s and 1980s in the UK, and are associated with nostalgia for that period. Their slogan, "Get busy with the fizzy", started as an advertising jingle in 1979 and proved so popular that they added it to their logo. They finally dropped it in 1996 after 17 years. Whilst commercially successful, there was a general perception that some of the soft drinks produced by the machines were a poor approximation of their commercial counterparts. It is notable that, in addition to the slightly different flavours of the end result, the bubbles produced by SodaStreams are significantly larger and shorter-lived. # Company Originally the company operated as a subsidiary of W & A Gilbey, Ltd. In 1985, after various changes of ownership, SodaStream became a wholly owned subsidiary of Cadbury Schweppes, although it operated as an autonomous business within the group. In 1998 SodaStream was bought by Soda-Club, an Israeli company founded in 1991 by Peter Wiseburgh, who from 1978 to 1991 had been Israel's exclusive distributor for SodaStream, creating the world's largest home carbonation systems supplier. In 2003 Soda-Club closed the SodaStream factory in Peterborough, moving the company's gas cylinder refilling and refurbishment department to Germany. Under the ownership of Soda-Club the brand has been relaunched in many markets with new machines, and new flavours, as of 2007 being available in the United Kingdom, United States, Sweden, Denmark, Finland, Norway, Australia, New Zealand, Canada and South Africa. Soda-Club still markets its drinks under the SodaStream brand, its application for the trademark "soda-club" having been successfully opposed in 1998 by Cantrell & Cochrane (Belfast) Ltd, owner of the trademark "club soda". Instead of the soft-drinks approach of the past several decades, Sodastream today addresses the growing health awareness with a wide range of diet concentrates and is used as much for plain sparkling water as for soft drinks.	Sodastream SodaStream is the name of a brand of home carbonation systems that was invented by Guy Gilbey in 1903.[1][2] Later versions allowed the addition of concentrates to create carbonated flavored beverages. It was popular in the 1970s and 1980s when there were a number of brand name syrups available,[3][4] and, after the company merged with Soda-Club in 1998, it was relaunched with an emphasis on healthier drinks. In the UK (where it was first sold) the SodaStream machine is strongly associated with late-1970s/early-1980s childhood nostalgia. # Product The SodaStream drinksmaker is a device which can force carbon dioxide gas (stored under pressure in a cylinder) into water, making it fizzy. The product includes a machine, a carbon dioxide canister, and one or more reusable beverage bottles (suitable for pressurizing). The bottle, filled with water, is threaded onto the machine, and with a button push, compressed CO2 from the canister is injected, creating sparkling water (also known as seltzer). Varieties of concentrated syrups are available, in order to create regular or diet soft drinks by adding a small amount of concentrate to the water bottle after carbonation. Once a canister is empty, it is returned to a supplier and a new canister is purchased for a fee. By using the appropriate variety of concentrate, different flavours of soft drink can be created. During its heyday, several famous brands were available in SodaStream concentrate form including Tizer, Fanta, Sunkist and Irn-Bru.[5] Milkstream was a variation on the SodaStream for making milkshakes, created by the same company. The ingredients (milk, ice cream and Crusha syrup) were mixed in a tall glass and inserted into the machine, so that the wand extended into the glass to froth up the shake. # History The forerunner of the machine, the "Apparatus for aerating liquids",[6] was created in 1903 by Guy Hugh Gilbey of the London gin distillers, W & A Gilbey Ltd.,[5] and was sold to the upper classes (including the royal household).[3] Flavored concentrates such as cherry ciderette and sarsaparilla, were introduced in the 1920s, along with commercial carbonation machines,[2][3] and the first machine for home carbonation of drinks was produced in 1955.[5] The SodaStream was originally sold in the UK, but later spread to other countries, including Australia, New Zealand, and Germany. SodaStream machines were popular during the 1970s and 1980s in the UK, and are associated with nostalgia for that period.[3][4] Their slogan, "Get busy with the fizzy", started as an advertising jingle in 1979 and proved so popular that they added it to their logo. They finally dropped it in 1996 after 17 years.[7] Whilst commercially successful, there was a general perception that some of the soft drinks produced by the machines were a poor approximation of their commercial counterparts.[8][9] It is notable that, in addition to the slightly different flavours of the end result, the bubbles produced by SodaStreams are significantly larger and shorter-lived.[9] # Company Originally the company operated as a subsidiary of W & A Gilbey, Ltd.[5] In 1985, after various changes of ownership, SodaStream became a wholly owned subsidiary of Cadbury Schweppes, although it operated as an autonomous business within the group.[5] In 1998 SodaStream was bought by Soda-Club, an Israeli company founded in 1991 by Peter Wiseburgh, who from 1978 to 1991 had been Israel's exclusive distributor for SodaStream, creating the world's largest home carbonation systems supplier.[2][10] In 2003 Soda-Club closed the SodaStream factory in Peterborough, moving the company's gas cylinder refilling and refurbishment department to Germany.[11] Under the ownership of Soda-Club the brand has been relaunched in many markets with new machines, and new flavours, as of 2007 being available in the United Kingdom, United States, Sweden, Denmark, Finland, Norway, Australia, New Zealand, Canada and South Africa. Soda-Club still markets its drinks under the SodaStream brand, its application for the trademark "soda-club" having been successfully opposed in 1998 by Cantrell & Cochrane (Belfast) Ltd, owner of the trademark "club soda".[12] Instead of the soft-drinks approach of the past several decades, Sodastream today addresses the growing health awareness with a wide range of diet concentrates and is used as much for plain sparkling water as for soft drinks.	https://www.wikidoc.org/index.php/Sodastream
09f25cd86bc87858f6ed5268a40a346cbe967063	wikidoc	Thiopental	Thiopental # 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 Thiopental is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding Thiopental FDA-Labeled Indications and Dosage (Adult) in the drug label. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Thiopental in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Thiopental in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Thiopental FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Thiopental in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Thiopental in pediatric patients. # Contraindications There is limited information regarding Thiopental Contraindications in the drug label. # Warnings There is limited information regarding Thiopental Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Thiopental Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Thiopental Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Thiopental Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Thiopental in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Thiopental in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Thiopental during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Thiopental in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Thiopental in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Thiopental in geriatric settings. ### Gender There is no FDA guidance on the use of Thiopental with respect to specific gender populations. ### Race There is no FDA guidance on the use of Thiopental with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Thiopental in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Thiopental in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Thiopental in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Thiopental in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Thiopental Administration in the drug label. ### Monitoring There is limited information regarding Thiopental Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Thiopental and IV administrations. # Overdosage There is limited information regarding Thiopental overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology There is limited information regarding Thiopental Pharmacology in the drug label. ## Mechanism of Action There is limited information regarding Thiopental Mechanism of Action in the drug label. ## Structure There is limited information regarding Thiopental Structure in the drug label. ## Pharmacodynamics There is limited information regarding Thiopental Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Thiopental Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Thiopental Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Thiopental Clinical Studies in the drug label. # How Supplied There is limited information regarding Thiopental How Supplied in the drug label. ## Storage There is limited information regarding Thiopental Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Thiopental Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Thiopental 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 Thiopental Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Thiopental Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Thiopental Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, 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. # Overview Thiopental is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding Thiopental FDA-Labeled Indications and Dosage (Adult) in the drug label. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Thiopental in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Thiopental in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Thiopental FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Thiopental in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Thiopental in pediatric patients. # Contraindications There is limited information regarding Thiopental Contraindications in the drug label. # Warnings There is limited information regarding Thiopental Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Thiopental Clinical Trials Experience in the drug label. ## Postmarketing Experience There is limited information regarding Thiopental Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Thiopental Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Thiopental in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Thiopental in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Thiopental during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Thiopental in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Thiopental in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Thiopental in geriatric settings. ### Gender There is no FDA guidance on the use of Thiopental with respect to specific gender populations. ### Race There is no FDA guidance on the use of Thiopental with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Thiopental in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Thiopental in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Thiopental in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Thiopental in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Thiopental Administration in the drug label. ### Monitoring There is limited information regarding Thiopental Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Thiopental and IV administrations. # Overdosage There is limited information regarding Thiopental overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology There is limited information regarding Thiopental Pharmacology in the drug label. ## Mechanism of Action There is limited information regarding Thiopental Mechanism of Action in the drug label. ## Structure There is limited information regarding Thiopental Structure in the drug label. ## Pharmacodynamics There is limited information regarding Thiopental Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Thiopental Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Thiopental Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Thiopental Clinical Studies in the drug label. # How Supplied There is limited information regarding Thiopental How Supplied in the drug label. ## Storage There is limited information regarding Thiopental Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Thiopental Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Thiopental 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 Thiopental Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Thiopental Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Sodium_thiopental
e446b946bcb8080ea2746801d5516fd03704507b	wikidoc	Sofosbuvir	Sofosbuvir # 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 Sofosbuvir is an antiviral that is FDA approved for the treatment of chronic hepatitis C (CHC) infection. Common adverse reactions include diarrhea, anemia, headache, insomnia, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) The recommended dose of sofosbuvir is one 400 mg tablet, taken orally, once daily with or without food. Sofosbuvir should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of CHC in adults. The recommended regimen and treatment duration for sofosbuvir combination therapy is provided in the table below. SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for CHC patients with genotype 1 infection who are ineligible to receive an interferon-based regimen . Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient. Sofosbuvir in combination with ribavirin is recommended for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection . ### Dose Modification Dose reduction of sofosbuvir is not recommended. If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose. If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient's hemoglobin concentration and cardiac status. ### Discontinuation of Dosing If the other agents used in combination with sofosbuvir are permanently discontinued, sofosbuvir should also be discontinued. ### Severe Renal Impairment and End Stage Renal Disease No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite . ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sofosbuvir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sofosbuvir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Sofosbuvir 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 Sofosbuvir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sofosbuvir in pediatric patients. # Contraindications - When sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications. - Sofosbuvir combination treatment with ribavirin or peginterferon alfa/ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin. # Warnings Ribavirin may cause birth defects and/or death of the exposed fetus and animal studies have shown that interferons have abortifacient effects. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. When sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. There are no data on the effectiveness of systemic hormonal contraceptives in women taking sofosbuvir, therefore, two non-hormonal methods of contraception should be used during treatment with sofosbuvir and concomitant ribavirin. Refer also to the prescribing information for ribavirin. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin, St. John's wort) may significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of sofosbuvir. Rifampin and St. John's wort should not be used with sofosbuvir. # Adverse Reactions ## Clinical Trials Experience Sofosbuvir should be administered with ribavirin or peginterferon alfa/ribavirin. Refer to the prescribing information of peginterferon alfa and ribavirin for a description of adverse reactions associated with their use. 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 assessment of sofosbuvir is based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including 650 subjects who received sofosbuvir + ribavirin (RBV) combination therapy for 12 weeks, 98 subjects who received sofosbuvir + ribavirin combination therapy for 16 weeks, 250 subjects who received sofosbuvir + ribavirin combination therapy for 24 weeks, 327 subjects who received sofosbuvir + peginterferon (Peg-IFN) alfa + ribavirin combination therapy for 12 weeks, 243 subjects who received peginterferon alfa + ribavirin for 24 weeks and 71 subjects who received placebo (PBO) for 12 weeks. The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving sofosbuvir + ribavirin for 12 weeks, <1% for subjects receiving sofosbuvir + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving sofosbuvir + peginterferon alfa + ribavirin for 12 weeks. Treatment-emergent adverse events observed in ≥15% of subjects in clinical trials are provided in the table below. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. The most common adverse events (≥ 20%) for sofosbuvir + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥ 20%) for sofosbuvir + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia. With the exception of anemia and neutropenia, the majority of events presented in Table 3 occurred at severity of grade 1 in sofosbuvir-containing regimens. The following ADRs occurred in <1% of subjects receiving sofosbuvir in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship. - Hematologic Effects: Pancytopenia (particularly in subjects receiving concomitant pegylated interferon). - Psychiatric Disorders: Severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide. Changes in selected hematological parameters are described in the table below. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. Total bilirubin elevation of more than 2.5×ULN was observed in none of the subjects in the sofosbuvir + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon alfa + ribavirin 24 weeks, sofosbuvir + ribavirin 12 weeks and sofosbuvir + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline levels by post-treatment Week 4. These bilirubin elevations were not associated with transaminase elevations. Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10×ULN was observed in <1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, sofosbuvir + peginterferon alfa + ribavirin 12 weeks and sofosbuvir + ribavirin 12 weeks groups, respectively. Isolated, asymptomatic lipase elevation of greater than 3×ULN was observed in <1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively. ## Postmarketing Experience There is limited information regarding adverse reactions in postmarketing experience of Sofosbuvir provided by the label. # Drug Interactions After oral administration, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir accounts for approximately 4% of drug related material. In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses. Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John's wort) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of sofosbuvir and thus should not be used with sofosbuvir. Coadministration of sofosbuvir with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, sofosbuvir may be coadministered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these transporters. The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs. Drug interaction information for sofosbuvir with potential concomitant drugs is summarized in the table below. The drug interactions described are based on potential drug interactions that may occur with sofosbuvir. The table is not all-inclusive. In addition to the drugs included in the table above, the interaction between sofosbuvir and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine,tacrolimus, or tenofovir disoproxil fumarate. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B There are no adequate and well-controlled studies with sofosbuvir in pregnant women. - No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to the predominant circulating metabolite GS-331007 increased over the course of gestation from approximately 5- to 10-fold and 12- to 28-fold the exposure in humans at the recommended clinical dose, respectively. ### Pregnancy Category X: Use with Ribavirin or Peginterferon Alfa/Ribavirin - Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using two forms of effective contraception during treatment with ribavirin and for 6 months after treatment has concluded. There are no data on the effectiveness of systemic hormonal contraceptives in women taking sofosbuvir. Therefore, two effective non-hormonal methods of contraception should be used during treatment with sofosbuvir and concomitant ribavirin. - In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling Ribavirin Pregnancy Registry at 1-800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263. - Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sofosbuvir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sofosbuvir during labor and delivery. ### Nursing Mothers It is not known whether sofosbuvir and its metabolites are present in human breast milk. The predominant circulating metabolite GS-331007 was the primary component observed in the milk of lactating rats, without effect on nursing pups. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with ribavirin-containing regimens, taking into account the importance of the therapy to the mother. See also the prescribing information for ribavirin. ### Pediatric Use Safety and effectiveness of sofosbuvir in children less than 18 years of age have not been established. ### Geriatic Use Sofosbuvir was administered to 90 subjects aged 65 and over. The response rates observed for subjects over 65 years of age were similar to that of younger subjects across treatment groups. No dose adjustment of sofosbuvir is warranted in geriatric patients ### Gender There is no FDA guidance on the use of Sofosbuvir with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sofosbuvir with respect to specific racial populations. ### Renal Impairment No dose adjustment of sofosbuvir is required for patients with mild or moderate renal impairment. The safety and efficacy of sofosbuvir have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring hemodialysis. No dose recommendation can be given for patients with severe renal impairment or ESRD. Refer also to ribavirin and peginterferon alfa prescribing information for patients with CrCl <50 mL/min. ### Hepatic Impairment No dose adjustment of sofosbuvir is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C). Safety and efficacy of sofosbuvir have not been established in patients with decompensated cirrhosis. See peginterferon alfa prescribing information for contraindication in hepatic decompensation. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sofosbuvir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sofosbuvir in patients who are immunocompromised. ### Others The safety and efficacy of sofosbuvir was assessed in 223 HCV/HIV-1 co-infected subjects. The safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving sofosbuvir + ribavirin in Phase 3 trials. Sofosbuvir was studied in HCV-infected subjects with hepatocellular carcinoma prior to undergoing liver transplantation in an open-label clinical trial evaluating the safety and efficacy of sofosbuvir and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant virologic response (pTVR) defined as HCV RNA < lower limit of quantification (LLOQ) at 12 weeks post-transplant. HCV-infected subjects, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the MILAN criteria (defined as the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter in patients with multiple tumors and no extrahepatic manifestations of the cancer or evidence of vascular invasion of tumor) received 400 mg sofosbuvir and weight-based 1000–1200 mg ribavirin daily for 24–48 weeks or until the time of liver transplantation, whichever occurred first. An interim analysis was conducted on 61 subjects who received sofosbuvir and ribavirin; 45 subjects had HCV genotype 1; 44 subjects had a baseline CPT score less than 7 and all subjects had a baseline unadjusted MELD score ≤14. Of these 61 subjects, 41 subjects underwent liver transplantation following up to 48 weeks of treatment with sofosbuvir and ribavirin; 37 had HCV RNA < LLOQ at the time of transplantation. Of the 37 subjects, the post-transplant virologic response (pTVR) rate is 64% (23/36) in the 36 evaluable subjects who have reached the 12 week post-transplant time point. The safety profile of sofosbuvir and ribavirin in HCV-infected subjects prior to liver transplantation was comparable to that observed in subjects treated with sofosbuvir and ribavirin in Phase 3 clinical trials. The safety and efficacy of sofosbuvir have not been established in post-liver transplant patients. Available data on subjects with genotype 5 or 6 HCV infection are insufficient for dosing recommendations. # Administration and Monitoring ### Administration Oral ### Monitoring In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling Ribavirin Pregnancy Registry at 1-800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263. # IV Compatibility There is limited information regarding the compatibility of Sofosbuvir and IV administrations. # Overdosage The highest documented dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1200 mg administered to 59 healthy subjects. In that trial, there were no untoward effects observed at this dose level, and adverse events were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher doses are not known. No specific antidote is available for overdose with sofosbuvir. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with sofosbuvir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. A 4-hour hemodialysis session removed 18% of the administered dose. # Pharmacology ## Mechanism of Action Sofosbuvir is a direct-acting antiviral agent against the hepatitis C virus. ## Structure sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase. The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula: Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥ 2 mg/mL across the pH range of 2–7.7 at 37 °C and is slightly soluble in water. Sofosbuvir tablets are for oral administration. Each tablet contains 400 mg of sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. ## Pharmacodynamics The effect of sofosbuvir 400 and 1200 mg on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent. ## Pharmacokinetics The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of sofosbuvir was absorbed with a peak plasma concentration observed at ~0.5–2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in subjects with genotype 1 to 6 HCV infection who were coadministered ribavirin (with or without pegylated interferon), geometric mean steady state sofosbuvir (N=838) and GS-331007 (N=1695) AUC0–24 were 828 ng∙hr/mL and 6790 ng∙hr/mL, respectively. Relative to healthy subjects administered sofosbuvir alone (N = 272), the sofosbuvir AUC0–24 was 39% higher and GS-331007 AUC0–24 was 39% lower, respectively, in HCV-infected subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg. Relative to fasting conditions, the administration of a single dose of sofosbuvir with a standardized high fat meal did not substantially affect the sofosbuvir Cmax or AUC0–inf. The exposure of GS-331007 was not altered in the presence of a high-fat meal. Therefore, sofosbuvir can be administered without regard to food. Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of -sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7. Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. After a single 400 mg oral dose of -sofosbuvir, sofosbuvir and GS-331007 accounted for approximately 4% and >90% of drug related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure, respectively. Following a single 400 mg oral dose of -sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively. ### Specific Populations Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No clinically relevant pharmacokinetic differences have been observed between men and women for sofosbuvir and GS-331007. The pharmacokinetics of sofosbuvir in pediatric patients have not been established. Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (19 to 75 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007. The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR ≥ 50 and 80 mL/min/1.73m2), the sofosbuvir AUC0–inf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC0–inf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0–inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18% of administered dose. No dose adjustment is required for patients with mild or moderate renal impairment. The safety and efficacy of sofosbuvir have not been established in patients with severe renal impairment or ESRD. No dose recommendation can be given for patients with severe renal impairment or ESRD. The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0–24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0–24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No dose adjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepatic impairment. The effects of coadministered drugs on the exposure of sofosbuvir and GS-331007 are shown in Table 6. The effects of sofosbuvir on the exposure of coadministered drugs are shown in Table 7. No effect on the pharmacokinetic parameters of sofosbuvir and GS-331007 was observed with raltegravir. No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with sofosbuvir: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone or rilpivirine. Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with IC50 values ranging from 0.7 to 2.6 µM. GS-461203 is not an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotype 1a, 1b, 2a, 3a and 4a, and chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a ranged from 0.014 to 0.11 µM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.062 µM for genotype 1a (range 0.029–0.128 µM; N=67), 0.102 µM for genotype 1b (range 0.045–0.170 µM; N=29), 0.029 µM for genotype 2 (range 0.014–0.081 µM; N=15) and 0.081 µM for genotype 3a (range 0.024–0.181 µM; N=106). In infectious virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and 0.02 µM, respectively. The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir. Evaluation of sofosbuvir in combination with interferon alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. An M289L substitution developed along with the S282T substitution in genotype 2a, 5 and 6 replicons. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to respective wild-types. In a pooled analysis of 982 subjects who received sofosbuvir in Phase 3 trials, 224 subjects had post-baseline NS5B genotypic data from next generation nucleotide sequencing (assay cutoff of 1%). Treatment-emergent substitutions L159F (n= 6) and V321A (n= 5) were detected in post-baseline samples from GT3a-infected subjects across the Phase 3 trials. No detectable shift in the phenotypic susceptibility to sofosbuvir of subject isolates with L159F or V321A substitutions was seen. The sofosbuvir-associated resistance substitution S282T was not detected at baseline or in the failure isolates from Phase 3 trials. However, an S282T substitution was detected in one genotype 2b subject who relapsed at Week 4 post-treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial P7977-0523 . The isolate from this subject displayed a mean 13.5-fold reduced susceptibility to sofosbuvir. For this subject, the S282T substitution was no longer detectable at Week 12 post-treatment by next generation sequencing with an assay cut off of 1%. In the trial done in subjects with hepatocellular carcinoma awaiting liver transplantation where subjects received up to 48 weeks of sofosbuvir and ribavirin, the L159F substitution emerged in multiple subjects with GT1a or GT2b HCV who experienced virologic failure (breakthrough and relapse). Furthermore, the presence of substitutions L159F and/or C316N at baseline was associated with sofosbuvir breakthrough and relapse post-transplant in multiple subjects infected with GT1b HCV. In addition, S282R and L320F substitutions were detected on-treatment by next generation sequencing in a subject infected with GT1a HCV with a partial treatment response. The clinical significance of these substitutions is not known. HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were susceptible to NS5A inhibitors and ribavirin. HCV replicons expressing the ribavirin-associated substitutions T390I and F415Y were susceptible to sofosbuvir. Sofosbuvir was active against HCV replicons with NS3/4A protease inhibitor, NS5B non-nucleoside inhibitor and NS5A inhibitor resistant variants. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility Use with Ribavirin and/or Peginterferon alfa: Ribavirin was shown to be genotoxic in several in vitro and in vivo assays. Ribavirin was not oncogenic in a 6-month p53+/- transgenic mouse study or a 2-year carcinogenicity study in rats. See the prescribing information for ribavirin. Carcinogenicity studies of sofosbuvir in mice and rats are ongoing. Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays. Use with Ribavirin and/or Peginterferon alfa: In fertility studies in male animals, ribavirin induced reversible testicular toxicity, while peginterferon alfa may impair fertility in females. Refer to prescribing information for ribavirin and peginterferon alfa for additional information. Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 8-fold the exposure in humans at the recommended clinical dose. ### Animal Toxicology and/or Pharmacology Heart degeneration and inflammation were observed in rats following GS-9851 (a stereoisomeric mixture containing approximately 50% sofosbuvir) doses of 2000 mg/kg/day for up to 5 days. At this dose, AUC exposure to the predominant metabolite GS-331007 is approximately 29-fold higher than human exposure at the recommended clinical dose. No heart degeneration or inflammation was observed in rats following sofosbuvir doses of up to 500 mg/kg/day for 6 months at a GS-331007 AUC exposure approximately 9-fold higher than human exposure at the recommended clinical dose. In dogs and mice, heart degeneration and inflammation were not observed following sofosbuvir doses of up to 500 and 1000 mg/kg/day for 9 and 3 months, respectively, the highest doses tested. At these doses, GS-331007 AUC exposures are approximately 27- and 41-fold higher, respectively, than human exposure at the recommended clinical dose. # Clinical Studies The safety and efficacy of sofosbuvir was evaluated in five Phase 3 trials in a total of 1724 HCV mono-infected subjects with genotypes 1 to 6 chronic hepatitis C (CHC) and one Phase 3 trial in 223 HCV/HIV-1 co-infected subjects with genotype 1, 2 or 3 CHC. Among the five trials in HCV mono-infected subjects, one was conducted in treatment-naïve subjects with genotype 1, 4, 5 or 6 CHC in combination with peginterferon alfa 2a and ribavirin and the other four were conducted in subjects with genotype 2 or 3 CHC in combination with ribavirin, including one in treatment-naïve subjects, one in interferon intolerant, ineligible or unwilling subjects, one in subjects previously treated with an interferon-based regimen, and one in all subjects irrespective of prior treatment history or ability to take interferon. The trial in HCV/HIV-1 co-infected subjects was conducted in combination with ] in treatment-naïve subjects with genotype 1 CHC and all subjects with genotype 2 or 3 CHC irrespective of prior treatment history or ability to take interferon. Subjects in these trials had compensated liver disease including cirrhosis. Sofosbuvir was administered at a dose of 400 mg once daily. The ribavirin (RBV) dose was weight-based at 1000–1200 mg daily administered in two divided doses when used in combination with sofosbuvir, and the peginterferon alfa 2a dose, where applicable, was 180 micrograms per week. Treatment duration was fixed in each trial and was not guided by subjects' HCV RNA levels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response (SVR) was the primary endpoint which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment. NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment with sofosbuvir in combination with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 1, 4, 5 or 6 HCV infection compared to pre-specified historical control. Treated subjects (N=327) had a median age of 54 years (range: 19 to 70); 64% of the subjects were male; 79% were White, 17% were Black; 14% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU per mL; 17% had cirrhosis; 89% had HCV genotype 1; 9% had HCV genotype 4 and 2% had HCV genotype 5 or 6. Table 8 presents the response rates for the treatment group of sofosbuvir + peginterferon alfa + ribavirin. Response rates for selected subgroups are presented in Table 9. SVR rates were 98% (93/95) in subjects with baseline IL28B C/C allele and 87% (202/232) in subjects with baseline IL28B non-C/C alleles. It is estimated that the response rate in patients who previously failed pegylated interferon and ribavirin therapy will approximate the observed response rate in NEUTRINO subjects with multiple baseline factors traditionally associated with a lower response to interferon-based treatment (Table 9). The SVR rate in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C alleles, HCV RNA >800,000 IU/mL and Metavir F3/F4 fibrosis was 71% (37/52). FISSION was a randomized, open-label, active-controlled trial that evaluated 12 weeks of treatment with sofosbuvir and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 2 and 3 HCV. The ribavirin doses used in the sofosbuvir + ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based 1000–1200 mg per day and 800 mg per day regardless of weight, respectively. Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence), HCV genotype (2 vs. 3) and baseline HCV RNA level (<6 log10IU/mL vs. ≥6 log10IU/mL). Subjects with genotype 2 or 3 HCV were enrolled in an approximately 1:3 ratio. Treated subjects (N=499) had a median age of 50 years (range: 19 to 77); 66% of the subjects were male; 87% were White, 3% were Black; 14% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV RNA levels greater than 6 log10 IU per mL; 20% had cirrhosis; 72% had HCV genotype 3. Table 10 presents the response rates for the treatment groups of sofosbuvir + ribavirin and peginterferon alfa + ribavirin. Response rates for subjects with cirrhosis at baseline are presented in Table 11 by genotype. POSITRON was a randomized, double-blinded, placebo-controlled trial that evaluated 12 weeks of treatment with sofosbuvir and ribavirin (N=207) compared to placebo (N=71) in subjects who are interferon intolerant, ineligible or unwilling. Subjects were randomized in 3:1 ratio and stratified by cirrhosis (presence vs. absence). Treated subjects (N=278) had a median age of 54 years (range: 21 to 75); 54% of the subjects were male; 91% were White, 5% were Black; 11% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 53 kg/m2); 70% had baseline HCV RNA levels greater than 6 log10 IU per mL; 16% had cirrhosis; 49% had HCV genotype 3. The proportions of subjects who were interferon intolerant, ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most subjects had no prior HCV treatment (81%). Table 12 presents the response rates for the treatment groups of sofosbuvir + ribavirin and placebo. Table 13 presents the subgroup analysis by genotype for cirrhosis and interferon classification. FUSION was a randomized, double-blinded trial that evaluated 12 or 16 weeks of treatment with sofosbuvir and ribavirin in subjects who did not achieve SVR with prior interferon-based treatment (relapsers and nonresponders). Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence) and HCV genotype (2 vs. 3). Treated subjects (N=201) had a median age of 56 years (range: 24 to 70); 70% of the subjects were male; 87% were White; 3% were Black; 9% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 19 to 44 kg/m2); 73% had baseline HCV RNA levels greater than 6log10 IU per mL; 34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. Table 14 presents the response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks and 16 weeks. Table 15 presents the subgroup analysis by genotype for cirrhosis and response to prior HCV treatment. The VALENCE trial evaluated sofosbuvir in combination with weight-based ribavirin for the treatment of genotype 2 or 3 HCV infection in treatment-naïve subjects or subjects who did not achieve SVR with prior interferon-based treatment, including subjects with compensated cirrhosis. The original trial design was a 4 to 1 randomization to sofosbuvir + ribavirin for 12 weeks or placebo. Based on emerging data, this trial was unblinded and all genotype 2 HCV-infected subjects continued the original planned treatment and received sofosbuvir + ribavirin for 12 weeks, and duration of treatment with sofosbuvir + ribavirin in genotype 3 HCV-infected subjects was extended to 24 weeks. Eleven genotype 3 subjects had already completed sofosbuvir + ribavirin for 12 weeks at the time of the amendment. Treated subjects (N=419) had a median age of 51 years (range: 19 to 74); 60% of the subjects were male; mean body mass index was 26 kg/m2 (range: 17 to 44 kg/m2); the mean baseline HCV RNA level was 6.4 log10 IU per mL; 78% had HCV genotype 3; 58% of the subjects were treatment-experienced and 65% of those subjects experienced relapse/breakthrough to prior HCV treatment. Table 16 presents the response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks and 24 weeks. Table 17 presents the subgroup analysis by genotype for cirrhosis and prior HCV treatment experience. Sofosbuvir was studied in an open-label clinical trial (Study PHOTON-1) evaluating the safety and efficacy of 12 or 24 weeks of treatment with sofosbuvir and ribavirin in subjects with genotype 1, 2 or 3 chronic hepatitis C co-infected with HIV-1. Genotype 2 and 3 subjects were either HCV treatment-naïve or experienced, whereas genotype 1 subjects were all treatment-naïve. Subjects received 400 mg sofosbuvir and weight-based ribavirin (1000 mg for subjects weighing 500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ cell count >200 cells/mm3. Efficacy data 12 weeks post treatment are available for 210 subjects. In subjects with HCV genotype 1 infection, the SVR rate was 82% (74/90) in subjects with genotype 1a infection and 54% (13/24) in subjects with genotype 1b infection, with relapse accounting for the majority of treatment failures. SVR rates in subjects with HCV genotype 1 infection were 80% (24/30) in subjects with baseline IL28B C/C allele and 75% (62/83) in subjects with baseline IL28B non-C/C alleles. In the 223 CHC subjects with HIV-1 co-infection, the percentage of CD4+ cells did not change during treatment. Median CD4+ cell count decreases of 85 cells/mm3 and 84 cells/mm3 were observed at the end of treatment with sofosbuvir + ribavirin for 12 or 24 weeks, respectively. HIV-1 rebound during sofosbuvir + ribavirin treatment occurred in 2 subjects (0.9%) on antiretroviral therapy. # How Supplied - Sofosbuvir tablets are yellow, capsule-shaped, film-coated tablets containing 400 mg sofosbuvir debossed with "GSI" on one side and "7977" on the other side. - Each bottle contains 28 tablets (NDC 61958-1501-1), a silica gel desiccant, polyester coil and is closed with a child-resistant closure. ## Storage - Store at room temperature below 30 °C (86 °F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information). Ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant. Ribavirin therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy. When sofosbuvir is used in combination with peginterferon alfa/ribavirin or ribavirin, patients must be advised of the teratogenic/embryocidal risks of ribavirin and should be advised that extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients both during treatment and for 6 months after the completion of treatment. Women of childbearing potential and their male partners must use at least two forms of effective contraception during treatment and for 6 months after the treatment has been stopped; routine monthly pregnancy tests must be performed during this time. There is no data on the effectiveness of systemic hormonal contraceptives in women taking sofosbuvir; therefore, two alternative non-hormonal methods of contraception should be used. Patients should be advised to notify their health care provider immediately in the event of a pregnancy. There is a Ribavirin Pregnancy Registry established to monitor maternal and fetal outcomes of pregnant women exposed to ribavirin. Patients should be encouraged to register by calling 1-800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263. Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event of treatment failure should be taken. Patients should be advised that the recommended regimen for patients with genotype 1 or 4 HCV infection is sofosbuvir administered in combination with peginterferon alfa and ribavirin and the recommended regimen for patients with genotype 2 or 3 HCV infection is sofosbuvir administered in combination with ribavirin. If peginterferon alfa and/or ribavirin are permanently discontinued, sofosbuvir should also be discontinued. Patients should be advised that the dose of sofosbuvir must not be reduced and it should be taken on a regular dosing schedule with or without food. If a patient did not take the sofosbuvir at the regular time, it could be taken later in the day. However, no more than 400 mg of sofosbuvir should be taken on any calendar day. The patient should resume the regular dosing schedule on the next day. ## Patient Information Read this Patient Information before you start taking sofosbuvir 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 your treatment. Sofosbuvir is used in combination with other antiviral medicines. When taking sofosbuvir with ribavirin or in combination with peginterferon alfa and ribavirin you should also read those Medication Guides. The information in this Patient Information Leaflet talks about sofosbuvir when it is used with ribavirin and in combination with peginterferon alfa and ribavirin. Sofosbuvir , in combination with ribavirin or peginterferon alfa and ribavirin, may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant or plans to become pregnant, do not take these medicines. You or your sexual partner should not become pregnant while taking sofosbuvir with ribavirin or in combination with peginterferon alfa and ribavirin, and for 6 months after treatment is over. - Females and males must use 2 effective forms of birth control during treatment and for the 6 months after treatment with sofosbuvir and ribavirin or in combination with peginterferon alfa and ribavirin. Talk to your healthcare provider about forms of birth control that may be used during this time. - Females must have a negative pregnancy test before starting treatment with sofosbuvir and ribavirin or in combination with peginterferon alfa and ribavirin, every month while being treated, and for 6 months after your treatment ends. - If you or your female sexual partner becomes pregnant while taking or within 6 months after you stop taking sofosbuvir and ribavirin, or sofosbuvir in combination with peginterferon alfa and ribavirin, tell your healthcare provider right away. You or your healthcare provider should contact the Ribavirin Pregnancy Registry by calling 1-800-593-2214. The Ribavirin Pregnancy Registry collects information about what happens to mothers and their babies if the mother takes ribavirin while she is pregnant. If you are also infected with HIV and taking medicines to treat your HIV infection, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263. Sofosbuvir should be used together with ribavirin or in combination with peginterferon alfa and ribavirin to treat chronic hepatitis C infection. - Sofosbuvir is a prescription medicine used with other antiviral medicines to treat chronic (lasting a long time) hepatitis C infection in adults. - Sofosbuvir should not be taken alone. It is not known if sofosbuvir is safe and effective in children under 18 years of age. See "What is the most important information I should know about Sofosbuvir ?" Before taking Sofosbuvir, tell your healthcare provider if you: - Have liver problems other than hepatitis C infection - Have had a liver transplant - Have severe kidney problems or you are on dialysis - Have HIV - Have any other medical condition - Are breastfeeding or plan to breastfeed. It is not known if sofosbuvir passes into your breast milk. You and your healthcare provider should decide if you will take sofosbuvir or breastfeed. You should not do both. Especially tell your healthcare provider if you take any of the following medicines: - Carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®) - Oxcarbazepine (Trileptal®, Oxtellar XR™) - Phenytoin (Dilantin®, Phenytek®) - Phenobarbital (Luminal®) - Rifabutin (Mycobutin®) - Rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®) - Rifapentine (Priftin®) - St. John's wort (Hypericum perforatum) or a product that contains St. John's wort - Tipranavir (Aptivus®) Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. - Take sofosbuvir exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to. - Do not stop taking sofosbuvir without first talking with your healthcare provider. If you think there is a reason to stop taking sofosbuvir, talk to your healthcare provider before doing so. - Take sofosbuvir 1 time each day with or without food. - If you miss a dose of sofosbuvir, take the missed dose as soon as you remember the same day. Do not take more than 1 tablet (400 mg) of sofosbuvir in a day. Take your next dose of sofosbuvir at your regular time the next day. - If you take too much sofosbuvir, call your healthcare provider or go to the nearest hospital emergency room right away. See "What is the most important information I should know about sofosbuvir?" The most common side effects of sofosbuvir when used in combination with ribavirin include: - Tiredness - Headache The most common side effects of sofosbuvir when used in combination with peginterferon alfa and ribavirin include: - Tiredness - Headache - Nausea - Difficulty sleeping - Low red blood cell count Tell 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 sofosbuvir. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - Store sofosbuvir at room temperature below 86°F (30°C). - Keep sofosbuvir in its original container. - Do not use sofosbuvir if the seal over the bottle opening is broken or missing. - Keep sofosbuvir and all medicines out of the reach of children. It is not known if treatment with sofosbuvir will prevent you from infecting another person with the hepatitis C virus during treatment. Talk with your healthcare provider about ways to prevent spreading the hepatitis C virus. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use sofosbuvir for a condition for which it was not prescribed. Do not give sofosbuvir to other people, even if they have the same symptoms you have. It may harm them. If you would like more information about sofosbuvir, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about sofosbuvir that is written for health professionals. For more information, call 1-800-445-3235 or go to www.SOVALDI.com. - Active ingredient: sofosbuvir - Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. - The tablet film-coat contains: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. This Patient Information has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol Alcohol-Sofosbuvir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Sovaldi # Look-Alike Drug Names There is limited information regarding Sofosbuvir Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Sofosbuvir Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, 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 Sofosbuvir is an antiviral that is FDA approved for the treatment of chronic hepatitis C (CHC) infection. Common adverse reactions include diarrhea, anemia, headache, insomnia, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) The recommended dose of sofosbuvir is one 400 mg tablet, taken orally, once daily with or without food. Sofosbuvir should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of CHC in adults. The recommended regimen and treatment duration for sofosbuvir combination therapy is provided in the table below. SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for CHC patients with genotype 1 infection who are ineligible to receive an interferon-based regimen [See Use in Specific Populations (8.8) and Clinical Studies (14.4)]. Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient. Sofosbuvir in combination with ribavirin is recommended for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection [See Use in Specific Populations (8.9)]. ### Dose Modification Dose reduction of sofosbuvir is not recommended. If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose. If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient's hemoglobin concentration and cardiac status. ### Discontinuation of Dosing If the other agents used in combination with sofosbuvir are permanently discontinued, sofosbuvir should also be discontinued. ### Severe Renal Impairment and End Stage Renal Disease No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite [See Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sofosbuvir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sofosbuvir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Sofosbuvir 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 Sofosbuvir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sofosbuvir in pediatric patients. # Contraindications - When sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications. - Sofosbuvir combination treatment with ribavirin or peginterferon alfa/ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin. # Warnings Ribavirin may cause birth defects and/or death of the exposed fetus and animal studies have shown that interferons have abortifacient effects. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. When sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. There are no data on the effectiveness of systemic hormonal contraceptives in women taking sofosbuvir, therefore, two non-hormonal methods of contraception should be used during treatment with sofosbuvir and concomitant ribavirin. Refer also to the prescribing information for ribavirin. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin, St. John's wort) may significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of sofosbuvir. Rifampin and St. John's wort should not be used with sofosbuvir. # Adverse Reactions ## Clinical Trials Experience Sofosbuvir should be administered with ribavirin or peginterferon alfa/ribavirin. Refer to the prescribing information of peginterferon alfa and ribavirin for a description of adverse reactions associated with their use. 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 assessment of sofosbuvir is based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including 650 subjects who received sofosbuvir + ribavirin (RBV) combination therapy for 12 weeks, 98 subjects who received sofosbuvir + ribavirin combination therapy for 16 weeks, 250 subjects who received sofosbuvir + ribavirin combination therapy for 24 weeks, 327 subjects who received sofosbuvir + peginterferon (Peg-IFN) alfa + ribavirin combination therapy for 12 weeks, 243 subjects who received peginterferon alfa + ribavirin for 24 weeks and 71 subjects who received placebo (PBO) for 12 weeks. The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving sofosbuvir + ribavirin for 12 weeks, <1% for subjects receiving sofosbuvir + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving sofosbuvir + peginterferon alfa + ribavirin for 12 weeks. Treatment-emergent adverse events observed in ≥15% of subjects in clinical trials are provided in the table below. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. The most common adverse events (≥ 20%) for sofosbuvir + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥ 20%) for sofosbuvir + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia. With the exception of anemia and neutropenia, the majority of events presented in Table 3 occurred at severity of grade 1 in sofosbuvir-containing regimens. The following ADRs occurred in <1% of subjects receiving sofosbuvir in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship. - Hematologic Effects: Pancytopenia (particularly in subjects receiving concomitant pegylated interferon). - Psychiatric Disorders: Severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide. Changes in selected hematological parameters are described in the table below. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. Total bilirubin elevation of more than 2.5×ULN was observed in none of the subjects in the sofosbuvir + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon alfa + ribavirin 24 weeks, sofosbuvir + ribavirin 12 weeks and sofosbuvir + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline levels by post-treatment Week 4. These bilirubin elevations were not associated with transaminase elevations. Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10×ULN was observed in <1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, sofosbuvir + peginterferon alfa + ribavirin 12 weeks and sofosbuvir + ribavirin 12 weeks groups, respectively. Isolated, asymptomatic lipase elevation of greater than 3×ULN was observed in <1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively. ## Postmarketing Experience There is limited information regarding adverse reactions in postmarketing experience of Sofosbuvir provided by the label. # Drug Interactions After oral administration, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir accounts for approximately 4% of drug related material. In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses. Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John's wort) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of sofosbuvir and thus should not be used with sofosbuvir. Coadministration of sofosbuvir with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, sofosbuvir may be coadministered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these transporters. The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs. Drug interaction information for sofosbuvir with potential concomitant drugs is summarized in the table below. The drug interactions described are based on potential drug interactions that may occur with sofosbuvir. The table is not all-inclusive. In addition to the drugs included in the table above, the interaction between sofosbuvir and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine,tacrolimus, or tenofovir disoproxil fumarate. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B There are no adequate and well-controlled studies with sofosbuvir in pregnant women. - No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to the predominant circulating metabolite GS-331007 increased over the course of gestation from approximately 5- to 10-fold and 12- to 28-fold the exposure in humans at the recommended clinical dose, respectively. ### Pregnancy Category X: Use with Ribavirin or Peginterferon Alfa/Ribavirin - Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using two forms of effective contraception during treatment with ribavirin and for 6 months after treatment has concluded. There are no data on the effectiveness of systemic hormonal contraceptives in women taking sofosbuvir. Therefore, two effective non-hormonal methods of contraception should be used during treatment with sofosbuvir and concomitant ribavirin. - In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling Ribavirin Pregnancy Registry at 1-800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263. - Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sofosbuvir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sofosbuvir during labor and delivery. ### Nursing Mothers It is not known whether sofosbuvir and its metabolites are present in human breast milk. The predominant circulating metabolite GS-331007 was the primary component observed in the milk of lactating rats, without effect on nursing pups. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with ribavirin-containing regimens, taking into account the importance of the therapy to the mother. See also the prescribing information for ribavirin. ### Pediatric Use Safety and effectiveness of sofosbuvir in children less than 18 years of age have not been established. ### Geriatic Use Sofosbuvir was administered to 90 subjects aged 65 and over. The response rates observed for subjects over 65 years of age were similar to that of younger subjects across treatment groups. No dose adjustment of sofosbuvir is warranted in geriatric patients ### Gender There is no FDA guidance on the use of Sofosbuvir with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sofosbuvir with respect to specific racial populations. ### Renal Impairment No dose adjustment of sofosbuvir is required for patients with mild or moderate renal impairment. The safety and efficacy of sofosbuvir have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring hemodialysis. No dose recommendation can be given for patients with severe renal impairment or ESRD. Refer also to ribavirin and peginterferon alfa prescribing information for patients with CrCl <50 mL/min. ### Hepatic Impairment No dose adjustment of sofosbuvir is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C). Safety and efficacy of sofosbuvir have not been established in patients with decompensated cirrhosis. See peginterferon alfa prescribing information for contraindication in hepatic decompensation. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sofosbuvir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sofosbuvir in patients who are immunocompromised. ### Others The safety and efficacy of sofosbuvir was assessed in 223 HCV/HIV-1 co-infected subjects. The safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving sofosbuvir + ribavirin in Phase 3 trials. Sofosbuvir was studied in HCV-infected subjects with hepatocellular carcinoma prior to undergoing liver transplantation in an open-label clinical trial evaluating the safety and efficacy of sofosbuvir and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant virologic response (pTVR) defined as HCV RNA < lower limit of quantification (LLOQ) at 12 weeks post-transplant. HCV-infected subjects, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the MILAN criteria (defined as the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter in patients with multiple tumors and no extrahepatic manifestations of the cancer or evidence of vascular invasion of tumor) received 400 mg sofosbuvir and weight-based 1000–1200 mg ribavirin daily for 24–48 weeks or until the time of liver transplantation, whichever occurred first. An interim analysis was conducted on 61 subjects who received sofosbuvir and ribavirin; 45 subjects had HCV genotype 1; 44 subjects had a baseline CPT score less than 7 and all subjects had a baseline unadjusted MELD score ≤14. Of these 61 subjects, 41 subjects underwent liver transplantation following up to 48 weeks of treatment with sofosbuvir and ribavirin; 37 had HCV RNA < LLOQ at the time of transplantation. Of the 37 subjects, the post-transplant virologic response (pTVR) rate is 64% (23/36) in the 36 evaluable subjects who have reached the 12 week post-transplant time point. The safety profile of sofosbuvir and ribavirin in HCV-infected subjects prior to liver transplantation was comparable to that observed in subjects treated with sofosbuvir and ribavirin in Phase 3 clinical trials. The safety and efficacy of sofosbuvir have not been established in post-liver transplant patients. Available data on subjects with genotype 5 or 6 HCV infection are insufficient for dosing recommendations. # Administration and Monitoring ### Administration Oral ### Monitoring In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling Ribavirin Pregnancy Registry at 1-800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263. # IV Compatibility There is limited information regarding the compatibility of Sofosbuvir and IV administrations. # Overdosage The highest documented dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1200 mg administered to 59 healthy subjects. In that trial, there were no untoward effects observed at this dose level, and adverse events were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher doses are not known. No specific antidote is available for overdose with sofosbuvir. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with sofosbuvir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. A 4-hour hemodialysis session removed 18% of the administered dose. # Pharmacology ## Mechanism of Action Sofosbuvir is a direct-acting antiviral agent against the hepatitis C virus. ## Structure sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase. The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula: Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥ 2 mg/mL across the pH range of 2–7.7 at 37 °C and is slightly soluble in water. Sofosbuvir tablets are for oral administration. Each tablet contains 400 mg of sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. ## Pharmacodynamics The effect of sofosbuvir 400 and 1200 mg on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent. ## Pharmacokinetics The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of sofosbuvir was absorbed with a peak plasma concentration observed at ~0.5–2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in subjects with genotype 1 to 6 HCV infection who were coadministered ribavirin (with or without pegylated interferon), geometric mean steady state sofosbuvir (N=838) and GS-331007 (N=1695) AUC0–24 were 828 ng∙hr/mL and 6790 ng∙hr/mL, respectively. Relative to healthy subjects administered sofosbuvir alone (N = 272), the sofosbuvir AUC0–24 was 39% higher and GS-331007 AUC0–24 was 39% lower, respectively, in HCV-infected subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg. Relative to fasting conditions, the administration of a single dose of sofosbuvir with a standardized high fat meal did not substantially affect the sofosbuvir Cmax or AUC0–inf. The exposure of GS-331007 was not altered in the presence of a high-fat meal. Therefore, sofosbuvir can be administered without regard to food. Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7. Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007 accounted for approximately 4% and >90% of drug related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure, respectively. Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively. ### Specific Populations Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No clinically relevant pharmacokinetic differences have been observed between men and women for sofosbuvir and GS-331007. The pharmacokinetics of sofosbuvir in pediatric patients have not been established. Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (19 to 75 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007. The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR ≥ 50 and < 80 mL/min/1.73m2), moderate (eGFR ≥30 and <50 mL/min/1.73m2), severe renal impairment (eGFR <30 mL/min/1.73m2) and subjects with end stage renal disease (ESRD) requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR >80 mL/min/1.73m2), the sofosbuvir AUC0–inf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC0–inf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0–inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18% of administered dose. No dose adjustment is required for patients with mild or moderate renal impairment. The safety and efficacy of sofosbuvir have not been established in patients with severe renal impairment or ESRD. No dose recommendation can be given for patients with severe renal impairment or ESRD. The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0–24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0–24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No dose adjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepatic impairment. The effects of coadministered drugs on the exposure of sofosbuvir and GS-331007 are shown in Table 6. The effects of sofosbuvir on the exposure of coadministered drugs are shown in Table 7. No effect on the pharmacokinetic parameters of sofosbuvir and GS-331007 was observed with raltegravir. No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with sofosbuvir: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone or rilpivirine. Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with IC50 values ranging from 0.7 to 2.6 µM. GS-461203 is not an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotype 1a, 1b, 2a, 3a and 4a, and chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a ranged from 0.014 to 0.11 µM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.062 µM for genotype 1a (range 0.029–0.128 µM; N=67), 0.102 µM for genotype 1b (range 0.045–0.170 µM; N=29), 0.029 µM for genotype 2 (range 0.014–0.081 µM; N=15) and 0.081 µM for genotype 3a (range 0.024–0.181 µM; N=106). In infectious virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and 0.02 µM, respectively. The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir. Evaluation of sofosbuvir in combination with interferon alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. An M289L substitution developed along with the S282T substitution in genotype 2a, 5 and 6 replicons. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to respective wild-types. In a pooled analysis of 982 subjects who received sofosbuvir in Phase 3 trials, 224 subjects had post-baseline NS5B genotypic data from next generation nucleotide sequencing (assay cutoff of 1%). Treatment-emergent substitutions L159F (n= 6) and V321A (n= 5) were detected in post-baseline samples from GT3a-infected subjects across the Phase 3 trials. No detectable shift in the phenotypic susceptibility to sofosbuvir of subject isolates with L159F or V321A substitutions was seen. The sofosbuvir-associated resistance substitution S282T was not detected at baseline or in the failure isolates from Phase 3 trials. However, an S282T substitution was detected in one genotype 2b subject who relapsed at Week 4 post-treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial P7977-0523 [ELECTRON]. The isolate from this subject displayed a mean 13.5-fold reduced susceptibility to sofosbuvir. For this subject, the S282T substitution was no longer detectable at Week 12 post-treatment by next generation sequencing with an assay cut off of 1%. In the trial done in subjects with hepatocellular carcinoma awaiting liver transplantation where subjects received up to 48 weeks of sofosbuvir and ribavirin, the L159F substitution emerged in multiple subjects with GT1a or GT2b HCV who experienced virologic failure (breakthrough and relapse). Furthermore, the presence of substitutions L159F and/or C316N at baseline was associated with sofosbuvir breakthrough and relapse post-transplant in multiple subjects infected with GT1b HCV. In addition, S282R and L320F substitutions were detected on-treatment by next generation sequencing in a subject infected with GT1a HCV with a partial treatment response. The clinical significance of these substitutions is not known. HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were susceptible to NS5A inhibitors and ribavirin. HCV replicons expressing the ribavirin-associated substitutions T390I and F415Y were susceptible to sofosbuvir. Sofosbuvir was active against HCV replicons with NS3/4A protease inhibitor, NS5B non-nucleoside inhibitor and NS5A inhibitor resistant variants. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility Use with Ribavirin and/or Peginterferon alfa: Ribavirin was shown to be genotoxic in several in vitro and in vivo assays. Ribavirin was not oncogenic in a 6-month p53+/- transgenic mouse study or a 2-year carcinogenicity study in rats. See the prescribing information for ribavirin. Carcinogenicity studies of sofosbuvir in mice and rats are ongoing. Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays. Use with Ribavirin and/or Peginterferon alfa: In fertility studies in male animals, ribavirin induced reversible testicular toxicity, while peginterferon alfa may impair fertility in females. Refer to prescribing information for ribavirin and peginterferon alfa for additional information. Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 8-fold the exposure in humans at the recommended clinical dose. ### Animal Toxicology and/or Pharmacology Heart degeneration and inflammation were observed in rats following GS-9851 (a stereoisomeric mixture containing approximately 50% sofosbuvir) doses of 2000 mg/kg/day for up to 5 days. At this dose, AUC exposure to the predominant metabolite GS-331007 is approximately 29-fold higher than human exposure at the recommended clinical dose. No heart degeneration or inflammation was observed in rats following sofosbuvir doses of up to 500 mg/kg/day for 6 months at a GS-331007 AUC exposure approximately 9-fold higher than human exposure at the recommended clinical dose. In dogs and mice, heart degeneration and inflammation were not observed following sofosbuvir doses of up to 500 and 1000 mg/kg/day for 9 and 3 months, respectively, the highest doses tested. At these doses, GS-331007 AUC exposures are approximately 27- and 41-fold higher, respectively, than human exposure at the recommended clinical dose. # Clinical Studies The safety and efficacy of sofosbuvir was evaluated in five Phase 3 trials in a total of 1724 HCV mono-infected subjects with genotypes 1 to 6 chronic hepatitis C (CHC) and one Phase 3 trial in 223 HCV/HIV-1 co-infected subjects with genotype 1, 2 or 3 CHC. Among the five trials in HCV mono-infected subjects, one was conducted in treatment-naïve subjects with genotype 1, 4, 5 or 6 CHC in combination with peginterferon alfa 2a and ribavirin and the other four were conducted in subjects with genotype 2 or 3 CHC in combination with ribavirin, including one in treatment-naïve subjects, one in interferon intolerant, ineligible or unwilling subjects, one in subjects previously treated with an interferon-based regimen, and one in all subjects irrespective of prior treatment history or ability to take interferon. The trial in HCV/HIV-1 co-infected subjects was conducted in combination with [ribavirin]] in treatment-naïve subjects with genotype 1 CHC and all subjects with genotype 2 or 3 CHC irrespective of prior treatment history or ability to take interferon. Subjects in these trials had compensated liver disease including cirrhosis. Sofosbuvir was administered at a dose of 400 mg once daily. The ribavirin (RBV) dose was weight-based at 1000–1200 mg daily administered in two divided doses when used in combination with sofosbuvir, and the peginterferon alfa 2a dose, where applicable, was 180 micrograms per week. Treatment duration was fixed in each trial and was not guided by subjects' HCV RNA levels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response (SVR) was the primary endpoint which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment. NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment with sofosbuvir in combination with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 1, 4, 5 or 6 HCV infection compared to pre-specified historical control. Treated subjects (N=327) had a median age of 54 years (range: 19 to 70); 64% of the subjects were male; 79% were White, 17% were Black; 14% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU per mL; 17% had cirrhosis; 89% had HCV genotype 1; 9% had HCV genotype 4 and 2% had HCV genotype 5 or 6. Table 8 presents the response rates for the treatment group of sofosbuvir + peginterferon alfa + ribavirin. Response rates for selected subgroups are presented in Table 9. SVR rates were 98% (93/95) in subjects with baseline IL28B C/C allele and 87% (202/232) in subjects with baseline IL28B non-C/C alleles. It is estimated that the response rate in patients who previously failed pegylated interferon and ribavirin therapy will approximate the observed response rate in NEUTRINO subjects with multiple baseline factors traditionally associated with a lower response to interferon-based treatment (Table 9). The SVR rate in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C alleles, HCV RNA >800,000 IU/mL and Metavir F3/F4 fibrosis was 71% (37/52). FISSION was a randomized, open-label, active-controlled trial that evaluated 12 weeks of treatment with sofosbuvir and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 2 and 3 HCV. The ribavirin doses used in the sofosbuvir + ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based 1000–1200 mg per day and 800 mg per day regardless of weight, respectively. Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence), HCV genotype (2 vs. 3) and baseline HCV RNA level (<6 log10IU/mL vs. ≥6 log10IU/mL). Subjects with genotype 2 or 3 HCV were enrolled in an approximately 1:3 ratio. Treated subjects (N=499) had a median age of 50 years (range: 19 to 77); 66% of the subjects were male; 87% were White, 3% were Black; 14% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV RNA levels greater than 6 log10 IU per mL; 20% had cirrhosis; 72% had HCV genotype 3. Table 10 presents the response rates for the treatment groups of sofosbuvir + ribavirin and peginterferon alfa + ribavirin. Response rates for subjects with cirrhosis at baseline are presented in Table 11 by genotype. POSITRON was a randomized, double-blinded, placebo-controlled trial that evaluated 12 weeks of treatment with sofosbuvir and ribavirin (N=207) compared to placebo (N=71) in subjects who are interferon intolerant, ineligible or unwilling. Subjects were randomized in 3:1 ratio and stratified by cirrhosis (presence vs. absence). Treated subjects (N=278) had a median age of 54 years (range: 21 to 75); 54% of the subjects were male; 91% were White, 5% were Black; 11% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 53 kg/m2); 70% had baseline HCV RNA levels greater than 6 log10 IU per mL; 16% had cirrhosis; 49% had HCV genotype 3. The proportions of subjects who were interferon intolerant, ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most subjects had no prior HCV treatment (81%). Table 12 presents the response rates for the treatment groups of sofosbuvir + ribavirin and placebo. Table 13 presents the subgroup analysis by genotype for cirrhosis and interferon classification. FUSION was a randomized, double-blinded trial that evaluated 12 or 16 weeks of treatment with sofosbuvir and ribavirin in subjects who did not achieve SVR with prior interferon-based treatment (relapsers and nonresponders). Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence) and HCV genotype (2 vs. 3). Treated subjects (N=201) had a median age of 56 years (range: 24 to 70); 70% of the subjects were male; 87% were White; 3% were Black; 9% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 19 to 44 kg/m2); 73% had baseline HCV RNA levels greater than 6log10 IU per mL; 34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. Table 14 presents the response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks and 16 weeks. Table 15 presents the subgroup analysis by genotype for cirrhosis and response to prior HCV treatment. The VALENCE trial evaluated sofosbuvir in combination with weight-based ribavirin for the treatment of genotype 2 or 3 HCV infection in treatment-naïve subjects or subjects who did not achieve SVR with prior interferon-based treatment, including subjects with compensated cirrhosis. The original trial design was a 4 to 1 randomization to sofosbuvir + ribavirin for 12 weeks or placebo. Based on emerging data, this trial was unblinded and all genotype 2 HCV-infected subjects continued the original planned treatment and received sofosbuvir + ribavirin for 12 weeks, and duration of treatment with sofosbuvir + ribavirin in genotype 3 HCV-infected subjects was extended to 24 weeks. Eleven genotype 3 subjects had already completed sofosbuvir + ribavirin for 12 weeks at the time of the amendment. Treated subjects (N=419) had a median age of 51 years (range: 19 to 74); 60% of the subjects were male; mean body mass index was 26 kg/m2 (range: 17 to 44 kg/m2); the mean baseline HCV RNA level was 6.4 log10 IU per mL; 78% had HCV genotype 3; 58% of the subjects were treatment-experienced and 65% of those subjects experienced relapse/breakthrough to prior HCV treatment. Table 16 presents the response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks and 24 weeks. Table 17 presents the subgroup analysis by genotype for cirrhosis and prior HCV treatment experience. Sofosbuvir was studied in an open-label clinical trial (Study PHOTON-1) evaluating the safety and efficacy of 12 or 24 weeks of treatment with sofosbuvir and ribavirin in subjects with genotype 1, 2 or 3 chronic hepatitis C co-infected with HIV-1. Genotype 2 and 3 subjects were either HCV treatment-naïve or experienced, whereas genotype 1 subjects were all treatment-naïve. Subjects received 400 mg sofosbuvir and weight-based ribavirin (1000 mg for subjects weighing <75 kg or 1200 mg for subjects weighing ≥75kg) daily for 12 or 24 weeks based on genotype and prior treatment history. Subjects were either not on antiretroviral therapy with a CD4+ cell count >500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ cell count >200 cells/mm3. Efficacy data 12 weeks post treatment are available for 210 subjects. In subjects with HCV genotype 1 infection, the SVR rate was 82% (74/90) in subjects with genotype 1a infection and 54% (13/24) in subjects with genotype 1b infection, with relapse accounting for the majority of treatment failures. SVR rates in subjects with HCV genotype 1 infection were 80% (24/30) in subjects with baseline IL28B C/C allele and 75% (62/83) in subjects with baseline IL28B non-C/C alleles. In the 223 CHC subjects with HIV-1 co-infection, the percentage of CD4+ cells did not change during treatment. Median CD4+ cell count decreases of 85 cells/mm3 and 84 cells/mm3 were observed at the end of treatment with sofosbuvir + ribavirin for 12 or 24 weeks, respectively. HIV-1 rebound during sofosbuvir + ribavirin treatment occurred in 2 subjects (0.9%) on antiretroviral therapy. # How Supplied - Sofosbuvir tablets are yellow, capsule-shaped, film-coated tablets containing 400 mg sofosbuvir debossed with "GSI" on one side and "7977" on the other side. - Each bottle contains 28 tablets (NDC 61958-1501-1), a silica gel desiccant, polyester coil and is closed with a child-resistant closure. ## Storage - Store at room temperature below 30 °C (86 °F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information). Ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant. Ribavirin therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy. When sofosbuvir is used in combination with peginterferon alfa/ribavirin or ribavirin, patients must be advised of the teratogenic/embryocidal risks of ribavirin and should be advised that extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients both during treatment and for 6 months after the completion of treatment. Women of childbearing potential and their male partners must use at least two forms of effective contraception during treatment and for 6 months after the treatment has been stopped; routine monthly pregnancy tests must be performed during this time. There is no data on the effectiveness of systemic hormonal contraceptives in women taking sofosbuvir; therefore, two alternative non-hormonal methods of contraception should be used. Patients should be advised to notify their health care provider immediately in the event of a pregnancy. There is a Ribavirin Pregnancy Registry established to monitor maternal and fetal outcomes of pregnant women exposed to ribavirin. Patients should be encouraged to register by calling 1-800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263. Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event of treatment failure should be taken. Patients should be advised that the recommended regimen for patients with genotype 1 or 4 HCV infection is sofosbuvir administered in combination with peginterferon alfa and ribavirin and the recommended regimen for patients with genotype 2 or 3 HCV infection is sofosbuvir administered in combination with ribavirin. If peginterferon alfa and/or ribavirin are permanently discontinued, sofosbuvir should also be discontinued. Patients should be advised that the dose of sofosbuvir must not be reduced and it should be taken on a regular dosing schedule with or without food. If a patient did not take the sofosbuvir at the regular time, it could be taken later in the day. However, no more than 400 mg of sofosbuvir should be taken on any calendar day. The patient should resume the regular dosing schedule on the next day. ## Patient Information Read this Patient Information before you start taking sofosbuvir 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 your treatment. Sofosbuvir is used in combination with other antiviral medicines. When taking sofosbuvir with ribavirin or in combination with peginterferon alfa and ribavirin you should also read those Medication Guides. The information in this Patient Information Leaflet talks about sofosbuvir when it is used with ribavirin and in combination with peginterferon alfa and ribavirin. Sofosbuvir , in combination with ribavirin or peginterferon alfa and ribavirin, may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant or plans to become pregnant, do not take these medicines. You or your sexual partner should not become pregnant while taking sofosbuvir with ribavirin or in combination with peginterferon alfa and ribavirin, and for 6 months after treatment is over. - Females and males must use 2 effective forms of birth control during treatment and for the 6 months after treatment with sofosbuvir and ribavirin or in combination with peginterferon alfa and ribavirin. Talk to your healthcare provider about forms of birth control that may be used during this time. - Females must have a negative pregnancy test before starting treatment with sofosbuvir and ribavirin or in combination with peginterferon alfa and ribavirin, every month while being treated, and for 6 months after your treatment ends. - If you or your female sexual partner becomes pregnant while taking or within 6 months after you stop taking sofosbuvir and ribavirin, or sofosbuvir in combination with peginterferon alfa and ribavirin, tell your healthcare provider right away. You or your healthcare provider should contact the Ribavirin Pregnancy Registry by calling 1-800-593-2214. The Ribavirin Pregnancy Registry collects information about what happens to mothers and their babies if the mother takes ribavirin while she is pregnant. If you are also infected with HIV and taking medicines to treat your HIV infection, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263. Sofosbuvir should be used together with ribavirin or in combination with peginterferon alfa and ribavirin to treat chronic hepatitis C infection. - Sofosbuvir is a prescription medicine used with other antiviral medicines to treat chronic (lasting a long time) hepatitis C infection in adults. - Sofosbuvir should not be taken alone. It is not known if sofosbuvir is safe and effective in children under 18 years of age. See "What is the most important information I should know about Sofosbuvir ?" Before taking Sofosbuvir, tell your healthcare provider if you: - Have liver problems other than hepatitis C infection - Have had a liver transplant - Have severe kidney problems or you are on dialysis - Have HIV - Have any other medical condition - Are breastfeeding or plan to breastfeed. It is not known if sofosbuvir passes into your breast milk. You and your healthcare provider should decide if you will take sofosbuvir or breastfeed. You should not do both. Especially tell your healthcare provider if you take any of the following medicines: - Carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®) - Oxcarbazepine (Trileptal®, Oxtellar XR™) - Phenytoin (Dilantin®, Phenytek®) - Phenobarbital (Luminal®) - Rifabutin (Mycobutin®) - Rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®) - Rifapentine (Priftin®) - St. John's wort (Hypericum perforatum) or a product that contains St. John's wort - Tipranavir (Aptivus®) Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. - Take sofosbuvir exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to. - Do not stop taking sofosbuvir without first talking with your healthcare provider. If you think there is a reason to stop taking sofosbuvir, talk to your healthcare provider before doing so. - Take sofosbuvir 1 time each day with or without food. - If you miss a dose of sofosbuvir, take the missed dose as soon as you remember the same day. Do not take more than 1 tablet (400 mg) of sofosbuvir in a day. Take your next dose of sofosbuvir at your regular time the next day. - If you take too much sofosbuvir, call your healthcare provider or go to the nearest hospital emergency room right away. See "What is the most important information I should know about sofosbuvir?" The most common side effects of sofosbuvir when used in combination with ribavirin include: - Tiredness - Headache The most common side effects of sofosbuvir when used in combination with peginterferon alfa and ribavirin include: - Tiredness - Headache - Nausea - Difficulty sleeping - Low red blood cell count Tell 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 sofosbuvir. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - Store sofosbuvir at room temperature below 86°F (30°C). - Keep sofosbuvir in its original container. - Do not use sofosbuvir if the seal over the bottle opening is broken or missing. - Keep sofosbuvir and all medicines out of the reach of children. It is not known if treatment with sofosbuvir will prevent you from infecting another person with the hepatitis C virus during treatment. Talk with your healthcare provider about ways to prevent spreading the hepatitis C virus. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use sofosbuvir for a condition for which it was not prescribed. Do not give sofosbuvir to other people, even if they have the same symptoms you have. It may harm them. If you would like more information about sofosbuvir, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about sofosbuvir that is written for health professionals. For more information, call 1-800-445-3235 or go to www.SOVALDI.com. - Active ingredient: sofosbuvir - Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. - The tablet film-coat contains: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. This Patient Information has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol Alcohol-Sofosbuvir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Sovaldi # Look-Alike Drug Names There is limited information regarding Sofosbuvir Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Sofosbuvir
36405d8c776fb11782abe96f2e0f68f7bd11d23c	wikidoc	Somatropin	Somatropin # 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 Somatropin is a endocrine-metabolic agent that is FDA approved for the treatment of HIV patients with wasting or cachexia to increase lean body mass and body weight, and improve physical endurance. Common adverse reactions include tissue turgor (edema, myalgia, hypoesthesia) and musculoskeletal discomfort (arthralgia, pain in extremities). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The usual starting dose of Serostim® is 0.1 mg/kg subcutaneously once daily (up to a total dose of 6 mg). Serostim® should be administered subcutaneously once daily at bedtime according to the following body weight-based dosage recommendations: - Treatment with Serostim® 0.1 mg/kg every other day was associated with fewer side effects, and resulted in a similar improvement in work output, as compared with Serostim® 0.1 mg/kg daily. Therefore, a starting dose of Serostim® 0.1 mg/kg every other day should be considered in patients at increased risk for adverse effects related to recombinant human growth hormone therapy (i.e., glucose intolerance). In general, dose reductions (i.e., reducing the total daily dose or the number of doses per week) should be considered for side effects potentially related to recombinant human growth hormone therapy. - Most of the effect of Serostim® on work output and lean body mass was apparent after 12 weeks of treatment. The effect was maintained during an additional 12 weeks of therapy. There are no safety or efficacy data available from controlled studies in which patients were treated with Serostim® continuously for more than 48 weeks. There are no safety or efficacy data available from trials in which patients with HIV wasting or cachexia were treated intermittently with Serostim®. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Somatropin in adult patients. ### Non–Guideline-Supported Use - Serostim(R) 4 mg subcutaneously every other day, 4 mg once daily. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Somatropin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Somatropin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Somatropin in pediatric patients. # Contraindications - Acute Critical Illness - Growth hormone therapy should not be initiated in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. - Active Malignancy - In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. - Diabetic Retinopathy - Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy. - Hypersensitivity - Serostim® is contraindicated in patients with a known hypersensitivity to somatropin or diluent. # Warnings ### Precautions - Concomitant Antiretroviral Therapy - In some experimental systems, somatropin has been shown to potentiate HIV replication in vitro at concentrations ranging from 50-250 ng/mL. There was no increase in virus production when the antiretroviral agents, zidovudine, didanosine or lamivudine were added to the culture medium. Additional in vitro studies have shown that somatropin does not interfere with the antiviral activity of zalcitabine or stavudine. In the controlled clinical trials, no significant somatropin-associated increase in viral burden was observed. However, the protocol required all participants to be on concomitant antiretroviral therapy for the duration of the study. In view of the potential for acceleration of virus replication, it is recommended that HIV patients be maintained on antiretroviral therapy for the duration of Serostim® treatment. - Impaired Glucose Tolerance/Diabetes - Hyperglycemia may occur in HIV infected individuals due to a variety of reasons. In wasting patients, treatment with Serostim® 0.1 mg/kg daily and 0.1 mg/kg every other day for 12 weeks was associated with approximately 10 mg/dL and 6 mg/dL increases in mean fasting blood glucose concentrations, respectively. The increases occurred early in treatment. Patients with other risk factors for glucose intolerance should be monitored closely during Serostim® therapy. - During safety surveillance of patients with HIV-associated wasting, cases of new onset impaired glucose tolerance, new onset type 2 diabetes mellitus and exacerbation of preexisting diabetes mellitus have been reported in patients receiving Serostim®. Some patients developed diabetic ketoacidosis and diabetic coma. In some patients, these conditions improved when Serostim® was discontinued, while in others, the glucose intolerance persisted. Some of these patients required initiation or adjustment of antidiabetic treatment while on Serostim®. - In clinical trials of Serostim® conducted in HIV patients with lipodystrophy (an unapproved indication), evidence of dose-dependent glucose intolerance and related adverse reaction was observed at doses of 4 mg Serostim® daily and 4 mg Serostim® every other day for 12 weeks. - Intracranial Hypertension - Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. - Fluid Retention/Carpal Tunnel Syndrome - Increased tissue turgor (swelling, particularly in the hands and feet) and musculoskeletal discomfort (pain, swelling and/or stiffness) may occur during treatment with Serostim®, but may resolve spontaneously, with analgesic therapy, or after reducing the frequency of dosing. - Carpal tunnel syndrome may occur during treatment with Serostim®. If the symptoms of carpal tunnel syndrome do not resolve by decreasing the weekly number of doses of Serostim®, it is recommended that treatment be discontinued. - Local and Systemic Reactions - When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site. As with any protein, local or systemic allergic reactions may occur. Patients should be informed that allergic reactions are possible and that prompt medical attention should be sought if allergic reactions occur. - Neoplasms - Because malignancies are more common in HIV positive individuals, the risks and benefits of starting somatropin in HIV positive patients should be carefully considered before initiating Serostim® treatment and patients should be monitored carefully for the development of neoplasms if treatment with somatropin is initiated. - Monitor all patients with a history of any neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor. - Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes of preexisting nevi. - Pancreatitis - Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin-treated patient, especially a child who develops abdominal pain. # Adverse Reactions ## Clinical Trials Experience - In the 12-week, placebo-controlled Clinical Trial 2, 510 patients were treated with Serostim®. The most common adverse reactions judged to be associated with Serostim® were musculoskeletal discomfort and increased tissue turgor (swelling, particularly of the hands or feet), and were more frequently observed when Serostim® 0.1 mg/kg was administered on a daily basis These symptoms often subsided with continued treatment or dose reduction. Approximately 23% of patients receiving Serostim® 0.1 mg/kg daily and 11% of patients receiving 0.1 mg/kg every other day required dose reductions. Discontinuations as a result of adverse reactions occurred in 10.3% of patients receiving Serostim® 0.1 mg/kg daily and 6.6% of patients receiving 0.1 mg/kg every other day. The most common reasons for dose reduction and/or drug discontinuation were arthralgia, myalgia, edema, carpal tunnel syndrome, elevated glucose levels, and elevated triglyceride levels. - Clinical adverse reactions which occurred during the first 12 weeks of study in at least 5% of the patients in either active treatment group and at an incidence greater than placebo are listed below, without regard to causality assessment. - Adverse reactions that occurred in 1% to less than 5% of trial participants receiving Serostim® during the first 12 weeks of Clinical Trial 2 thought to be related to Serostim® included dose dependent edema, periorbital edema, carpal tunnel syndrome, hyperglycemia and hypertriglyceridemia. - During the 12-week, placebo-controlled portion of Clinical Trial 2, the incidence of hyperglycemia reported as an adverse reaction was 3.6% for the placebo group, 1.9% for the 0.1 mg/kg every other day group and 3.2% for the 0.1 mg/kg daily group. One case of diabetes mellitus was noted in the 0.1 mg/kg daily group during the first 12-weeks of therapy. In addition, during the extension phase of Clinical Trial 2, two patients converted from placebo to full dose Serostim®, and 1 patient converted from placebo to half-dose Serostim®, were discontinued because of the development of diabetes mellitus. - The types and incidences of adverse reactions reported during the Clinical Trial 2 extension phase were not different from, or greater in frequency than those observed during the 12-week, placebo-controlled portion of Clinical Trial 2. - Serostim® was evaluated for the treatment of patients with HIV lipodystrophy in two double-blind, placebo-controlled trials that excluded patients with a history of diabetes, impaired fasting glucose or impaired glucose (approximately 20% of the patients screened were excluded from study enrollment as a result of a diagnosis of diabetes or glucose intolerance). The studies included a 12-week double-blind, placebo-controlled, parallel group "induction" phase followed by maintenance phases of different durations (12 and 24 weeks, respectively). In the initial 12-week treatment periods of the two, placebo-controlled clinical trials, 406 patients were treated with Serostim®. Clinical adverse reactions which occurred during the first 12 weeks of both studies combined in at least 5% of the patients in either of the two active treatment groups are listed by treatment group in Table 2, without regard to causality assessment. The most common adverse reactions judged to be associated with Serostim® were edema, arthralgia, pain in extremity, hypoesthesia, myalgia, and blood glucose increased, all of which were more frequently observed when Serostim® 4 mg was administered on a daily basis compared with alternate days. These symptoms often subsided with dose reduction. During the 12-week induction phase, 1) approximately 26% of patients receiving Serostim® 4 mg daily and 19% of patients receiving Serostim® 4 mg every other day required dose reductions; and 2) discontinuations as a result of adverse reactions occurred in 13% of patients receiving Serostim® 4 mg daily and 5% of patients receiving Serostim® 4 mg every other day. The most common reasons for dose reduction and/or drug discontinuation were peripheral edema, hyperglycemia (including blood glucose increased, blood glucose abnormal, and hyperglycemia), and arthralgia. - Glucose metabolism related adverse reactions: During the initial 12-week treatment periods of Studies 1 and 2, the incidence of glucose-related adverse reactions was 4% for the placebo group, 13% for the 4 mg every other day group and 22% for the 4 mg daily group. - Twenty-three patients discontinued due to hyperglycemia while receiving Serostim® during any phase of these studies (3.2% in the 12-week induction phases and 2.1% in the extension phases). - Breast-Related Terms: When grouped together, breast-related adverse reactions (e.g. nipple pain, gynecomastia, breast pain/mass/tenderness/swelling/edema/hypertrophy) had an incidence of 1% for the placebo group, 3% for the Serostim® 4 mg every other day group and 6% for the Serostim® 4 mg daily group. - Adverse reactions that occurred in 1% to less than 5% of trial participants receiving Serostim® during the first 12 weeks of HIV Lipodystrophy Studies 1 and 2 thought to be related to Serostim® include carpal tunnel syndrome, Tinel's sign and facial edema. - The adverse reactions reported for Serostim® 4 mg every other day during the maintenance phase of HIV Lipodystrophy Study 1 (Week 12 to Week 24) were similar in frequency and quality to those observed after treatment with Serostim® 4 mg every other day during the 12-week induction phase. - IGF-1 serum concentrations increased statistically in Serostim®-treated patients when compared to placebo (Table 3). In the Serostim® treated patients at baseline, the proportion of subjects with serum IGF-1 SDS levels ≥ +2 was approximately 10 to 20%, while with treatment with either dose regimen of Serostim® the percentage increased to 80 to 90% by Week 12. - 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 influences 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 Serostim® with the incidence of antibodies to other products may be misleading. - After 12 weeks of treatment, none of the 651 study participants with HIV-associated wasting treated with Serostim® for the first time developed detectable antibodies to growth hormone (> 4 pg binding). Patients were not rechallenged. Data beyond 3 months is not available. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of Serostim®. 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. - Endocrine: - new onset impaired glucose tolerance - new onset type 2 diabetes mellitus - exacerbation of preexisting diabetes mellitus - diabetic ketoacidosis - diabetic coma - In some patients, these conditions improved when Serostim® was discontinued, while in others the glucose intolerance persisted. Some of these patients required initiation or adjustment of antidiabetic treatment while on Serostim®. - Gastrointestinal-Pancreatitis. Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment. # Drug Interactions - β-Hydroxysteroid Dehydrogenase Type 1 - The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Somatropin inhibit 11βHSD-1. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1. - Cytochrome P450-metabolized drugs - Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds metabolized by CYP450 liver enzymes (e.g., corticosteroids, six steroids, anticonvulsants, cyclosporine). Therefore, careful monitoring is advised when somatropin is administered in combination with drugs metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted. - Oral Estrogen - Because oral estrogens may reduce the serum IGF-1 response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages. - Insulin and/or Other Oral/Injectable Hypoglycemic Agents - Patients with diabetes mellitus who receive concomitant treatment with somatropin may require adjustment of their doses of insulin and/or other hypoglycemic agents. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies have been performed in rats and rabbits. Doses up to 5 to 10 times the human dose, based on body surface area, have revealed no evidence of impaired fertility or harm to the fetus due to Serostim®. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Serostim® 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 Somatropin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Somatropin during labor and delivery. ### Nursing Mothers - It is not known whether Serostim® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Serostim® is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients with HIV have not been established. Available evidence suggests that somatropin clearance is similar in adults and children, but no pharmacokinetic studies have been conducted in children with HIV. - In two small studies, 11 children with HIV-associated failure to thrive were treated subcutaneously with human growth hormone. In one study, five children (age range, 6 to 17 years) were treated with 0.04 mg/kg/day for 26 weeks. In a second study, six children (age range, 8 to 14 years) were treated with 0.07 mg/kg/day for 4 weeks. Treatment appeared to be well tolerated in both studies. The preliminary data collected on a limited number of patients with HIV-associated failure to thrive appear to be consistent with safety observations in growth hormone-treated adults with HIV wasting. - Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. ### Geriatic Use - Clinical studies with Serostim® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may be more sensitive to the action of somatropin, and therefore, may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients. ### Gender - Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH could exist (clearance of r-hGH in males > clearance of r-hGH in females). However, no gender-based analysis is available for Serostim® in normal volunteers or patients infected with HIV. ### Race There is no FDA guidance on the use of Somatropin with respect to specific racial populations. ### Renal Impairment - Subjects with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted for Serostim® in patients with renal impairment. ### Hepatic Impairment - No studies have been conducted for Serostim® in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Somatropin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Somatropin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Subcutaneous ### Monitoring There is limited information regarding Monitoring of Somatropin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Somatropin in the drug label. # Overdosage ## Acute Overdose - Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. ## Chronic Overdose - Long-term overdosage could result in signs and symptoms of acromegaly consistent with the known effects of excess growth hormone. # Pharmacology There is limited information regarding Somatropin Pharmacology in the drug label. ## Mechanism of Action - Serostim® is an anabolic and anticatabolic agent which exerts its influence by interacting with specific receptors on a variety of cell types including myocytes, hepatocytes, adipocytes, lymphocytes, and hematopoietic cells. Some, but not all of its effects, are mediated by insulin-like growth factor-1 (IGF-1). ## Structure - Serostim® is a human growth hormone (hGH) produced by recombinant DNA technology. Serostim® has 191 amino acid residues and a molecular weight of 22,125 daltons. Its amino acid sequence and structure are identical to the dominant form of human pituitary growth hormone. Serostim® is produced by a mammalian cell line (mouse C127) that has been modified by the addition of the hGH gene. Serostim® is secreted directly through the cell membrane into the cell-culture medium for collection and purification. - Serostim® is a sterile lyophilized powder intended for subcutaneous injection after reconstitution to its liquid form. - Vials of Serostim® contain either 4 mg, 5 mg, or 6 mg. Each vial contains the following: - Each 4 mg multi-vial is supplied in a combination package with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol). The pH is adjusted with sodium hydroxide of phosphoric acid to give a pH of 7.4 to 8.5 after reconstitution. - Each 5 mg single-use vial is supplied in a combination package with Sterile Water for Injection, USP. The pH is adjusted with sodium hydroxide or phosphoric acid to give a pH of 6.5 to 8.5 after reconstitution. - Each 6 mg single-use vial is supplied in a combination package with Sterile Water for Injection, USP. The pH is adjusted with sodium hydroxide of phosphoric acid to give a pH of 7.4 to 8.5 after reconstitution. ## Pharmacodynamics - Effects on Protein, Lipid and Carbohydrate Metabolism - A one-week study in 6 patients with HIV-associated wasting has shown that treatment with Serostim® 0.1 mg/kg/day improved nitrogen balance, increased protein-sparing lipid oxidation, and had little effect on overall carbohydrate metabolism. - Decreases in trunk fat and total body fat, and increases in lean body mass were observed during two double-blind, placebo-controlled studies wherein Serostim® vs. placebo were administered daily for 12 weeks to patients with HIV Lipodystrophy. - Effects on Nitrogen and Mineral Retention - In the one-week study in 6 patients with HIV-associated wasting, treatment with Serostim® resulted in the retention of phosphorous, potassium, nitrogen, and sodium. The ratio of retained potassium and nitrogen during Serostim® therapy was consistent with retention of these elements in lean tissue. - Physical Performance - Cycle ergometry work output and treadmill performance were examined in separate 12-week, placebo-controlled trials. In both studies, work output improved significantly in the group receiving Serostim® 0.1 mg/kg/day subcutaneously vs placebo. Isometric muscle performance, as measured by grip strength dynamometry, declined, probably as a result of a transient increase in tissue turgor known to occur with Serostim® therapy. ## Pharmacokinetics - Absorption: The absolute bioavailability after subcutaneous was determined to be 70 to 90%. The mean t½ after subcutaneous administration is significantly longer than that seen after intravenous administration in normal male volunteers down-regulated with somatostatin (approximately 4.0 hrs. vs. 0.6 hrs.), indicating that the subcutaneous absorption of somatropin is a rate-limiting process. - Distribution: The steady-state volume of distribution (Mean ± SD) following intravenous administration of somatropin in normal male volunteers is 12.0 ± 1.08 L. - Metabolism: Although the liver plays a role in the metabolism of GH, GH is primarily cleaved in the kidney. GH undergoes glomerular filtration and, after cleavage within the renal cells, the peptides and amino acids are returned to the systemic circulation. - Elimination: The t½ in nine patients with HIV-associated wasting with an average weight of 56.7 ± 6.8 kg, given a fixed dose of 6.0 mg somatropin subcutaneously was 4.28 ± 2.15 hrs, similar to that observed in normal male volunteers. The renal clearance of r-hGH after subcutaneous administration in nine patients with HIV-associated wasting was 0.0015 ± 0.0037 L/h. No significant accumulation of r-hGH appears to occur after 6 weeks of daily dosing as indicated. - Specific Populations: - Pediatric: Available evidence suggests that r-hGH clearances are similar in adults and children, but no pharmacokinetic studies have been conducted in children with HIV. - Gender: Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH could exist (clearance of r-hGH in males > clearance of r-hGH in females). However, no gender-based analysis is available in normal volunteers or patients infected with HIV. - Race: No studies have been conducted to determine the effect of race on the pharmacokinetics of Serostim®. - Renal Impairment: Subjects with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted to determine the effect of renal impairment on the pharmacokinetics of Serostim®. - Hepatic Impairment: No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetic of Serostim®. ## Nonclinical Toxicology - Long-term animal studies for carcinogenicity have not been performed with Serostim®. There is no evidence from animal studies to date of Serostim®-induced mutagenicity or impairment of fertility. # Clinical Studies - The clinical efficacy of Serostim® in HIV-associated wasting or cachexia was assessed in two placebo-controlled trials. All study subjects received concomitant antiretroviral therapy. There was no increase in the incidence of Kaposi's sarcoma (KS), lymphoma, or in the progression of cutaneous Kaposi's sarcoma in clinical studies of Serostim. Patients with internal KS lesions were excluded from the studies. Potential effects on other malignancies are unknown. - Clinical Trial 1: - A 12-week, randomized, double-blind, placebo-controlled study followed by an open-label extension phase enrolled 178 patients with severe HIV wasting taking nucleoside analogue therapy (pre-HAART era). The primary endpoint was body weight. Body composition was assessed using dual energy X-ray absorptiometry (DXA) and physical function was assessed by treadmill exercise testing. Patients meeting the inclusion/exclusion criteria were treated with either placebo or Serostim® 0.1 mg/kg daily. Ninety-six percent (96%) were male. The average baseline CD4 count/microliter was 85. The results from one hundred forty (140) evaluable patients were analyzed (those completing the 12-week course of treatment and who were at least 80% compliant with study drug). After 12 weeks of therapy, the mean difference in weight increase between the Serostim®-treated group and the placebo-treated group was 1.6 kg (3.5 lb). Mean difference in lean body mass (LBM) change between the Serostim®-treated group and the placebo-treated group was 3.1 kg (6.8 lbs) as measured by DXA. Mean increase in weight and LBM, and mean decrease in body fat, were significantly greater in the Serostim®-treated group than in the placebo group (p=0.011, p<0.001, p<0.001, respectively) after 12 weeks of treatment (Figure 1). There were no significant changes with continued treatment beyond 12 weeks suggesting that the original gains of weight and LBM were maintained (Figure 1). - Treatment with Serostim® resulted in a significant increase in physical function as assessed by treadmill exercise testing. The median treadmill work output increased by 13% (p=0.039) at 12 weeks in the group receiving Serostim® (Figure 2). There was no improvement in the placebo-treated group at 12 weeks. Changes in treadmill performance were significantly correlated with changes in LBM. - Clinical Trial 2: - A 12-week, randomized, double-blind, placebo-controlled study enrolled 757 patients with HIV-associated wasting, or cachexia. The primary efficacy endpoint was physical function as measured by cycle ergometry work output. Body composition was assessed using bioelectrical impedance spectroscopy (BIS) and also by dual energy X-ray absorptiometry (DXA) at a subset of centers. Patients meeting the inclusion/exclusion criteria were treated with either placebo, approximately 0.1 mg/kg every other day (qod) of Serostim®, or approximately 0.1 mg/kg daily at bedtime of Serostim®. All results were analyzed in intent-to-treat populations (for cycle ergometry work output, n=670). Ninety-one percent (91%) were male and 88% were on HAART anti-retroviral therapy. The average baseline CD4 count/µL was 446. Six hundred forty-six patients (646) completed the 12-week study and continued in the Serostim® treatment extension phase of the trial. - Clinical Trial 2 results are summarized in Tables 4 and 5: - The mean maximum cycle work output until exhaustion increased after 12 weeks by 2.57 kilojoules (kJ) in the Serostim® 0.1 mg/kg daily group (p<0.01) and by 2.53 kJ in the Serostim® 0.1 mg/kg every other day group (p<0.01) compared with placebo (Table 4). Cycle work output improved approximately 9% in both active treatment arms and decreased <1% in the placebo group. Lean body mass (LBM) and body weight (BW) increased, and fat mass decreased, in a dose-related fashion after treatment with Serostim® and placebo (Table 5). The LBM results obtained by BIS were confirmed with DXA. - Patients' perceptions of the impact of 12 weeks of treatment on their wasting symptoms as assessed by the Bristol-Meyers Anorexia/Cachexia Recovery Instrument improved with both doses of Serostim® in Clinical Trial 2. - Extension Phase: All patients (n=646) completing the 12-week placebo-controlled phase of Clinical Trial 2 continued Serostim® treatment into an extension phase. Five hundred and forty eight of these patients completed an additional 12 weeks of active treatment. In these patients, changes in cycle ergometry work output, LBM, BW, and fat mass either improved further or were maintained with continued Serostim® treatment. # How Supplied - Serostim® is available in the following forms: - Serostim® single-use vials containing 5 mg with Sterile Water for Injection, USP. Package of 7 vials. NDC 44087-0005-7 - Serostim® single-use vials containing 6 mg with Sterile Water for Injection, USP. Package of 7 vials. NDC 44087-0006-7 - Serostim® multiple-use vials containing 4 mg with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol). Package of 7 vials. NDC 44087-0004-7 - Storage and Handling - Before reconstitution: Vials of Serostim® and diluent should be stored at room temperature, (15°-30°C/59°-86°F). Expiration dates are stated on product labels. - Single-use vials: After reconstitution with Sterile Water for Injection, USP, the reconstituted solution should be used immediately and any unused portion should be discarded. - Multi-use vials: After reconstitution with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol), the reconstituted solution should be stored under refrigeration (2-8°C/36-46°F) for up to 14 days. - Avoid freezing reconstituted vials of Serostim®. ## Storage There is limited information regarding Somatropin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients being treated with Serostim® should be informed of the potential benefits and risks associated with treatment. Patients should be instructed to contact their physician should they experience any side effects or discomfort during treatment with Serostim®. - It is recommended that Serostim® be administered using sterile, disposable syringes and needles. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. An appropriate container for the disposal of used syringes and needles should be employed. - Patients should be instructed to rotate injection sites to avoid localized tissue atrophy. - Never Share a Serostim® Pen or Needle Between Patients - Counsel patients that they should never share Serostim® or Serostim® injection devices with another person, even if the needle or nozzle is changed. Sharing of Serostim® or Serostim® injection devices between patients may pose a risk of transmission of infection. - Patients should be informed about the management of common side effects relating tissue turgor, glucose intolerance and musculoskeletal discomfort. # Precautions with Alcohol - Alcohol-Somatropin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SEROSTIM® # Look-Alike Drug Names There is limited information regarding Somatropin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Somatropin 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. # Overview Somatropin is a endocrine-metabolic agent that is FDA approved for the treatment of HIV patients with wasting or cachexia to increase lean body mass and body weight, and improve physical endurance. Common adverse reactions include tissue turgor (edema, myalgia, hypoesthesia) and musculoskeletal discomfort (arthralgia, pain in extremities). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The usual starting dose of Serostim® is 0.1 mg/kg subcutaneously once daily (up to a total dose of 6 mg). Serostim® should be administered subcutaneously once daily at bedtime according to the following body weight-based dosage recommendations: - Treatment with Serostim® 0.1 mg/kg every other day was associated with fewer side effects, and resulted in a similar improvement in work output, as compared with Serostim® 0.1 mg/kg daily. Therefore, a starting dose of Serostim® 0.1 mg/kg every other day should be considered in patients at increased risk for adverse effects related to recombinant human growth hormone therapy (i.e., glucose intolerance). In general, dose reductions (i.e., reducing the total daily dose or the number of doses per week) should be considered for side effects potentially related to recombinant human growth hormone therapy. - Most of the effect of Serostim® on work output and lean body mass was apparent after 12 weeks of treatment. The effect was maintained during an additional 12 weeks of therapy. There are no safety or efficacy data available from controlled studies in which patients were treated with Serostim® continuously for more than 48 weeks. There are no safety or efficacy data available from trials in which patients with HIV wasting or cachexia were treated intermittently with Serostim®. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Somatropin in adult patients. ### Non–Guideline-Supported Use - Serostim(R) 4 mg subcutaneously every other day, 4 mg once daily. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Somatropin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Somatropin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Somatropin in pediatric patients. # Contraindications - Acute Critical Illness - Growth hormone therapy should not be initiated in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. - Active Malignancy - In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. - Diabetic Retinopathy - Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy. - Hypersensitivity - Serostim® is contraindicated in patients with a known hypersensitivity to somatropin or diluent. # Warnings ### Precautions - Concomitant Antiretroviral Therapy - In some experimental systems, somatropin has been shown to potentiate HIV replication in vitro at concentrations ranging from 50-250 ng/mL. There was no increase in virus production when the antiretroviral agents, zidovudine, didanosine or lamivudine were added to the culture medium. Additional in vitro studies have shown that somatropin does not interfere with the antiviral activity of zalcitabine or stavudine. In the controlled clinical trials, no significant somatropin-associated increase in viral burden was observed. However, the protocol required all participants to be on concomitant antiretroviral therapy for the duration of the study. In view of the potential for acceleration of virus replication, it is recommended that HIV patients be maintained on antiretroviral therapy for the duration of Serostim® treatment. - Impaired Glucose Tolerance/Diabetes - Hyperglycemia may occur in HIV infected individuals due to a variety of reasons. In wasting patients, treatment with Serostim® 0.1 mg/kg daily and 0.1 mg/kg every other day for 12 weeks was associated with approximately 10 mg/dL and 6 mg/dL increases in mean fasting blood glucose concentrations, respectively. The increases occurred early in treatment. Patients with other risk factors for glucose intolerance should be monitored closely during Serostim® therapy. - During safety surveillance of patients with HIV-associated wasting, cases of new onset impaired glucose tolerance, new onset type 2 diabetes mellitus and exacerbation of preexisting diabetes mellitus have been reported in patients receiving Serostim®. Some patients developed diabetic ketoacidosis and diabetic coma. In some patients, these conditions improved when Serostim® was discontinued, while in others, the glucose intolerance persisted. Some of these patients required initiation or adjustment of antidiabetic treatment while on Serostim®. - In clinical trials of Serostim® conducted in HIV patients with lipodystrophy (an unapproved indication), evidence of dose-dependent glucose intolerance and related adverse reaction was observed at doses of 4 mg Serostim® daily and 4 mg Serostim® every other day for 12 weeks. - Intracranial Hypertension - Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. - Fluid Retention/Carpal Tunnel Syndrome - Increased tissue turgor (swelling, particularly in the hands and feet) and musculoskeletal discomfort (pain, swelling and/or stiffness) may occur during treatment with Serostim®, but may resolve spontaneously, with analgesic therapy, or after reducing the frequency of dosing. - Carpal tunnel syndrome may occur during treatment with Serostim®. If the symptoms of carpal tunnel syndrome do not resolve by decreasing the weekly number of doses of Serostim®, it is recommended that treatment be discontinued. - Local and Systemic Reactions - When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site. As with any protein, local or systemic allergic reactions may occur. Patients should be informed that allergic reactions are possible and that prompt medical attention should be sought if allergic reactions occur. - Neoplasms - Because malignancies are more common in HIV positive individuals, the risks and benefits of starting somatropin in HIV positive patients should be carefully considered before initiating Serostim® treatment and patients should be monitored carefully for the development of neoplasms if treatment with somatropin is initiated. - Monitor all patients with a history of any neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor. - Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes of preexisting nevi. - Pancreatitis - Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin-treated patient, especially a child who develops abdominal pain. # Adverse Reactions ## Clinical Trials Experience - In the 12-week, placebo-controlled Clinical Trial 2, 510 patients were treated with Serostim®. The most common adverse reactions judged to be associated with Serostim® were musculoskeletal discomfort and increased tissue turgor (swelling, particularly of the hands or feet), and were more frequently observed when Serostim® 0.1 mg/kg was administered on a daily basis These symptoms often subsided with continued treatment or dose reduction. Approximately 23% of patients receiving Serostim® 0.1 mg/kg daily and 11% of patients receiving 0.1 mg/kg every other day required dose reductions. Discontinuations as a result of adverse reactions occurred in 10.3% of patients receiving Serostim® 0.1 mg/kg daily and 6.6% of patients receiving 0.1 mg/kg every other day. The most common reasons for dose reduction and/or drug discontinuation were arthralgia, myalgia, edema, carpal tunnel syndrome, elevated glucose levels, and elevated triglyceride levels. - Clinical adverse reactions which occurred during the first 12 weeks of study in at least 5% of the patients in either active treatment group and at an incidence greater than placebo are listed below, without regard to causality assessment. - Adverse reactions that occurred in 1% to less than 5% of trial participants receiving Serostim® during the first 12 weeks of Clinical Trial 2 thought to be related to Serostim® included dose dependent edema, periorbital edema, carpal tunnel syndrome, hyperglycemia and hypertriglyceridemia. - During the 12-week, placebo-controlled portion of Clinical Trial 2, the incidence of hyperglycemia reported as an adverse reaction was 3.6% for the placebo group, 1.9% for the 0.1 mg/kg every other day group and 3.2% for the 0.1 mg/kg daily group. One case of diabetes mellitus was noted in the 0.1 mg/kg daily group during the first 12-weeks of therapy. In addition, during the extension phase of Clinical Trial 2, two patients converted from placebo to full dose Serostim®, and 1 patient converted from placebo to half-dose Serostim®, were discontinued because of the development of diabetes mellitus. - The types and incidences of adverse reactions reported during the Clinical Trial 2 extension phase were not different from, or greater in frequency than those observed during the 12-week, placebo-controlled portion of Clinical Trial 2. - Serostim® was evaluated for the treatment of patients with HIV lipodystrophy in two double-blind, placebo-controlled trials that excluded patients with a history of diabetes, impaired fasting glucose or impaired glucose (approximately 20% of the patients screened were excluded from study enrollment as a result of a diagnosis of diabetes or glucose intolerance). The studies included a 12-week double-blind, placebo-controlled, parallel group "induction" phase followed by maintenance phases of different durations (12 and 24 weeks, respectively). In the initial 12-week treatment periods of the two, placebo-controlled clinical trials, 406 patients were treated with Serostim®. Clinical adverse reactions which occurred during the first 12 weeks of both studies combined in at least 5% of the patients in either of the two active treatment groups are listed by treatment group in Table 2, without regard to causality assessment. The most common adverse reactions judged to be associated with Serostim® were edema, arthralgia, pain in extremity, hypoesthesia, myalgia, and blood glucose increased, all of which were more frequently observed when Serostim® 4 mg was administered on a daily basis compared with alternate days. These symptoms often subsided with dose reduction. During the 12-week induction phase, 1) approximately 26% of patients receiving Serostim® 4 mg daily and 19% of patients receiving Serostim® 4 mg every other day required dose reductions; and 2) discontinuations as a result of adverse reactions occurred in 13% of patients receiving Serostim® 4 mg daily and 5% of patients receiving Serostim® 4 mg every other day. The most common reasons for dose reduction and/or drug discontinuation were peripheral edema, hyperglycemia (including blood glucose increased, blood glucose abnormal, and hyperglycemia), and arthralgia. - Glucose metabolism related adverse reactions: During the initial 12-week treatment periods of Studies 1 and 2, the incidence of glucose-related adverse reactions was 4% for the placebo group, 13% for the 4 mg every other day group and 22% for the 4 mg daily group. - Twenty-three patients discontinued due to hyperglycemia while receiving Serostim® during any phase of these studies (3.2% in the 12-week induction phases and 2.1% in the extension phases). - Breast-Related Terms: When grouped together, breast-related adverse reactions (e.g. nipple pain, gynecomastia, breast pain/mass/tenderness/swelling/edema/hypertrophy) had an incidence of 1% for the placebo group, 3% for the Serostim® 4 mg every other day group and 6% for the Serostim® 4 mg daily group. - Adverse reactions that occurred in 1% to less than 5% of trial participants receiving Serostim® during the first 12 weeks of HIV Lipodystrophy Studies 1 and 2 thought to be related to Serostim® include carpal tunnel syndrome, Tinel's sign and facial edema. - The adverse reactions reported for Serostim® 4 mg every other day during the maintenance phase of HIV Lipodystrophy Study 1 (Week 12 to Week 24) were similar in frequency and quality to those observed after treatment with Serostim® 4 mg every other day during the 12-week induction phase. - IGF-1 serum concentrations increased statistically in Serostim®-treated patients when compared to placebo (Table 3). In the Serostim® treated patients at baseline, the proportion of subjects with serum IGF-1 SDS levels ≥ +2 was approximately 10 to 20%, while with treatment with either dose regimen of Serostim® the percentage increased to 80 to 90% by Week 12. - 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 influences 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 Serostim® with the incidence of antibodies to other products may be misleading. - After 12 weeks of treatment, none of the 651 study participants with HIV-associated wasting treated with Serostim® for the first time developed detectable antibodies to growth hormone (> 4 pg binding). Patients were not rechallenged. Data beyond 3 months is not available. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of Serostim®. 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. - Endocrine: - new onset impaired glucose tolerance - new onset type 2 diabetes mellitus - exacerbation of preexisting diabetes mellitus - diabetic ketoacidosis - diabetic coma - In some patients, these conditions improved when Serostim® was discontinued, while in others the glucose intolerance persisted. Some of these patients required initiation or adjustment of antidiabetic treatment while on Serostim®. - Gastrointestinal-Pancreatitis. Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment. # Drug Interactions - β-Hydroxysteroid Dehydrogenase Type 1 - The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Somatropin inhibit 11βHSD-1. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1. - Cytochrome P450-metabolized drugs - Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds metabolized by CYP450 liver enzymes (e.g., corticosteroids, six steroids, anticonvulsants, cyclosporine). Therefore, careful monitoring is advised when somatropin is administered in combination with drugs metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted. - Oral Estrogen - Because oral estrogens may reduce the serum IGF-1 response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages. - Insulin and/or Other Oral/Injectable Hypoglycemic Agents - Patients with diabetes mellitus who receive concomitant treatment with somatropin may require adjustment of their doses of insulin and/or other hypoglycemic agents. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies have been performed in rats and rabbits. Doses up to 5 to 10 times the human dose, based on body surface area, have revealed no evidence of impaired fertility or harm to the fetus due to Serostim®. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Serostim® 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 Somatropin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Somatropin during labor and delivery. ### Nursing Mothers - It is not known whether Serostim® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Serostim® is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients with HIV have not been established. Available evidence suggests that somatropin clearance is similar in adults and children, but no pharmacokinetic studies have been conducted in children with HIV. - In two small studies, 11 children with HIV-associated failure to thrive were treated subcutaneously with human growth hormone. In one study, five children (age range, 6 to 17 years) were treated with 0.04 mg/kg/day for 26 weeks. In a second study, six children (age range, 8 to 14 years) were treated with 0.07 mg/kg/day for 4 weeks. Treatment appeared to be well tolerated in both studies. The preliminary data collected on a limited number of patients with HIV-associated failure to thrive appear to be consistent with safety observations in growth hormone-treated adults with HIV wasting. - Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. ### Geriatic Use - Clinical studies with Serostim® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may be more sensitive to the action of somatropin, and therefore, may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients. ### Gender - Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH could exist (clearance of r-hGH in males > clearance of r-hGH in females). However, no gender-based analysis is available for Serostim® in normal volunteers or patients infected with HIV. ### Race There is no FDA guidance on the use of Somatropin with respect to specific racial populations. ### Renal Impairment - Subjects with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted for Serostim® in patients with renal impairment. ### Hepatic Impairment - No studies have been conducted for Serostim® in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Somatropin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Somatropin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Subcutaneous ### Monitoring There is limited information regarding Monitoring of Somatropin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Somatropin in the drug label. # Overdosage ## Acute Overdose - Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. ## Chronic Overdose - Long-term overdosage could result in signs and symptoms of acromegaly consistent with the known effects of excess growth hormone. # Pharmacology There is limited information regarding Somatropin Pharmacology in the drug label. ## Mechanism of Action - Serostim® is an anabolic and anticatabolic agent which exerts its influence by interacting with specific receptors on a variety of cell types including myocytes, hepatocytes, adipocytes, lymphocytes, and hematopoietic cells. Some, but not all of its effects, are mediated by insulin-like growth factor-1 (IGF-1). ## Structure - Serostim® is a human growth hormone (hGH) produced by recombinant DNA technology. Serostim® has 191 amino acid residues and a molecular weight of 22,125 daltons. Its amino acid sequence and structure are identical to the dominant form of human pituitary growth hormone. Serostim® is produced by a mammalian cell line (mouse C127) that has been modified by the addition of the hGH gene. Serostim® is secreted directly through the cell membrane into the cell-culture medium for collection and purification. - Serostim® is a sterile lyophilized powder intended for subcutaneous injection after reconstitution to its liquid form. - Vials of Serostim® contain either 4 mg, 5 mg, or 6 mg. Each vial contains the following: - Each 4 mg multi-vial is supplied in a combination package with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol). The pH is adjusted with sodium hydroxide of phosphoric acid to give a pH of 7.4 to 8.5 after reconstitution. - Each 5 mg single-use vial is supplied in a combination package with Sterile Water for Injection, USP. The pH is adjusted with sodium hydroxide or phosphoric acid to give a pH of 6.5 to 8.5 after reconstitution. - Each 6 mg single-use vial is supplied in a combination package with Sterile Water for Injection, USP. The pH is adjusted with sodium hydroxide of phosphoric acid to give a pH of 7.4 to 8.5 after reconstitution. ## Pharmacodynamics - Effects on Protein, Lipid and Carbohydrate Metabolism - A one-week study in 6 patients with HIV-associated wasting has shown that treatment with Serostim® 0.1 mg/kg/day improved nitrogen balance, increased protein-sparing lipid oxidation, and had little effect on overall carbohydrate metabolism. - Decreases in trunk fat and total body fat, and increases in lean body mass were observed during two double-blind, placebo-controlled studies wherein Serostim® vs. placebo were administered daily for 12 weeks to patients with HIV Lipodystrophy. - Effects on Nitrogen and Mineral Retention - In the one-week study in 6 patients with HIV-associated wasting, treatment with Serostim® resulted in the retention of phosphorous, potassium, nitrogen, and sodium. The ratio of retained potassium and nitrogen during Serostim® therapy was consistent with retention of these elements in lean tissue. - Physical Performance - Cycle ergometry work output and treadmill performance were examined in separate 12-week, placebo-controlled trials. In both studies, work output improved significantly in the group receiving Serostim® 0.1 mg/kg/day subcutaneously vs placebo. Isometric muscle performance, as measured by grip strength dynamometry, declined, probably as a result of a transient increase in tissue turgor known to occur with Serostim® therapy. ## Pharmacokinetics - Absorption: The absolute bioavailability after subcutaneous was determined to be 70 to 90%. The mean t½ after subcutaneous administration is significantly longer than that seen after intravenous administration in normal male volunteers down-regulated with somatostatin (approximately 4.0 hrs. vs. 0.6 hrs.), indicating that the subcutaneous absorption of somatropin is a rate-limiting process. - Distribution: The steady-state volume of distribution (Mean ± SD) following intravenous administration of somatropin in normal male volunteers is 12.0 ± 1.08 L. - Metabolism: Although the liver plays a role in the metabolism of GH, GH is primarily cleaved in the kidney. GH undergoes glomerular filtration and, after cleavage within the renal cells, the peptides and amino acids are returned to the systemic circulation. - Elimination: The t½ in nine patients with HIV-associated wasting with an average weight of 56.7 ± 6.8 kg, given a fixed dose of 6.0 mg somatropin subcutaneously was 4.28 ± 2.15 hrs, similar to that observed in normal male volunteers. The renal clearance of r-hGH after subcutaneous administration in nine patients with HIV-associated wasting was 0.0015 ± 0.0037 L/h. No significant accumulation of r-hGH appears to occur after 6 weeks of daily dosing as indicated. - Specific Populations: - Pediatric: Available evidence suggests that r-hGH clearances are similar in adults and children, but no pharmacokinetic studies have been conducted in children with HIV. - Gender: Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH could exist (clearance of r-hGH in males > clearance of r-hGH in females). However, no gender-based analysis is available in normal volunteers or patients infected with HIV. - Race: No studies have been conducted to determine the effect of race on the pharmacokinetics of Serostim®. - Renal Impairment: Subjects with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted to determine the effect of renal impairment on the pharmacokinetics of Serostim®. - Hepatic Impairment: No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetic of Serostim®. ## Nonclinical Toxicology - Long-term animal studies for carcinogenicity have not been performed with Serostim®. There is no evidence from animal studies to date of Serostim®-induced mutagenicity or impairment of fertility. # Clinical Studies - The clinical efficacy of Serostim® in HIV-associated wasting or cachexia was assessed in two placebo-controlled trials. All study subjects received concomitant antiretroviral therapy. There was no increase in the incidence of Kaposi's sarcoma (KS), lymphoma, or in the progression of cutaneous Kaposi's sarcoma in clinical studies of Serostim. Patients with internal KS lesions were excluded from the studies. Potential effects on other malignancies are unknown. - Clinical Trial 1: - A 12-week, randomized, double-blind, placebo-controlled study followed by an open-label extension phase enrolled 178 patients with severe HIV wasting taking nucleoside analogue therapy (pre-HAART era). The primary endpoint was body weight. Body composition was assessed using dual energy X-ray absorptiometry (DXA) and physical function was assessed by treadmill exercise testing. Patients meeting the inclusion/exclusion criteria were treated with either placebo or Serostim® 0.1 mg/kg daily. Ninety-six percent (96%) were male. The average baseline CD4 count/microliter was 85. The results from one hundred forty (140) evaluable patients were analyzed (those completing the 12-week course of treatment and who were at least 80% compliant with study drug). After 12 weeks of therapy, the mean difference in weight increase between the Serostim®-treated group and the placebo-treated group was 1.6 kg (3.5 lb). Mean difference in lean body mass (LBM) change between the Serostim®-treated group and the placebo-treated group was 3.1 kg (6.8 lbs) as measured by DXA. Mean increase in weight and LBM, and mean decrease in body fat, were significantly greater in the Serostim®-treated group than in the placebo group (p=0.011, p<0.001, p<0.001, respectively) after 12 weeks of treatment (Figure 1). There were no significant changes with continued treatment beyond 12 weeks suggesting that the original gains of weight and LBM were maintained (Figure 1). - Treatment with Serostim® resulted in a significant increase in physical function as assessed by treadmill exercise testing. The median treadmill work output increased by 13% (p=0.039) at 12 weeks in the group receiving Serostim® (Figure 2). There was no improvement in the placebo-treated group at 12 weeks. Changes in treadmill performance were significantly correlated with changes in LBM. - Clinical Trial 2: - A 12-week, randomized, double-blind, placebo-controlled study enrolled 757 patients with HIV-associated wasting, or cachexia. The primary efficacy endpoint was physical function as measured by cycle ergometry work output. Body composition was assessed using bioelectrical impedance spectroscopy (BIS) and also by dual energy X-ray absorptiometry (DXA) at a subset of centers. Patients meeting the inclusion/exclusion criteria were treated with either placebo, approximately 0.1 mg/kg every other day (qod) of Serostim®, or approximately 0.1 mg/kg daily at bedtime of Serostim®. All results were analyzed in intent-to-treat populations (for cycle ergometry work output, n=670). Ninety-one percent (91%) were male and 88% were on HAART anti-retroviral therapy. The average baseline CD4 count/µL was 446. Six hundred forty-six patients (646) completed the 12-week study and continued in the Serostim® treatment extension phase of the trial. - Clinical Trial 2 results are summarized in Tables 4 and 5: - The mean maximum cycle work output until exhaustion increased after 12 weeks by 2.57 kilojoules (kJ) in the Serostim® 0.1 mg/kg daily group (p<0.01) and by 2.53 kJ in the Serostim® 0.1 mg/kg every other day group (p<0.01) compared with placebo (Table 4). Cycle work output improved approximately 9% in both active treatment arms and decreased <1% in the placebo group. Lean body mass (LBM) and body weight (BW) increased, and fat mass decreased, in a dose-related fashion after treatment with Serostim® and placebo (Table 5). The LBM results obtained by BIS were confirmed with DXA. - Patients' perceptions of the impact of 12 weeks of treatment on their wasting symptoms as assessed by the Bristol-Meyers Anorexia/Cachexia Recovery Instrument improved with both doses of Serostim® in Clinical Trial 2. - Extension Phase: All patients (n=646) completing the 12-week placebo-controlled phase of Clinical Trial 2 continued Serostim® treatment into an extension phase. Five hundred and forty eight of these patients completed an additional 12 weeks of active treatment. In these patients, changes in cycle ergometry work output, LBM, BW, and fat mass either improved further or were maintained with continued Serostim® treatment. # How Supplied - Serostim® is available in the following forms: - Serostim® single-use vials containing 5 mg with Sterile Water for Injection, USP. Package of 7 vials. NDC 44087-0005-7 - Serostim® single-use vials containing 6 mg with Sterile Water for Injection, USP. Package of 7 vials. NDC 44087-0006-7 - Serostim® multiple-use vials containing 4 mg with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol). Package of 7 vials. NDC 44087-0004-7 - Storage and Handling - Before reconstitution: Vials of Serostim® and diluent should be stored at room temperature, (15°-30°C/59°-86°F). Expiration dates are stated on product labels. - Single-use vials: After reconstitution with Sterile Water for Injection, USP, the reconstituted solution should be used immediately and any unused portion should be discarded. - Multi-use vials: After reconstitution with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol), the reconstituted solution should be stored under refrigeration (2-8°C/36-46°F) for up to 14 days. - Avoid freezing reconstituted vials of Serostim®. ## Storage There is limited information regarding Somatropin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients being treated with Serostim® should be informed of the potential benefits and risks associated with treatment. Patients should be instructed to contact their physician should they experience any side effects or discomfort during treatment with Serostim®. - It is recommended that Serostim® be administered using sterile, disposable syringes and needles. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. An appropriate container for the disposal of used syringes and needles should be employed. - Patients should be instructed to rotate injection sites to avoid localized tissue atrophy. - Never Share a Serostim® Pen or Needle Between Patients - Counsel patients that they should never share Serostim® or Serostim® injection devices with another person, even if the needle or nozzle is changed. Sharing of Serostim® or Serostim® injection devices between patients may pose a risk of transmission of infection. - Patients should be informed about the management of common side effects relating tissue turgor, glucose intolerance and musculoskeletal discomfort. # Precautions with Alcohol - Alcohol-Somatropin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SEROSTIM®[1] # Look-Alike Drug Names There is limited information regarding Somatropin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Somatropin
95bd15f844cbf438fdab19c0ae3f37ff7c801688	wikidoc	Sortilin 1	Sortilin 1 Sortilin (SORT1) is a protein that in humans is encoded by the SORT1 gene on chromosome 1. This protein is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors. While it is ubiquitously expressed in many tissues, sortilin is most abundant in the central nervous system. At the cellular level, sortilin functions in protein transport between the Golgi apparatus, endosome, lysosome, and plasma membrane, leading to its involvement in multiple biological processes such as glucose and lipid metabolism as well as neural development and cell death. Moreover, the function and role of sortilin is now emerging in several major human diseases such as atherosclerosis and coronary artery disease, Alzheimer’s disease, and cancer. The SORT1 gene also contains one of 27 loci associated with increased risk of coronary artery disease. # Structure ## Gene The SORT1 gene resides on chromosome 1 at the band 1p13.3 and includes 23 exons. This gene encodes 2 isoforms through alternative splicing. ## Protein Sortilin is a member of the Vps10p sorting receptor family. Crystallization studies of the protein reveal that, when complexed with the ligand neurotensin, the Vps10 ectodomain of sortilin forms a ten-bladed beta-propeller structure with an inner tunnel that contains multiple ligand binding sites. To prevent premature ligand binding during its synthesis, the precursor protein of sortilin contains a 44-amino acid pro-peptide that serves as a chaperone for the Vps10p domain. In addition, two hydrophobic loops have been detected in this domain and act to anchor the protein in the cell membrane. # Function In humans, sortilin is expressed over a wide range of cell types and tissues such as the brain, spinal cord, adrenal gland, thyroid, B-lymphocytes, adipocytes, skeletal muscle, and heart. As a sorting receptor on the cell surface and on the endoplasmic reticulum-Golgi apparatus within the cell, sortilin is involved in the transport of a wide variety of intracellular proteins between the trans-Golgi network, endosome, lysosome, and secretory granules, as well as the plasma membrane. This molecular function enables sortilin to participate in various biological processes, including the transport of GLUT4 to the plasma membrane of fat and skeletal muscle cells in response to insulin. It also mediates the interaction between proNGF and the p75NTR:sortilin complex by acting as a co-receptor to signal cell death. The fine regulation of the brain-derived neurotrophic factor (BDNF) by sortilin is required for both neuronal and tumor cell survival. Moreover, sortilin has been implicated in LDL-cholesterol metabolism, VLDL secretion, and PCSK9 secretion, and thus plays a role in the development of atherosclerotic lesions. Other processes involving sortilin include endocytosis, negative regulation of lipoprotein lipase activity, myotube differentiation, ossification, and regulation of gene expression. # Clinical significance Given its function in facilitating lysosomal degradation or recycling of ligands in lipid metabolism and the neural system, sortilin likely plays an important role in the underlying mechanisms and pathophysiology of atherogenesis and coronary artery disease, as well as in neurological disorders. For example, sortilin has been identified as an important receptor for brain apolipoprotein E (APOE) metabolism, which is implicated in the underlying mechanisms of Alzheimer’s disease. A significant role for sortilin has recently also been reported in the field of oncology, as it has been detected in several cancer cell lines. Notably, human cancerous epithelial cells exhibited increased levels of sortilin as compared to normal epithelial tissues. Furthermore, it appears that sortilin participates in the progression of breast cancer and contributes to tumor cell adhesion and invasion. ## Clinical marker In 2007, chromosome 1p13.3 was identified as a promising locus through a genome-wide approach in patients with coronary artery disease. Subsequently, accumulating evidence suggests that the SORT1 gene at the 1p13 locus is an important risk factor for coronary artery disease, which is attributed to lipid metabolism disorders. As the role of sortilin in lipid metabolism and the development of atherosclerosis has been established, a recent study further reported that increased release of soluble sortilin from platelets, measured as circulating sortilin, may be associated with in vivo platelet activation. This observation also indicates that sortilin has a potential application as a clinical biomarker for diagnosis and prognosis. Additionally, a multi-locus genetic risk score study, based on a combination of 27 loci including the SORT1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). # Interactions Sortilin has been shown to interact with GGA1 and GGA2. ## Interactive Pathway Map Sortilin participates in interactions within the trans-Golgi network vesicle budding and BDNF signaling pathways.	Sortilin 1 Sortilin (SORT1) is a protein that in humans is encoded by the SORT1 gene on chromosome 1.[1] This protein is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors. While it is ubiquitously expressed in many tissues,[2] sortilin is most abundant in the central nervous system.[3] At the cellular level, sortilin functions in protein transport between the Golgi apparatus, endosome, lysosome, and plasma membrane, leading to its involvement in multiple biological processes such as glucose and lipid metabolism as well as neural development and cell death.[4][5][6][7][8] Moreover, the function and role of sortilin is now emerging in several major human diseases such as atherosclerosis and coronary artery disease, Alzheimer’s disease, and cancer.[9][10][11] The SORT1 gene also contains one of 27 loci associated with increased risk of coronary artery disease.[12] # Structure ## Gene The SORT1 gene resides on chromosome 1 at the band 1p13.3 and includes 23 exons.[1] This gene encodes 2 isoforms through alternative splicing.[13] ## Protein Sortilin is a member of the Vps10p sorting receptor family.[3] Crystallization studies of the protein reveal that, when complexed with the ligand neurotensin, the Vps10 ectodomain of sortilin forms a ten-bladed beta-propeller structure with an inner tunnel that contains multiple ligand binding sites.[14] To prevent premature ligand binding during its synthesis, the precursor protein of sortilin contains a 44-amino acid pro-peptide that serves as a chaperone for the Vps10p domain.[15] In addition, two hydrophobic loops have been detected in this domain and act to anchor the protein in the cell membrane.[16] # Function In humans, sortilin is expressed over a wide range of cell types and tissues such as the brain, spinal cord, adrenal gland, thyroid, B-lymphocytes, adipocytes, skeletal muscle, and heart.[17] As a sorting receptor on the cell surface and on the endoplasmic reticulum-Golgi apparatus within the cell, sortilin is involved in the transport of a wide variety of intracellular proteins between the trans-Golgi network, endosome, lysosome, and secretory granules, as well as the plasma membrane.[4] This molecular function enables sortilin to participate in various biological processes, including the transport of GLUT4 to the plasma membrane of fat and skeletal muscle cells in response to insulin.[5] It also mediates the interaction between proNGF and the p75NTR:sortilin complex by acting as a co-receptor to signal cell death.[8][15] The fine regulation of the brain-derived neurotrophic factor (BDNF) by sortilin is required for both neuronal and tumor cell survival.[18] Moreover, sortilin has been implicated in LDL-cholesterol metabolism, VLDL secretion, and PCSK9 secretion, and thus plays a role in the development of atherosclerotic lesions.[6][7] Other processes involving sortilin include endocytosis,[4] negative regulation of lipoprotein lipase activity,[19] myotube differentiation,[20] ossification,[21] and regulation of gene expression.[20] # Clinical significance Given its function in facilitating lysosomal degradation or recycling of ligands in lipid metabolism[7][9][22][23][24] and the neural system,[25] sortilin likely plays an important role in the underlying mechanisms and pathophysiology of atherogenesis and coronary artery disease, as well as in neurological disorders. For example, sortilin has been identified as an important receptor for brain apolipoprotein E (APOE) metabolism, which is implicated in the underlying mechanisms of Alzheimer’s disease.[25][26][27][28] A significant role for sortilin has recently also been reported in the field of oncology, as it has been detected in several cancer cell lines. Notably, human cancerous epithelial cells exhibited increased levels of sortilin as compared to normal epithelial tissues. Furthermore, it appears that sortilin participates in the progression of breast cancer and contributes to tumor cell adhesion and invasion.[10][11] ## Clinical marker In 2007, chromosome 1p13.3 was identified as a promising locus through a genome-wide approach in patients with coronary artery disease.[29] Subsequently, accumulating evidence suggests that the SORT1 gene at the 1p13 locus is an important risk factor for coronary artery disease, which is attributed to lipid metabolism disorders.[29][30][31] As the role of sortilin in lipid metabolism and the development of atherosclerosis has been established, a recent study further reported that increased release of soluble sortilin from platelets, measured as circulating sortilin, may be associated with in vivo platelet activation.[32] This observation also indicates that sortilin has a potential application as a clinical biomarker for diagnosis and prognosis.[6][32] Additionally, a multi-locus genetic risk score study, based on a combination of 27 loci including the SORT1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[12] # Interactions Sortilin has been shown to interact with GGA1[33] and GGA2.[4][33] ## Interactive Pathway Map Sortilin participates in interactions within the trans-Golgi network vesicle budding and BDNF signaling pathways.	https://www.wikidoc.org/index.php/Sortilin_1
bc9a55a706674b3b59bda7b8d2e8fe080c70df4f	wikidoc	Spallation	Spallation In general, spallation is a process in which fragments of material (spall) are ejected from a body due to impact or stress. In nuclear physics, it is the process in which a heavy nucleus emits a large number of nucleons as a result of being hit by a high-energy particle, thus greatly reducing its atomic weight. In the context of impact physics it describes ejection or vaporization of material from a target during impact by a projectile. In planetary physics, spallation describes meteoritic impacts on a planetary surface and the effects of a stellar wind on a planetary atmosphere. In the context of mining or geology, spallation can refer to pieces of rock breaking off a rock face due to the internal stresses in the rock; it commonly occurs on mine shaft walls. In the context of anthropology, spallation is a process used to make stone tools such as arrowheads by knapping. # Nuclear spallation Nuclear spallation occurs naturally in earth's atmosphere owing to the impacts of cosmic rays, and also on the surfaces of bodies in space such as meteorites and the moon. Evidence of cosmic ray spallation is evidence that the material in question has been exposed on the surface of the body of which it is part, and gives a means of measuring the length of time of exposure. The composition of the cosmic rays themselves also indicates that they have suffered spallation before reaching Earth, because the proportion of light elements such as Li, B,and Be in them exceeds average cosmic abundances; these elements in the cosmic rays were evidently formed from spallation of oxygen, nitrogen, carbon and perhaps silicon in the cosmic ray sources or during their lengthy travel here. Cosmogenic isotopes of aluminium, beryllium, chlorine, iodine and neon, formed by spallation of terrestrial elements under cosmic ray bombardment, have been detected on earth. Nuclear spallation is one of the processes by which a particle accelerator may be used to produce a beam of neutrons. A mercury, tantalum or other heavy metal target is used, and 20 to 30 neutrons are expelled after each impact. Although this is a far more expensive way of producing neutron beams than by a chain reaction of nuclear fission in a nuclear reactor, it has the advantage that the beam can be pulsed with relative ease. The concept of nuclear spallation was first coined by Nobelist Glenn T. Seaborg in his doctoral thesis on the inelastic scattering of neutrons in 1937. # Laser spallation Laser induced spallation is a recent experimental technique developed to understand the adhesion of thin films with substrates. A high energy pulsed laser (typically Nd:YAG) is used to create a compressive stress pulse in the substrate wherein it propagates and reflects of as a tensile wave at the free boundary. This tensile pulse spalls/peels the thin film while propagating towards the substrate. Using theory of wave propagation in solids it is possible to extract the interface strength. The stress pulse created in this fashion is usually around 3-8 nanoseconds in duration while its magnitude varies as a function of laser fluence. Due to the non-contact application of load, this technique is very well suited to spall ultra-thin films (1 micrometre in thickness or less). It is also possible to mode convert a longitudinal stress wave into a shear stress using a pulse shaping prism and achieve shear spallation. # Production of neutrons at a spallation neutron source Generally the production of neutrons at a spallation source begins with a high powered accelerator. This is more often than not a synchrotron. As an example, the ISIS neutron source is based on some components of the former Nimrod synchrotron. Nimrod was uncompetitive for high energy physics so it was replaced with a new synchrotron, initially using the original injectors, but which produces a highly intense pulsed beam of protons. Whereas Nimrod would produce around 2ųA at 7GeV, ISIS produces 200 ųA at 800 MeV. This is pulsed at the rate of 50 Hz, and this intense beam of protons is focused onto a target. Experiments have been done with depleted uranium targets but although these produce the most intense neutron beams, they also have the shortest lives. Generally, therefore, tantalum targets have been used. Spallation processes in the target produce the neutrons, initially at very high energies - a good fraction of the proton energy. These neutrons are then slowed in moderators filled with liquid hydrogen or liquid methane to the energies that are needed for the scattering instruments. Whilst protons can be focused since they have charge, chargeless neutrons cannot be, so in this arrangement the instruments are arranged around the moderators. Inertial fusion energy has the potential to produce orders of magnitude more neutrons than spallation. Neutrons are capable of locating hydrogen atoms in structures, resolving atomic thermal motion and studying collective excitations of photons more effectively than X-rays.	Spallation In general, spallation is a process in which fragments of material (spall) are ejected from a body due to impact or stress. In nuclear physics, it is the process in which a heavy nucleus emits a large number of nucleons as a result of being hit by a high-energy particle, thus greatly reducing its atomic weight. In the context of impact physics it describes ejection or vaporization of material from a target during impact by a projectile. In planetary physics, spallation describes meteoritic impacts on a planetary surface and the effects of a stellar wind on a planetary atmosphere. In the context of mining or geology, spallation can refer to pieces of rock breaking off a rock face due to the internal stresses in the rock; it commonly occurs on mine shaft walls. In the context of anthropology, spallation is a process used to make stone tools such as arrowheads by knapping. # Nuclear spallation Nuclear spallation occurs naturally in earth's atmosphere owing to the impacts of cosmic rays, and also on the surfaces of bodies in space such as meteorites and the moon. Evidence of cosmic ray spallation is evidence that the material in question has been exposed on the surface of the body of which it is part, and gives a means of measuring the length of time of exposure. The composition of the cosmic rays themselves also indicates that they have suffered spallation before reaching Earth, because the proportion of light elements such as Li, B,and Be in them exceeds average cosmic abundances; these elements in the cosmic rays were evidently formed from spallation of oxygen, nitrogen, carbon and perhaps silicon in the cosmic ray sources or during their lengthy travel here. Cosmogenic isotopes of aluminium, beryllium, chlorine, iodine and neon, formed by spallation of terrestrial elements under cosmic ray bombardment, have been detected on earth. Nuclear spallation is one of the processes by which a particle accelerator may be used to produce a beam of neutrons. A mercury, tantalum or other heavy metal target is used, and 20 to 30 neutrons are expelled after each impact. Although this is a far more expensive way of producing neutron beams than by a chain reaction of nuclear fission in a nuclear reactor, it has the advantage that the beam can be pulsed with relative ease. The concept of nuclear spallation was first coined by Nobelist Glenn T. Seaborg in his doctoral thesis on the inelastic scattering of neutrons in 1937.[1] # Laser spallation Laser induced spallation is a recent experimental technique developed to understand the adhesion of thin films with substrates. A high energy pulsed laser (typically Nd:YAG) is used to create a compressive stress pulse in the substrate wherein it propagates and reflects of as a tensile wave at the free boundary. This tensile pulse spalls/peels the thin film while propagating towards the substrate. Using theory of wave propagation in solids it is possible to extract the interface strength. The stress pulse created in this fashion is usually around 3-8 nanoseconds in duration while its magnitude varies as a function of laser fluence. Due to the non-contact application of load, this technique is very well suited to spall ultra-thin films (1 micrometre in thickness or less). It is also possible to mode convert a longitudinal stress wave into a shear stress using a pulse shaping prism and achieve shear spallation. # Production of neutrons at a spallation neutron source Generally the production of neutrons at a spallation source begins with a high powered accelerator. This is more often than not a synchrotron. As an example, the ISIS neutron source is based on some components of the former Nimrod synchrotron. Nimrod was uncompetitive for high energy physics so it was replaced with a new synchrotron, initially using the original injectors, but which produces a highly intense pulsed beam of protons. Whereas Nimrod would produce around 2ųA at 7GeV, ISIS produces 200 ųA at 800 MeV. This is pulsed at the rate of 50 Hz, and this intense beam of protons is focused onto a target. Experiments have been done with depleted uranium targets but although these produce the most intense neutron beams, they also have the shortest lives. Generally, therefore, tantalum targets have been used. Spallation processes in the target produce the neutrons, initially at very high energies - a good fraction of the proton energy. These neutrons are then slowed in moderators filled with liquid hydrogen or liquid methane to the energies that are needed for the scattering instruments. Whilst protons can be focused since they have charge, chargeless neutrons cannot be, so in this arrangement the instruments are arranged around the moderators. Template:Seealso Inertial fusion energy has the potential to produce orders of magnitude more neutrons than spallation. Neutrons are capable of locating hydrogen atoms in structures, resolving atomic thermal motion and studying collective excitations of photons more effectively than X-rays.[2]	https://www.wikidoc.org/index.php/Spallation
fede3084d3489448c42376d1005682c9e4645203	wikidoc	Spermicide	Spermicide Spermicide is a substance that kills sperm, inserted vaginally prior to intercourse to prevent pregnancy. As a contraceptive, spermicide may be used alone. However, the pregnancy rate experienced by couples using only spermicide is higher than that of couples using other methods. Usually, spermicides are combined with contraceptive barrier methods such as diaphragms, condoms, cervical caps, and sponges. Combined methods are believed to result in lower pregnancy rates than either method alone. Spermicides are unscented, clear, unflavored, non-staining, and lubricative. # Types and effectiveness The most common active ingredient of spermicides is nonoxynol-9. Spermicides containing nonoxynol-9 are available in many forms, such as jelly (gel), films, and foams. Contraceptive Technology states that spermicides have a failure rate of 18% per year when used correctly and consistently, and 29% under typical use. Menfegol is a spermicide manufactured as a foaming tablet. It is only available in Europe. Octoxynol-9 was previously a common spermicide, but was removed from the U.S. market in 2002 after manufacturers failed to perform new studies required by the FDA. The spermicides benzalkonium chloride and sodium cholate are used in some contraceptive sponges. Benzalkonium chloride might also be available in Canada as a suppository. A common urban legend suggests that Coca-Cola or other soft drinks serve as an effective spermicide. This is false,. Lemon juice solutions have been shown to immobilize sperm in the laboratory, as has Krest Bitter Lemon drink. While the authors of the Krest Bitter Lemon study suggested its use as a postcoital douche, this is unlikely to be effective, as sperm begin leaving the ejaculate (out of the reach of any douche) within 1.5 minutes of deposition. No published studies appear to have been done on the effectiveness of lemon juice preparations in preventing pregnancy, though they are advocated by some as 'natural' spermicides. Lactic acid preparations have also been shown to have some spermicidal effect, and commercial lactic acid-based spermicides are available. However, no published studies on the effectiveness of lactic acid in preventing pregnancy appear to have been done since 1936. Thomas Moench, a former assistant professor of medicine, has said that research into acids as spermicides has "pretty much been abandoned." Extratives of the neem plant such as neem oil have also been proposed as spermicides based on laboratory studies. Animal studies of creams and pessaries derived from neem have shown they have contraceptive effects, however trials in humans to determine its effectiveness in preventing pregnancy have not yet been conducted. # Use as microbicide To date, the only sexual lubricant proven thus far via animal testing as a microbicide effective against HIV and Herpes infection is Viva Gel. Because of its first in class potential, Viva Gel is slated for immediate further clinical trials with human subjects in Australia and the United Sates. . Previously, it was believed that nonoxynol-9 reduced the risk of HIV infection, as it prevents transmission of the virus in the laboratory. However, many human studies have shown no protective effect. Because nonoxynol-9 creates abrasions in the vaginal and rectal walls, it may even make transmission of HIV and other STDs more likely, especially if used frequently. While lemon juice has been proposed as a microbicide based on laboratory studies, human testing has shown that, at the concentrations needed to kill HIV, it causes the same abrasions as nonoxynol-9. Because these abrasions increase risk of pathogen transmission, lemon juice is not recommended as a microbicide. Neem extracts have also been researched as microbicides, as they have anti-microbial properties in the laboratory. In the Phase I clinical trial (to determine safety), almost half of the study participants reported negative side effects such as genital itching, burning, and pain. Because there were no serious adverse health effects, though, the researchers recommended continuing to a Phase II clinical trial (to determine efficacy). The Phase II trial has not yet been completed. # Use with condoms Some condoms are lubricated at the manufacturer with a small amount of nonoxynyl-9. According to Consumer Reports, spermicidally lubricated condoms have no additional benefit in preventing pregnancy, have a shorter shelf life, and may cause urinary-tract infections in women. The World Health Organization says that spermicidally lubricated condoms should no longer be promoted. However, they recommend using a nonoxynol-9 lubricated condom over no condom at all. In contrast, application of separately packaged spermicide is believed to increase the contraceptive efficacy of condoms. # Side effects Nonoxynyl-9 has a number of possible side effects. These include irritation, itching, or burning of the sex organs (either partner), and in women, urinary tract infections, yeast infection, and bacterial vaginosis. These side effects are uncommon; one study found that only 3-5% of women who try spermicides discontinue use due to side effects. Concern has been raised over possible increased risk of birth defects in children conceived despite spermicide use, and also in children of women who, not yet aware of their condition, continued spermicide use during early pregnancy. However, a review in 1990 of large studies on spermicides concluded "there appears to be no increased risk of congenital anomalies, altered sex ratio, or early pregnancy loss among spermicide users." # History The first written record of spermicide use is found in the Kahun Papyrus, an Egyptian document dating to 1850 BC. It described a pessary of crocodile dung and fermented dough. It is believed that the low pH of the dung may have had a spermicidal effect. Further formulations are found in the Ebers Papyrus from approximately 1500 BCE. It recommended mixing seed wool, acacia, dates and honey, and placing the mixture in the vagina. It probably had some effectiveness, in part as a physical barrier due to the thick, sticky consistency, and also because of the lactic acid (a known spermicide) formed from the acacia. Writings by Soranus, a 2nd century Greek physician, contained formulations for a number of acidic concoctions claimed to be spermicidal. His instructions were to soak wool in one of the mixtures, then place near the cervix. Laboratory testing of substances to see if they inhibited sperm motility began in the 1800s. Modern spermicides nonoxynol-9 and menfegol were developed from this line of research. However, many other substances of dubious contraceptive value were also promoted. Especially after the illegallization of contraception in the U.S. by the 1873 Comstock Act, spermicides - the most popular of which was Lysol - were marketed only as "feminine hygiene" products and were not held to any standard of effectiveness. Worse, many manufacturers recommended using the products as a douche after intercourse, too late to affect all the sperm. Medical estimates during the 1930s placed the pregnancy rate of women using many over-the-counter spermicides at seventy percent per year.	Spermicide Template:BirthControl infobox Spermicide is a substance that kills sperm, inserted vaginally prior to intercourse to prevent pregnancy. As a contraceptive, spermicide may be used alone. However, the pregnancy rate experienced by couples using only spermicide is higher than that of couples using other methods. Usually, spermicides are combined with contraceptive barrier methods such as diaphragms, condoms, cervical caps, and sponges. Combined methods are believed to result in lower pregnancy rates than either method alone.[1] Spermicides are unscented, clear, unflavored, non-staining, and lubricative. # Types and effectiveness The most common active ingredient of spermicides is nonoxynol-9. Spermicides containing nonoxynol-9 are available in many forms, such as jelly (gel), films, and foams. Contraceptive Technology states that spermicides have a failure rate of 18% per year when used correctly and consistently, and 29% under typical use.[2] Menfegol is a spermicide manufactured as a foaming tablet.[3] It is only available in Europe. Octoxynol-9 was previously a common spermicide, but was removed from the U.S. market in 2002 after manufacturers failed to perform new studies required by the FDA.[4] The spermicides benzalkonium chloride and sodium cholate are used in some contraceptive sponges.[5] Benzalkonium chloride might also be available in Canada as a suppository.[6] A common urban legend suggests that Coca-Cola or other soft drinks serve as an effective spermicide. This is false,[7]. Lemon juice solutions have been shown to immobilize sperm in the laboratory,[8] as has Krest Bitter Lemon drink.[9] While the authors of the Krest Bitter Lemon study suggested its use as a postcoital douche, this is unlikely to be effective, as sperm begin leaving the ejaculate (out of the reach of any douche) within 1.5 minutes of deposition.[10] No published studies appear to have been done on the effectiveness of lemon juice preparations in preventing pregnancy, though they are advocated by some as 'natural' spermicides.[11] Lactic acid preparations have also been shown to have some spermicidal effect, and commercial lactic acid-based spermicides are available.[12][13] However, no published studies on the effectiveness of lactic acid in preventing pregnancy appear to have been done since 1936.[14] Thomas Moench, a former assistant professor of medicine, has said that research into acids as spermicides has "pretty much been abandoned."[15] Extratives of the neem plant such as neem oil have also been proposed as spermicides based on laboratory studies.[16] Animal studies of creams and pessaries derived from neem have shown they have contraceptive effects,[17] however trials in humans to determine its effectiveness in preventing pregnancy have not yet been conducted. # Use as microbicide To date, the only sexual lubricant proven thus far via animal testing as a microbicide effective against HIV and Herpes infection is Viva Gel. Because of its first in class potential, Viva Gel is slated for immediate further clinical trials with human subjects in Australia and the United Sates. [18]. Previously, it was believed that nonoxynol-9 reduced the risk of HIV infection, as it prevents transmission of the virus in the laboratory. However, many human studies have shown no protective effect. Because nonoxynol-9 creates abrasions in the vaginal and rectal walls, it may even make transmission of HIV and other STDs more likely, especially if used frequently.[19] While lemon juice has been proposed as a microbicide based on laboratory studies,[20] human testing has shown that, at the concentrations needed to kill HIV, it causes the same abrasions as nonoxynol-9. Because these abrasions increase risk of pathogen transmission, lemon juice is not recommended as a microbicide.[21] Neem extracts have also been researched as microbicides, as they have anti-microbial properties in the laboratory. In the Phase I clinical trial (to determine safety), almost half of the study participants reported negative side effects such as genital itching, burning, and pain. Because there were no serious adverse health effects, though, the researchers recommended continuing to a Phase II clinical trial (to determine efficacy).[22] The Phase II trial has not yet been completed. # Use with condoms Some condoms are lubricated at the manufacturer with a small amount of nonoxynyl-9. According to Consumer Reports, spermicidally lubricated condoms have no additional benefit in preventing pregnancy, have a shorter shelf life, and may cause urinary-tract infections in women.[23] The World Health Organization says that spermicidally lubricated condoms should no longer be promoted. However, they recommend using a nonoxynol-9 lubricated condom over no condom at all.[24] In contrast, application of separately packaged spermicide is believed to increase the contraceptive efficacy of condoms.[1] # Side effects Nonoxynyl-9 has a number of possible side effects. These include irritation, itching, or burning of the sex organs (either partner), and in women, urinary tract infections, yeast infection, and bacterial vaginosis.[25] These side effects are uncommon; one study found that only 3-5% of women who try spermicides discontinue use due to side effects.[26] Concern has been raised over possible increased risk of birth defects in children conceived despite spermicide use, and also in children of women who, not yet aware of their condition, continued spermicide use during early pregnancy.[27] However, a review in 1990 of large studies on spermicides concluded "there appears to be no increased risk of congenital anomalies, altered sex ratio, or early pregnancy loss among spermicide users."[28] # History The first written record of spermicide use is found in the Kahun Papyrus, an Egyptian document dating to 1850 BC. It described a pessary of crocodile dung and fermented dough.[29] It is believed that the low pH of the dung may have had a spermicidal effect.[30] Further formulations are found in the Ebers Papyrus from approximately 1500 BCE. It recommended mixing seed wool, acacia, dates and honey, and placing the mixture in the vagina. It probably had some effectiveness, in part as a physical barrier due to the thick, sticky consistency, and also because of the lactic acid (a known spermicide) formed from the acacia.[30] Writings by Soranus, a 2nd century Greek physician, contained formulations for a number of acidic concoctions claimed to be spermicidal. His instructions were to soak wool in one of the mixtures, then place near the cervix.[29] Laboratory testing of substances to see if they inhibited sperm motility began in the 1800s. Modern spermicides nonoxynol-9 and menfegol were developed from this line of research.[29] However, many other substances of dubious contraceptive value were also promoted. Especially after the illegallization of contraception in the U.S. by the 1873 Comstock Act, spermicides - the most popular of which was Lysol - were marketed only as "feminine hygiene" products and were not held to any standard of effectiveness. Worse, many manufacturers recommended using the products as a douche after intercourse, too late to affect all the sperm. Medical estimates during the 1930s placed the pregnancy rate of women using many over-the-counter spermicides at seventy percent per year.[31]	https://www.wikidoc.org/index.php/Spermicidal_gel
5a6888a1b4b682beab822b9fc53abf419e085f95	wikidoc	Spiramycin	Spiramycin # Overview Spiramycin is a macrolide antibiotic. It is used to treat toxoplasmosis and various other infections of soft tissues. Although used in Europe, Canada and Mexico, spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of pregnancy. Spiramycin has been used in Europe since the year 2000 under the trade name "Rovamycine", produced by Rhone-Poulenc Rorer and Famar Lyon, France and Eczacibasi Ilae, Turkey. It also goes under the name Rovamycine in Canada (distributed by OdanLaboratories), where it is mostly marketed to dentists for mouth infections. Spiramycin is a 16-membered ring macrolide (antibiotic). It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibacterial action involves inhibition of protein synthesis in the bacterial cell during translocation. Resistance to spiramycin can develop by several mechanisms and its prevalence is to a considerable extent proportional to the frequency of prescription in a given area. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium sp., Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action. As compared with erythromycin, it is in vitro weight for weight 5 to 20 less effective, an equipotential therapeutic dose is, however, only double. This difference between the effectiveness in vitro and in vivo is explained above all by the great affinity of spiramycin to tissues where it achieves concentrations many times higher than serum levels. An important part is played also by the slow release of the antibiotic from the tissue compartment, the marked action on microbes in sub-inhibition concentrations and the relatively long persisting post-antibiotic effect. Its great advantage is the exceptionally favourable tolerance-gastrointestinal and general. It is available for parenteral and oral administration	Spiramycin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Spiramycin is a macrolide antibiotic. It is used to treat toxoplasmosis and various other infections of soft tissues. Although used in Europe, Canada and Mexico,[1] spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of pregnancy.[2] Spiramycin has been used in Europe since the year 2000 under the trade name "Rovamycine", produced by Rhone-Poulenc Rorer and Famar Lyon, France and Eczacibasi Ilae, Turkey. It also goes under the name Rovamycine in Canada (distributed by OdanLaboratories), where it is mostly marketed to dentists for mouth infections. Spiramycin is a 16-membered ring macrolide (antibiotic). It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibacterial action involves inhibition of protein synthesis in the bacterial cell during translocation. Resistance to spiramycin can develop by several mechanisms and its prevalence is to a considerable extent proportional to the frequency of prescription in a given area. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium sp., Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action. As compared with erythromycin, it is in vitro weight for weight 5 to 20 less effective, an equipotential therapeutic dose is, however, only double. This difference between the effectiveness in vitro and in vivo is explained above all by the great affinity of spiramycin to tissues where it achieves concentrations many times higher than serum levels. An important part is played also by the slow release of the antibiotic from the tissue compartment, the marked action on microbes in sub-inhibition concentrations and the relatively long persisting post-antibiotic effect. Its great advantage is the exceptionally favourable tolerance-gastrointestinal and general. It is available for parenteral and oral administration	https://www.wikidoc.org/index.php/Spiramycin
00db7810cdead6eb17b4320b2d89db13a815d346	wikidoc	Tiotropium	Tiotropium # 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 Tiotropium is a cholinergic muscarinic agonist that is FDA approved for the treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema. Common adverse reactions include constipation, xerostomia, pharyngitis, sinusitis, upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Bronchospasm - Dosing information - DO NOT SWALLOW Tiotropium CAPSULES - FOR USE WITH HANDIHALER DEVICE ONLY - FOR ORAL INHALATION ONLY - Tiotropium capsules must not be swallowed as the intended effects on the lungs will not be obtained. The contents of the Tiotropium capsules are only for oral inhalation and should only be used with the HandiHaler device - Recommended dosage: two inhalations of the powder contents of one Tiotropium capsule, once-daily, with the HandiHaler device - For administration of Tiotropium HandiHaler, a Tiotropium capsule is placed into the center chamber of the HandiHaler device. The Tiotropium capsule is pierced by pressing and releasing the green piercing button on the side of the HandiHaler device. The tiotropium formulation is dispersed into the air stream when the patient inhales through the mouthpiece. - No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given Tiotropium HandiHaler should be monitored closely for anticholinergic effects ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tiotropium in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiotropium in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Tiotropium HandiHaler 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 Tiotropium in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiotropium in pediatric patients. # Contraindications Tiotropium HandiHaler is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of Tiotropium capsules . In clinical trials and postmarketing experience with Tiotropium HandiHaler, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported. # Warnings ## Not for Acute Use Tiotropium HandiHaler is intended as a once-daily maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of bronchospasm (i.e., rescue therapy). ## Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue, or throat), rash, bronchospasm, anaphylaxis, or itching, may occur after administration of Tiotropium HandiHaler. If such a reaction occurs, therapy with Tiotropium HandiHaler should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to Tiotropium HandiHaler. In addition, Tiotropium HandiHaler should be used with caution in patients with severe hypersensitivity to milk proteins. ## Paradoxical Bronchospasm Inhaled medicines, including Tiotropium HandiHaler, can produce paradoxical bronchospasm. If this occurs, treatment with Tiotropium HandiHaler should be stopped and other treatments considered. ## Worsening of Narrow-Angle Glaucoma Tiotropium HandiHaler should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. ## Worsening of Urinary Retention Tiotropium HandiHaler should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. ## Renal Impairment As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with Tiotropium HandiHaler should be monitored closely for anticholinergic side effects . # 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. 6-Month to 1-Year Trials The data described below reflect exposure to Tiotropium HandiHaler in 2663 patients. Tiotropium HandiHaler was studied in two 1-year placebo-controlled trials, two 1-year active-controlled trials, and two 6-month placebo-controlled trials in patients with COPD. In these trials, 1308 patients were treated with Tiotropium HandiHaler at the recommended dose of 18 mcg once a day. The population had an age ranging from 39 to 87 years with 65% to 85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. An additional 6-month trial conducted in a Veteran's Affairs setting is not included in this safety database because only serious adverse events were collected. The most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, tachycardia, blurred vision, glaucoma (new onset or worsening), dysuria, and urinary retention. Four multicenter, 1-year, placebo-controlled and active-controlled trials evaluated Tiotropium HandiHaler in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥3% in the Tiotropium HandiHaler group in the 1-year placebo-controlled trials where the rates in the Tiotropium HandiHaler group exceeded placebo by ≥1%. The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison. Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥3% in the Tiotropium HandiHaler treatment group, but were <1% in excess of the placebo group. Other reactions that occurred in the Tiotropium HandiHaler group at a frequency of 1% to 3% in the placebo-controlled trials where the rates exceeded that in the placebo group include: Body as a Whole: allergic reaction, leg pain; Central and Peripheral Nervous System: dysphonia, paresthesia; Gastrointestinal System Disorders: gastrointestinal disorder not otherwise specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis); Metabolic and Nutritional Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis; Vision Disorder: cataract. In addition, among the adverse reactions observed in the clinical trials with an incidence of <1% were atrial fibrillation, supraventricular tachycardia, angioedema, and urinary retention. In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased with age . Two multicenter, 6-month, controlled studies evaluated Tiotropium HandiHaler in patients with COPD. The adverse reactions and the incidence rates were similar to those seen in the 1-year controlled trials. 4-Year Trial The data described below reflect exposure to Tiotropium HandiHaler in 5992 COPD patients in a 4-year placebo-controlled trial. In this trial, 2986 patients were treated with Tiotropium HandiHaler at the recommended dose of 18 mcg once a day. The population had an age range from 40 to 88 years, was 75% male, 90% Caucasian, and had COPD with a mean pre-bronchodilator FEV1 percent predicted of 40%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. When the adverse reactions were analyzed with a frequency of ≥3% in the Tiotropium HandiHaler group where the rates in the Tiotropium HandiHaler group exceeded placebo by ≥1%, adverse reactions included (Tiotropium HandiHaler, placebo): pharyngitis (12.5%, 10.8%), sinusitis (6.5%, 5.3%), headache (5.7%, 4.5%), constipation (5.1%, 3.7%), dry mouth (5.1%, 2.7%), depression (4.4%, 3.3%), insomnia (4.4%, 3.0%), and arthralgia (4.2%, 3.1%). Additional Adverse Reactions Other adverse reactions not previously listed that were reported more frequently in COPD patients treated with Tiotropium HandiHaler than placebo include: dehydration, skin ulcer, stomatitis, gingivitis, oropharyngeal candidiasis, dry skin, skin infection, and joint swelling. ## Postmarketing Experience Adverse reactions have been identified during worldwide post-approval use of Tiotropium HandiHaler. 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. These adverse reactions are: application site irritation (glossitis, mouth ulceration, and pharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinal obstruction including ileus paralytic, intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachycardia, throat irritation, and urticaria. # Drug Interactions ## Sympathomimetics, Methylxanthines, Steroids Tiotropium HandiHaler has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without increases in adverse drug reactions. ## Anticholinergics There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of Tiotropium HandiHaler with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects . ## Cimetidine, Ranitidine No clinically significant interaction occurred between tiotropium and cimetidine or ranitidine # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies in pregnant women. Tiotropium HandiHaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No evidence of structural alterations was observed in rats and rabbits at inhalation tiotropium doses of up to approximately 660 and 6 times the recommended human daily inhalation dose (RHDID) on a mg/m2 basis, respectively. However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at inhalation tiotropium doses of approximately 35 times the RHDID on a mg/m2 basis. In rabbits, tiotropium caused an increase in post-implantation loss at an inhalation dose of approximately 360 times the RHDID on a mg/m2 basis. Such effects were not observed at inhalation doses of approximately 4 and 80 times the RHDID on a mg/m2 basis in rats and rabbits, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tiotropium in women who are pregnant. ### Labor and Delivery The safety and effectiveness of Tiotropium HandiHaler has not been studied during labor and delivery. ### Nursing Mothers Clinical data from nursing women exposed to tiotropium are not available. Based on lactating rodent studies, tiotropium is excreted into breast milk. It is not known whether tiotropium is excreted in human milk, but because many drugs are excreted in human milk and given these findings in rats, caution should be exercised if Tiotropium HandiHaler is administered to a nursing woman. ### Pediatric Use Tiotropium HandiHaler is approved for use in the maintenance treatment of bronchospasm associated with COPD and for the reduction of COPD exacerbations. COPD does not normally occur in children. The safety and effectiveness of Tiotropium HandiHaler in pediatric patients have not been established. ### Geriatic Use Of the total number of patients who received Tiotropium HandiHaler in the 1-year clinical trials, 426 were <65 years, 375 were 65 to 74 years, and 105 were ≥75 years of age. Within each age subgroup, there were no differences between the proportion of patients with adverse events in the Tiotropium HandiHaler and the comparator groups for most events. Dry mouth increased with age in the Tiotropium HandiHaler group (differences from placebo were 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups). A higher frequency of constipation and urinary tract infections with increasing age was observed in the Tiotropium HandiHaler group in the placebo-controlled studies. The differences from placebo for constipation were 0%, 1.8%, and 7.8% for each of the age groups. The differences from placebo for urinary tract infections were –0.6%, 4.6%, and 4.5%. No overall differences in effectiveness were observed among these groups. Based on available data, no adjustment of Tiotropium HandiHaler dosage in geriatric patients is warranted ### Gender There is no FDA guidance on the use of Tiotropium with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tiotropium with respect to specific racial populations. ### Renal Impairment Patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with Tiotropium HandiHaler should be monitored closely for anticholinergic side effects ### Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tiotropium in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tiotropium in patients who are immunocompromised. # Administration and Monitoring ### Administration - DO NOT SWALLOW Tiotropium CAPSULES - FOR USE WITH HANDIHALER DEVICE ONLY - FOR ORAL INHALATION ONLY ### Monitoring FDA Package Insert for Tiotropium contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once-daily inhalation of 141 mcg of tiotropium. Accidental Ingestion Acute intoxication by inadvertent oral ingestion of Tiotropium capsules is unlikely since it is not well-absorbed systemically. A case of overdose has been reported from postmarketing experience. A female patient was reported to have inhaled 30 capsules over a 2.5 day period, and developed altered mental status, tremors, abdominal pain, and severe constipation. The patient was hospitalized, Tiotropium HandiHaler was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day. No mortality was observed at inhalation tiotropium doses up to 32.4 mg/kg in mice, 267.7 mg/kg in rats, and 0.6 mg/kg in dogs. These doses correspond to 7300, 120,000, and 850 times the recommended human daily inhalation dose on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies. # Pharmacology ## Mechanism of Action Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect. ## Structure Tiotropium HandiHaler consists of a capsule dosage form containing a dry powder formulation of tiotropium intended for oral inhalation only with the HandiHaler device. Each light green, hard gelatin Tiotropium capsule contains 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate) blended with lactose monohydrate (which may contain milk proteins) as the carrier. The dry powder formulation within the Tiotropium capsule is intended for oral inhalation only. The active component of Tiotropium HandiHaler is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2β, 4 β, 5α, 7β)-7--9,9-dimethyl-3-oxa-9-azoniatricyclononane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol. The structural formula is: Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C19H22NO4S2Br - H2O. The HandiHaler device is an inhalation device used to inhale the dry powder contained in the Tiotropium capsule. The dry powder is delivered from the HandiHaler device at flow rates as low as 20 L/min. Under standardized in vitro testing, the HandiHaler device delivers a mean of 10.4 mcg tiotropium when tested at a flow rate of 39 L/min for 3.1 seconds (2 L total). In a study of 26 adult patients with COPD and severely compromised lung function , the median peak inspiratory flow (PIF) through the HandiHaler device was 30.0 L/min (range 20.4 to 45.6 L/min). The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak inspiratory flow through the HandiHaler device, which may vary from patient to patient, and may vary with the exposure time of the Tiotropium capsule outside the blister pack. ## Pharmacodynamics Cardiovascular Effects In a multicenter, randomized, double-blind trial that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30 to 60 msec was higher in the Tiotropium HandiHaler group as compared with placebo. This difference was apparent using both the Bazett (QTcB) and Fredericia (QTcF) corrections of QT for heart rate. No patients in either group had either QTcB or QTcF of >500 msec. Other clinical studies with Tiotropium HandiHaler did not detect an effect of the drug on QTc intervals. The effect of Tiotropium HandiHaler on QT interval was also evaluated in a randomized, placebo- and positive-controlled crossover study in 53 healthy volunteers. Subjects received Tiotropium HandiHaler 18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG assessments were performed at baseline and throughout the dosing interval following the first and last dose of study medication. Relative to placebo, the maximum mean change from baseline in study-specific QTc interval was 3.2 msec and 0.8 msec for Tiotropium HandiHaler 18 mcg and 54 mcg, respectively. No subject showed a new onset of QTc >500 msec or QTc changes from baseline of ≥60 msec. ## Pharmacokinetics Tiotropium is administered by dry powder inhalation. In common with other inhaled drugs, the majority of the delivered dose is deposited in the gastrointestinal tract and, to a lesser extent, in the lung, the intended organ. Many of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy. Absorption Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. It is expected from the chemical structure of the compound (quaternary ammonium compound) that tiotropium is poorly absorbed from the gastrointestinal tract. The effect of food on tiotropium's bioavailability has not been studied. Oral solutions of tiotropium have an absolute bioavailability of 2% to 3%. Maximum tiotropium plasma concentrations were observed 5 minutes after inhalation. Distribution Tiotropium shows a volume of distribution of 32 L/kg indicating that the drug binds extensively to tissues. The human plasma protein binding for tiotropium is 72%. At steady state, peak tiotropium plasma levels in COPD patients were 17 to 19 pg/mL when measured 5 minutes after dry powder inhalation of an 18 mcg dose and decreased in a multi-compartmental manner. Steady-state trough plasma concentrations were 3 to 4 pg/mL. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not readily penetrate the blood-brain barrier. Metabolism The extent of metabolism appears to be small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which binds to muscarinic receptors. In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4. Elimination The terminal elimination half-life of tiotropium was between 5 and 6 days following inhalation. Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers with an inter-individual variability of 22%. Intravenously administered tiotropium was mainly excreted unchanged in urine (74%). After dry powder inhalation, urinary excretion was 14% of the dose, the remainder being mainly non-absorbed drug in the gut which was eliminated via the feces. The renal clearance of tiotropium exceeds the creatinine clearance, indicating active secretion into the urine. After chronic once-daily inhalation by COPD patients, pharmacokinetic steady state was reached after 2 to 3 weeks with no accumulation thereafter. Drug Interactions An interaction study with tiotropium (14.4 mcg intravenous infusion over 15 minutes) and cimetidine 400 mg three times daily or ranitidine 300 mg once daily was conducted. Concomitant administration of cimetidine with tiotropium resulted in a 20% increase in the AUC0-4h, a 28% decrease in the renal clearance of tiotropium and no significant change in the Cmax and amount excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of tiotropium. Specific Populations Geriatric Patients As expected for drugs predominantly excreted renally, advanced age was associated with a decrease of tiotropium renal clearance (326 mL/min in COPD patients 70 years), which may be explained by decreased renal function. Tiotropium excretion in urine after inhalation decreased from 14% (young healthy volunteers) to about 7% (COPD patients). Plasma concentrations were numerically increased with advancing age within COPD patients (43% increase in AUC0-4 after dry powder inhalation), which was not significant when considered in relation to inter- and intra-individual variability . Renal Impairment Since tiotropium is predominantly renally excreted, renal impairment was associated with increased plasma drug concentrations and reduced drug clearance after both intravenous infusion and dry powder inhalation. Mild renal impairment (creatinine clearance of 50 to 80 mL/min), which is often seen in elderly patients, increased tiotropium plasma concentrations (39% increase in AUC0-4 after intravenous infusion). In COPD patients with moderate to severe renal impairment (creatinine clearance of <50 mL/min), the intravenous administration of tiotropium resulted in doubling of the plasma concentrations (82% increase in AUC0-4), which was confirmed by plasma concentrations after dry powder inhalation. Patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with Tiotropium HandiHaler should be monitored closely for anticholinergic side effects . Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 0.059 mg/kg/day, in an 83-week inhalation study in female mice at doses up to 0.145 mg/kg/day, and in a 101-week inhalation study in male mice at doses up to 0.002 mg/kg/day. These doses correspond to approximately 25, 35, and 0.5 times the recommended human daily inhalation dose (RHDID) on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies. Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following assays: the bacterial gene mutation assay, the V79 Chinese hamster cell mutagenesis assay, the chromosomal aberration assays in human lymphocytes in vitro and mouse micronucleus formation in vivo, and the unscheduled DNA synthesis in primary rat hepatocytes in vitro assay. In rats, decreases in the number of corpora lutea and the percentage of implants were noted at inhalation tiotropium doses of 0.078 mg/kg/day or greater (approximately 35 times the RHDID on a mg/m2 basis). No such effects were observed at 0.009 mg/kg/day (approximately 4 times than the RHDID on a mg/m2 basis). The fertility index, however, was not affected at inhalation doses up to 1.689 mg/kg/day (approximately 760 times the RHDID on a mg/m2 basis). These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies. ## Animal Toxicology and Pharmacology Reproductive Toxicology Studies No evidence of fetal structural alteration was observed in rats and rabbits at inhalation tiotropium doses of up to 1.471 and 0.007 mg/kg/day, respectively. These doses correspond to approximately 660 and 6 times the RHDID on a mg/m2 basis, respectively. However, in rats, fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation were observed at inhalation tiotropium doses of ≥0.078 mg/kg (approximately 35 times the RHDID on a mg/m2 basis). In rabbits, an increase in post-implantation loss was observed at an inhalation dose of 0.4 mg/kg/day (approximately 360 times the RHDID on a mg/m2 basis). Such effects were not observed at inhalation doses of 0.009 and up to 0.088 mg/kg/day in rats and rabbits, respectively. These doses correspond to approximately 4 and 80 times the RHDID on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies. # Clinical Studies The Tiotropium HandiHaler (tiotropium bromide inhalation powder) clinical development program consisted of six Phase 3 studies in 2663 patients with COPD (1308 receiving Tiotropium HandiHaler): two 1-year, placebo‑controlled studies, two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlled studies. These studies enrolled patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a forced expiratory volume in one second (FEV1) less than or equal to 60% or 65% of predicted, and a ratio of FEV1/FVC of less than or equal to 0.7. In these studies, Tiotropium HandiHaler, administered once-daily in the morning, provided improvement in lung function (FEV1), with peak effect occurring within 3 hours following the first dose. Two additional trials evaluated exacerbations: a 6-month, randomized, double-blind, placebo-controlled, multicenter clinical trial of 1829 COPD patients in a US Veterans Affairs setting and a 4-year, randomized, double-blind, placebo-controlled, multicenter, clinical trial of 5992 COPD patients. Long-term effects on lung function and other outcomes were also evaluated in the 4-year multicenter trial. 6-Month to 1-Year Effects on Lung Function In the 1-year, placebo-controlled trials, the mean improvement in FEV1 at 30 minutes was 0.13 liters (13%) with a peak improvement of 0.24 liters (24%) relative to baseline after the first dose (Day 1). Further improvements in FEV1 and forced vital capacity (FVC) were observed with pharmacodynamic steady state reached by Day 8 with once-daily treatment. The mean peak improvement in FEV1, relative to baseline, was 0.28 to 0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily treatment. Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1-year treatment period with no evidence of tolerance. In the two 6-month, placebo-controlled trials, serial spirometric evaluations were performed throughout daytime hours in Trial A (12 hours) and limited to 3 hours in Trial B. The serial FEV1 values over 12 hours (Trial A) are displayed in Figure 1. These trials further support the improvement in pulmonary function (FEV1) with Tiotropium HandiHaler, which persisted over the spirometric observational period. Effectiveness was maintained for 24 hours after administration over the 6-month treatment period. Results of each of the 1-year ipratropium-controlled trials were similar to the results of the 1-year placebo-controlled trials. The results of one of these trials are shown in Figure 2. A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24-hour dosing interval in comparison to placebo, regardless of whether Tiotropium HandiHaler was administered in the morning or in the evening. Throughout each week of the one-year treatment period in the two placebo-controlled trials, patients taking Tiotropium HandiHaler had a reduced requirement for the use of rescue short-acting beta2-agonists. Reduction in the use of rescue short-acting beta2-agonists, as compared to placebo, was demonstrated in one of the two 6-month studies. 4-Year Effects on Lung Function A 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial involving 5992 COPD patients was conducted to evaluate the long-term effects of Tiotropium HandiHaler on disease progression (rate of decline in FEV1). Patients were permitted to use all respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. The patients were 40 to 88 years of age, 75% male, and 90% Caucasian with a diagnosis of COPD and a mean pre-bronchodilator FEV1 of 39% predicted (range = 9% to 76%) at study entry. There was no difference between the groups in either of the co-primary efficacy endpoints, yearly rate of decline in pre- and post-bronchodilator FEV1, as demonstrated by similar slopes of FEV1 decline over time (Figure 3). Tiotropium HandiHaler maintained improvements in trough (pre-dose) FEV1 (adjusted means over time: 87 to 103 mL) throughout the 4 years of the study (Figure 3). Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline trough FEV1 (observed mean) = 1.12. Patients with ≥3 acceptable pulmonary function tests after Day 30 and non-missing baseline value were included in the analysis. Exacerbations The effect of Tiotropium HandiHaler on COPD exacerbations was evaluated in two clinical trials: a 4-year clinical trial described above and a 6-month clinical trial of 1829 COPD patients in a Veterans Affairs setting. In the 6-month trial, COPD exacerbations were defined as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics, systemic steroids, or hospitalization. The population had an age ranging from 40 to 90 years with 99% males, 91% Caucasian, and had COPD with a mean pre-bronchodilator FEV1 percent predicted of 36% (range = 8% to 93%). Patients were permitted to use respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. In the 6-month trial, the co-primary endpoints were the proportion of patients with COPD exacerbation and the proportion of patients with hospitalization due to COPD exacerbation. Tiotropium HandiHaler significantly reduced the proportion of COPD patients who experienced exacerbations compared to placebo (27.9% vs 32.3%, respectively; Odds Ratio (OR) (tiotropium/placebo) = 0.81; 95% CI = 0.66, 0.99; p = 0.037). The proportion of patients with hospitalization due to COPD exacerbations in patients who used Tiotropium HandiHaler compared to placebo was 7.0% vs 9.5%, respectively; OR = 0.72; 95% CI = 0.51, 1.01; p = 0.056. Exacerbations were evaluated as a secondary outcome in the 4-year multicenter trial. In this trial, COPD exacerbations were defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea) with a duration of three or more days requiring treatment with antibiotics and/or systemic (oral, intramuscular, or intravenous) steroids. Tiotropium HandiHaler significantly reduced the risk of an exacerbation by 14% (Hazard Ratio (HR) = 0.86; 95% CI = 0.81, 0.91; p<0.001) and reduced the risk of exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI = 0.78, 0.95; p<0.002) compared to placebo. The median time to first exacerbation was delayed from 12.5 months (95% CI = 11.5, 13.8) in the placebo group to 16.7 months (95% CI = 14.9, 17.9) in the Tiotropium HandiHaler group. # How Supplied Tiotropium HandiHaler consists of Tiotropium capsules and the HandiHaler device. Tiotropium capsules contain 18 mcg of tiotropium and are light green, with the Boehringer Ingelheim company logo on the Tiotropium capsule cap and TI 01 on the Tiotropium capsule body, or vice versa. The HandiHaler device is gray colored with a green piercing button. It is imprinted with Tiotropium HandiHaler (tiotropium bromide inhalation powder), the Boehringer Ingelheim company logo, and the Pfizer company logo. It is also imprinted to indicate that Tiotropium capsules should not be stored in the HandiHaler device and that the HandiHaler device is only to be used with Tiotropium capsules. Tiotropium capsules are packaged in an aluminum/aluminum blister card and joined along a perforated-cut line. Tiotropium capsules should always be stored in the blister and only removed immediately before use. The drug should be used immediately after the packaging over an individual Tiotropium capsule is opened. The following packages are available: - carton containing 5 Tiotropium capsules (1 unit-dose blister card) and 1 HandiHaler inhalation device (NDC 0597-0075-75) - carton containing 30 Tiotropium capsules (3 unit-dose blister cards) and 1 HandiHaler inhalation device (NDC 0597-0075-41) - carton containing 90 Tiotropium capsules (9 unit-dose blister cards) and 1 HandiHaler inhalation device (NDC 0597-0075-47) ## Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) . The Tiotropium capsules should not be exposed to extreme temperature or moisture. Do not store Tiotropium capsules in the HandiHaler device. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol Alcohol-Tiotropium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Tiotropium # Look-Alike Drug Names Tiotropium - Inspra # Drug Shortage Status # Price	Tiotropium Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2];Aparna Vuppala, M.B.B.S. [3] # 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 Tiotropium is a cholinergic muscarinic agonist that is FDA approved for the treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema. Common adverse reactions include constipation, xerostomia, pharyngitis, sinusitis, upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Bronchospasm - Dosing information - DO NOT SWALLOW Tiotropium CAPSULES - FOR USE WITH HANDIHALER DEVICE ONLY - FOR ORAL INHALATION ONLY - Tiotropium capsules must not be swallowed as the intended effects on the lungs will not be obtained. The contents of the Tiotropium capsules are only for oral inhalation and should only be used with the HandiHaler device - Recommended dosage: two inhalations of the powder contents of one Tiotropium capsule, once-daily, with the HandiHaler device - For administration of Tiotropium HandiHaler, a Tiotropium capsule is placed into the center chamber of the HandiHaler device. The Tiotropium capsule is pierced by pressing and releasing the green piercing button on the side of the HandiHaler device. The tiotropium formulation is dispersed into the air stream when the patient inhales through the mouthpiece. - No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given Tiotropium HandiHaler should be monitored closely for anticholinergic effects ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tiotropium in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiotropium in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Tiotropium HandiHaler 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 Tiotropium in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiotropium in pediatric patients. # Contraindications Tiotropium HandiHaler is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of Tiotropium capsules . In clinical trials and postmarketing experience with Tiotropium HandiHaler, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported. # Warnings ## Not for Acute Use Tiotropium HandiHaler is intended as a once-daily maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of bronchospasm (i.e., rescue therapy). ## Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue, or throat), rash, bronchospasm, anaphylaxis, or itching, may occur after administration of Tiotropium HandiHaler. If such a reaction occurs, therapy with Tiotropium HandiHaler should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to Tiotropium HandiHaler. In addition, Tiotropium HandiHaler should be used with caution in patients with severe hypersensitivity to milk proteins. ## Paradoxical Bronchospasm Inhaled medicines, including Tiotropium HandiHaler, can produce paradoxical bronchospasm. If this occurs, treatment with Tiotropium HandiHaler should be stopped and other treatments considered. ## Worsening of Narrow-Angle Glaucoma Tiotropium HandiHaler should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. ## Worsening of Urinary Retention Tiotropium HandiHaler should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. ## Renal Impairment As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with Tiotropium HandiHaler should be monitored closely for anticholinergic side effects . # 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. 6-Month to 1-Year Trials The data described below reflect exposure to Tiotropium HandiHaler in 2663 patients. Tiotropium HandiHaler was studied in two 1-year placebo-controlled trials, two 1-year active-controlled trials, and two 6-month placebo-controlled trials in patients with COPD. In these trials, 1308 patients were treated with Tiotropium HandiHaler at the recommended dose of 18 mcg once a day. The population had an age ranging from 39 to 87 years with 65% to 85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. An additional 6-month trial conducted in a Veteran's Affairs setting is not included in this safety database because only serious adverse events were collected. The most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, tachycardia, blurred vision, glaucoma (new onset or worsening), dysuria, and urinary retention. Four multicenter, 1-year, placebo-controlled and active-controlled trials evaluated Tiotropium HandiHaler in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥3% in the Tiotropium HandiHaler group in the 1-year placebo-controlled trials where the rates in the Tiotropium HandiHaler group exceeded placebo by ≥1%. The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison. Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥3% in the Tiotropium HandiHaler treatment group, but were <1% in excess of the placebo group. Other reactions that occurred in the Tiotropium HandiHaler group at a frequency of 1% to 3% in the placebo-controlled trials where the rates exceeded that in the placebo group include: Body as a Whole: allergic reaction, leg pain; Central and Peripheral Nervous System: dysphonia, paresthesia; Gastrointestinal System Disorders: gastrointestinal disorder not otherwise specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis); Metabolic and Nutritional Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis; Vision Disorder: cataract. In addition, among the adverse reactions observed in the clinical trials with an incidence of <1% were atrial fibrillation, supraventricular tachycardia, angioedema, and urinary retention. In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased with age . Two multicenter, 6-month, controlled studies evaluated Tiotropium HandiHaler in patients with COPD. The adverse reactions and the incidence rates were similar to those seen in the 1-year controlled trials. 4-Year Trial The data described below reflect exposure to Tiotropium HandiHaler in 5992 COPD patients in a 4-year placebo-controlled trial. In this trial, 2986 patients were treated with Tiotropium HandiHaler at the recommended dose of 18 mcg once a day. The population had an age range from 40 to 88 years, was 75% male, 90% Caucasian, and had COPD with a mean pre-bronchodilator FEV1 percent predicted of 40%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. When the adverse reactions were analyzed with a frequency of ≥3% in the Tiotropium HandiHaler group where the rates in the Tiotropium HandiHaler group exceeded placebo by ≥1%, adverse reactions included (Tiotropium HandiHaler, placebo): pharyngitis (12.5%, 10.8%), sinusitis (6.5%, 5.3%), headache (5.7%, 4.5%), constipation (5.1%, 3.7%), dry mouth (5.1%, 2.7%), depression (4.4%, 3.3%), insomnia (4.4%, 3.0%), and arthralgia (4.2%, 3.1%). Additional Adverse Reactions Other adverse reactions not previously listed that were reported more frequently in COPD patients treated with Tiotropium HandiHaler than placebo include: dehydration, skin ulcer, stomatitis, gingivitis, oropharyngeal candidiasis, dry skin, skin infection, and joint swelling. ## Postmarketing Experience Adverse reactions have been identified during worldwide post-approval use of Tiotropium HandiHaler. 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. These adverse reactions are: application site irritation (glossitis, mouth ulceration, and pharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinal obstruction including ileus paralytic, intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachycardia, throat irritation, and urticaria. # Drug Interactions ## Sympathomimetics, Methylxanthines, Steroids Tiotropium HandiHaler has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without increases in adverse drug reactions. ## Anticholinergics There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of Tiotropium HandiHaler with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects . ## Cimetidine, Ranitidine No clinically significant interaction occurred between tiotropium and cimetidine or ranitidine # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies in pregnant women. Tiotropium HandiHaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No evidence of structural alterations was observed in rats and rabbits at inhalation tiotropium doses of up to approximately 660 and 6 times the recommended human daily inhalation dose (RHDID) on a mg/m2 basis, respectively. However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at inhalation tiotropium doses of approximately 35 times the RHDID on a mg/m2 basis. In rabbits, tiotropium caused an increase in post-implantation loss at an inhalation dose of approximately 360 times the RHDID on a mg/m2 basis. Such effects were not observed at inhalation doses of approximately 4 and 80 times the RHDID on a mg/m2 basis in rats and rabbits, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tiotropium in women who are pregnant. ### Labor and Delivery The safety and effectiveness of Tiotropium HandiHaler has not been studied during labor and delivery. ### Nursing Mothers Clinical data from nursing women exposed to tiotropium are not available. Based on lactating rodent studies, tiotropium is excreted into breast milk. It is not known whether tiotropium is excreted in human milk, but because many drugs are excreted in human milk and given these findings in rats, caution should be exercised if Tiotropium HandiHaler is administered to a nursing woman. ### Pediatric Use Tiotropium HandiHaler is approved for use in the maintenance treatment of bronchospasm associated with COPD and for the reduction of COPD exacerbations. COPD does not normally occur in children. The safety and effectiveness of Tiotropium HandiHaler in pediatric patients have not been established. ### Geriatic Use Of the total number of patients who received Tiotropium HandiHaler in the 1-year clinical trials, 426 were <65 years, 375 were 65 to 74 years, and 105 were ≥75 years of age. Within each age subgroup, there were no differences between the proportion of patients with adverse events in the Tiotropium HandiHaler and the comparator groups for most events. Dry mouth increased with age in the Tiotropium HandiHaler group (differences from placebo were 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups). A higher frequency of constipation and urinary tract infections with increasing age was observed in the Tiotropium HandiHaler group in the placebo-controlled studies. The differences from placebo for constipation were 0%, 1.8%, and 7.8% for each of the age groups. The differences from placebo for urinary tract infections were –0.6%, 4.6%, and 4.5%. No overall differences in effectiveness were observed among these groups. Based on available data, no adjustment of Tiotropium HandiHaler dosage in geriatric patients is warranted ### Gender There is no FDA guidance on the use of Tiotropium with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tiotropium with respect to specific racial populations. ### Renal Impairment Patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with Tiotropium HandiHaler should be monitored closely for anticholinergic side effects ### Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tiotropium in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tiotropium in patients who are immunocompromised. # Administration and Monitoring ### Administration - DO NOT SWALLOW Tiotropium CAPSULES - FOR USE WITH HANDIHALER DEVICE ONLY - FOR ORAL INHALATION ONLY ### Monitoring FDA Package Insert for Tiotropium contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once-daily inhalation of 141 mcg of tiotropium. Accidental Ingestion Acute intoxication by inadvertent oral ingestion of Tiotropium capsules is unlikely since it is not well-absorbed systemically. A case of overdose has been reported from postmarketing experience. A female patient was reported to have inhaled 30 capsules over a 2.5 day period, and developed altered mental status, tremors, abdominal pain, and severe constipation. The patient was hospitalized, Tiotropium HandiHaler was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day. No mortality was observed at inhalation tiotropium doses up to 32.4 mg/kg in mice, 267.7 mg/kg in rats, and 0.6 mg/kg in dogs. These doses correspond to 7300, 120,000, and 850 times the recommended human daily inhalation dose on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies. # Pharmacology ## Mechanism of Action Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect. ## Structure Tiotropium HandiHaler consists of a capsule dosage form containing a dry powder formulation of tiotropium intended for oral inhalation only with the HandiHaler device. Each light green, hard gelatin Tiotropium capsule contains 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate) blended with lactose monohydrate (which may contain milk proteins) as the carrier. The dry powder formulation within the Tiotropium capsule is intended for oral inhalation only. The active component of Tiotropium HandiHaler is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2β, 4 β, 5α, 7β)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol. The structural formula is: Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C19H22NO4S2Br • H2O. The HandiHaler device is an inhalation device used to inhale the dry powder contained in the Tiotropium capsule. The dry powder is delivered from the HandiHaler device at flow rates as low as 20 L/min. Under standardized in vitro testing, the HandiHaler device delivers a mean of 10.4 mcg tiotropium when tested at a flow rate of 39 L/min for 3.1 seconds (2 L total). In a study of 26 adult patients with COPD and severely compromised lung function [mean FEV1 1.02 L (range 0.45 to 2.24 L); 37.6% of predicted (range 16% to 65%)], the median peak inspiratory flow (PIF) through the HandiHaler device was 30.0 L/min (range 20.4 to 45.6 L/min). The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak inspiratory flow through the HandiHaler device, which may vary from patient to patient, and may vary with the exposure time of the Tiotropium capsule outside the blister pack. ## Pharmacodynamics Cardiovascular Effects In a multicenter, randomized, double-blind trial that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30 to 60 msec was higher in the Tiotropium HandiHaler group as compared with placebo. This difference was apparent using both the Bazett (QTcB) [20 (20%) patients vs 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs 1 (1%) patient] corrections of QT for heart rate. No patients in either group had either QTcB or QTcF of >500 msec. Other clinical studies with Tiotropium HandiHaler did not detect an effect of the drug on QTc intervals. The effect of Tiotropium HandiHaler on QT interval was also evaluated in a randomized, placebo- and positive-controlled crossover study in 53 healthy volunteers. Subjects received Tiotropium HandiHaler 18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG assessments were performed at baseline and throughout the dosing interval following the first and last dose of study medication. Relative to placebo, the maximum mean change from baseline in study-specific QTc interval was 3.2 msec and 0.8 msec for Tiotropium HandiHaler 18 mcg and 54 mcg, respectively. No subject showed a new onset of QTc >500 msec or QTc changes from baseline of ≥60 msec. ## Pharmacokinetics Tiotropium is administered by dry powder inhalation. In common with other inhaled drugs, the majority of the delivered dose is deposited in the gastrointestinal tract and, to a lesser extent, in the lung, the intended organ. Many of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy. Absorption Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. It is expected from the chemical structure of the compound (quaternary ammonium compound) that tiotropium is poorly absorbed from the gastrointestinal tract. The effect of food on tiotropium's bioavailability has not been studied. Oral solutions of tiotropium have an absolute bioavailability of 2% to 3%. Maximum tiotropium plasma concentrations were observed 5 minutes after inhalation. Distribution Tiotropium shows a volume of distribution of 32 L/kg indicating that the drug binds extensively to tissues. The human plasma protein binding for tiotropium is 72%. At steady state, peak tiotropium plasma levels in COPD patients were 17 to 19 pg/mL when measured 5 minutes after dry powder inhalation of an 18 mcg dose and decreased in a multi-compartmental manner. Steady-state trough plasma concentrations were 3 to 4 pg/mL. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not readily penetrate the blood-brain barrier. Metabolism The extent of metabolism appears to be small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which binds to muscarinic receptors. In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4. Elimination The terminal elimination half-life of tiotropium was between 5 and 6 days following inhalation. Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers with an inter-individual variability of 22%. Intravenously administered tiotropium was mainly excreted unchanged in urine (74%). After dry powder inhalation, urinary excretion was 14% of the dose, the remainder being mainly non-absorbed drug in the gut which was eliminated via the feces. The renal clearance of tiotropium exceeds the creatinine clearance, indicating active secretion into the urine. After chronic once-daily inhalation by COPD patients, pharmacokinetic steady state was reached after 2 to 3 weeks with no accumulation thereafter. Drug Interactions An interaction study with tiotropium (14.4 mcg intravenous infusion over 15 minutes) and cimetidine 400 mg three times daily or ranitidine 300 mg once daily was conducted. Concomitant administration of cimetidine with tiotropium resulted in a 20% increase in the AUC0-4h, a 28% decrease in the renal clearance of tiotropium and no significant change in the Cmax and amount excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of tiotropium. Specific Populations Geriatric Patients As expected for drugs predominantly excreted renally, advanced age was associated with a decrease of tiotropium renal clearance (326 mL/min in COPD patients <58 years to 163 mL/min in COPD patients >70 years), which may be explained by decreased renal function. Tiotropium excretion in urine after inhalation decreased from 14% (young healthy volunteers) to about 7% (COPD patients). Plasma concentrations were numerically increased with advancing age within COPD patients (43% increase in AUC0-4 after dry powder inhalation), which was not significant when considered in relation to inter- and intra-individual variability . Renal Impairment Since tiotropium is predominantly renally excreted, renal impairment was associated with increased plasma drug concentrations and reduced drug clearance after both intravenous infusion and dry powder inhalation. Mild renal impairment (creatinine clearance of 50 to 80 mL/min), which is often seen in elderly patients, increased tiotropium plasma concentrations (39% increase in AUC0-4 after intravenous infusion). In COPD patients with moderate to severe renal impairment (creatinine clearance of <50 mL/min), the intravenous administration of tiotropium resulted in doubling of the plasma concentrations (82% increase in AUC0-4), which was confirmed by plasma concentrations after dry powder inhalation. Patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with Tiotropium HandiHaler should be monitored closely for anticholinergic side effects . Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 0.059 mg/kg/day, in an 83-week inhalation study in female mice at doses up to 0.145 mg/kg/day, and in a 101-week inhalation study in male mice at doses up to 0.002 mg/kg/day. These doses correspond to approximately 25, 35, and 0.5 times the recommended human daily inhalation dose (RHDID) on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies. Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following assays: the bacterial gene mutation assay, the V79 Chinese hamster cell mutagenesis assay, the chromosomal aberration assays in human lymphocytes in vitro and mouse micronucleus formation in vivo, and the unscheduled DNA synthesis in primary rat hepatocytes in vitro assay. In rats, decreases in the number of corpora lutea and the percentage of implants were noted at inhalation tiotropium doses of 0.078 mg/kg/day or greater (approximately 35 times the RHDID on a mg/m2 basis). No such effects were observed at 0.009 mg/kg/day (approximately 4 times than the RHDID on a mg/m2 basis). The fertility index, however, was not affected at inhalation doses up to 1.689 mg/kg/day (approximately 760 times the RHDID on a mg/m2 basis). These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies. ## Animal Toxicology and Pharmacology Reproductive Toxicology Studies No evidence of fetal structural alteration was observed in rats and rabbits at inhalation tiotropium doses of up to 1.471 and 0.007 mg/kg/day, respectively. These doses correspond to approximately 660 and 6 times the RHDID on a mg/m2 basis, respectively. However, in rats, fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation were observed at inhalation tiotropium doses of ≥0.078 mg/kg (approximately 35 times the RHDID on a mg/m2 basis). In rabbits, an increase in post-implantation loss was observed at an inhalation dose of 0.4 mg/kg/day (approximately 360 times the RHDID on a mg/m2 basis). Such effects were not observed at inhalation doses of 0.009 and up to 0.088 mg/kg/day in rats and rabbits, respectively. These doses correspond to approximately 4 and 80 times the RHDID on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies. # Clinical Studies The Tiotropium HandiHaler (tiotropium bromide inhalation powder) clinical development program consisted of six Phase 3 studies in 2663 patients with COPD (1308 receiving Tiotropium HandiHaler): two 1-year, placebo‑controlled studies, two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlled studies. These studies enrolled patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a forced expiratory volume in one second (FEV1) less than or equal to 60% or 65% of predicted, and a ratio of FEV1/FVC of less than or equal to 0.7. In these studies, Tiotropium HandiHaler, administered once-daily in the morning, provided improvement in lung function (FEV1), with peak effect occurring within 3 hours following the first dose. Two additional trials evaluated exacerbations: a 6-month, randomized, double-blind, placebo-controlled, multicenter clinical trial of 1829 COPD patients in a US Veterans Affairs setting and a 4-year, randomized, double-blind, placebo-controlled, multicenter, clinical trial of 5992 COPD patients. Long-term effects on lung function and other outcomes were also evaluated in the 4-year multicenter trial. 6-Month to 1-Year Effects on Lung Function In the 1-year, placebo-controlled trials, the mean improvement in FEV1 at 30 minutes was 0.13 liters (13%) with a peak improvement of 0.24 liters (24%) relative to baseline after the first dose (Day 1). Further improvements in FEV1 and forced vital capacity (FVC) were observed with pharmacodynamic steady state reached by Day 8 with once-daily treatment. The mean peak improvement in FEV1, relative to baseline, was 0.28 to 0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily treatment. Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1-year treatment period with no evidence of tolerance. In the two 6-month, placebo-controlled trials, serial spirometric evaluations were performed throughout daytime hours in Trial A (12 hours) and limited to 3 hours in Trial B. The serial FEV1 values over 12 hours (Trial A) are displayed in Figure 1. These trials further support the improvement in pulmonary function (FEV1) with Tiotropium HandiHaler, which persisted over the spirometric observational period. Effectiveness was maintained for 24 hours after administration over the 6-month treatment period. Results of each of the 1-year ipratropium-controlled trials were similar to the results of the 1-year placebo-controlled trials. The results of one of these trials are shown in Figure 2. A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24-hour dosing interval in comparison to placebo, regardless of whether Tiotropium HandiHaler was administered in the morning or in the evening. Throughout each week of the one-year treatment period in the two placebo-controlled trials, patients taking Tiotropium HandiHaler had a reduced requirement for the use of rescue short-acting beta2-agonists. Reduction in the use of rescue short-acting beta2-agonists, as compared to placebo, was demonstrated in one of the two 6-month studies. 4-Year Effects on Lung Function A 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial involving 5992 COPD patients was conducted to evaluate the long-term effects of Tiotropium HandiHaler on disease progression (rate of decline in FEV1). Patients were permitted to use all respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. The patients were 40 to 88 years of age, 75% male, and 90% Caucasian with a diagnosis of COPD and a mean pre-bronchodilator FEV1 of 39% predicted (range = 9% to 76%) at study entry. There was no difference between the groups in either of the co-primary efficacy endpoints, yearly rate of decline in pre- and post-bronchodilator FEV1, as demonstrated by similar slopes of FEV1 decline over time (Figure 3). Tiotropium HandiHaler maintained improvements in trough (pre-dose) FEV1 (adjusted means over time: 87 to 103 mL) throughout the 4 years of the study (Figure 3). Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline trough FEV1 (observed mean) = 1.12. Patients with ≥3 acceptable pulmonary function tests after Day 30 and non-missing baseline value were included in the analysis. Exacerbations The effect of Tiotropium HandiHaler on COPD exacerbations was evaluated in two clinical trials: a 4-year clinical trial described above and a 6-month clinical trial of 1829 COPD patients in a Veterans Affairs setting. In the 6-month trial, COPD exacerbations were defined as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics, systemic steroids, or hospitalization. The population had an age ranging from 40 to 90 years with 99% males, 91% Caucasian, and had COPD with a mean pre-bronchodilator FEV1 percent predicted of 36% (range = 8% to 93%). Patients were permitted to use respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. In the 6-month trial, the co-primary endpoints were the proportion of patients with COPD exacerbation and the proportion of patients with hospitalization due to COPD exacerbation. Tiotropium HandiHaler significantly reduced the proportion of COPD patients who experienced exacerbations compared to placebo (27.9% vs 32.3%, respectively; Odds Ratio (OR) (tiotropium/placebo) = 0.81; 95% CI = 0.66, 0.99; p = 0.037). The proportion of patients with hospitalization due to COPD exacerbations in patients who used Tiotropium HandiHaler compared to placebo was 7.0% vs 9.5%, respectively; OR = 0.72; 95% CI = 0.51, 1.01; p = 0.056. Exacerbations were evaluated as a secondary outcome in the 4-year multicenter trial. In this trial, COPD exacerbations were defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea) with a duration of three or more days requiring treatment with antibiotics and/or systemic (oral, intramuscular, or intravenous) steroids. Tiotropium HandiHaler significantly reduced the risk of an exacerbation by 14% (Hazard Ratio (HR) = 0.86; 95% CI = 0.81, 0.91; p<0.001) and reduced the risk of exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI = 0.78, 0.95; p<0.002) compared to placebo. The median time to first exacerbation was delayed from 12.5 months (95% CI = 11.5, 13.8) in the placebo group to 16.7 months (95% CI = 14.9, 17.9) in the Tiotropium HandiHaler group. # How Supplied Tiotropium HandiHaler consists of Tiotropium capsules and the HandiHaler device. Tiotropium capsules contain 18 mcg of tiotropium and are light green, with the Boehringer Ingelheim company logo on the Tiotropium capsule cap and TI 01 on the Tiotropium capsule body, or vice versa. The HandiHaler device is gray colored with a green piercing button. It is imprinted with Tiotropium HandiHaler (tiotropium bromide inhalation powder), the Boehringer Ingelheim company logo, and the Pfizer company logo. It is also imprinted to indicate that Tiotropium capsules should not be stored in the HandiHaler device and that the HandiHaler device is only to be used with Tiotropium capsules. Tiotropium capsules are packaged in an aluminum/aluminum blister card and joined along a perforated-cut line. Tiotropium capsules should always be stored in the blister and only removed immediately before use. The drug should be used immediately after the packaging over an individual Tiotropium capsule is opened. The following packages are available: - carton containing 5 Tiotropium capsules (1 unit-dose blister card) and 1 HandiHaler inhalation device (NDC 0597-0075-75) - carton containing 30 Tiotropium capsules (3 unit-dose blister cards) and 1 HandiHaler inhalation device (NDC 0597-0075-41) - carton containing 90 Tiotropium capsules (9 unit-dose blister cards) and 1 HandiHaler inhalation device (NDC 0597-0075-47) ## Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. The Tiotropium capsules should not be exposed to extreme temperature or moisture. Do not store Tiotropium capsules in the HandiHaler device. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol Alcohol-Tiotropium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Tiotropium # Look-Alike Drug Names Tiotropium - Inspra[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Spiriva
029adad0fb081a849729a93312931aa0e82d8024	wikidoc	Sporophyte	Sporophyte All land plants, and some algae, have life cycles in which a haploid gametophyte generation alternates with a diploid sporophyte, the generation of a plant or alga that has a double set of chromosomes. A multicellular sporophyte generation or phase is present in the life cycle of all land plants and in some green algae. For common flowering plants (Angiosperms), the sporophyte generation comprises almost their whole life cycle (i.e. whole green plant, roots etc), except phases of small reproductive structures (pollen and ovule). # Overview The sporophyte produces spores (hence the name), by meiosis. These meiospores develop into a gametophyte. Both the spores and the resulting gametophyte are haploid, meaning they only have one set of homologous chromosomes. The mature gametophyte produces male or female gametes (or both) by mitosis. The fusion of male and female gametes produces a diploid zygote which develops into a new sporophyte. This cycle is known as alternation of generations or alternation of phases. In the normal course of events, the zygote and sporophyte will have a full double set of chromosomes again. An exception is when a diploid and haploid gamete fuse, resulting in a triploid sporophyte, which will usually be sterile, as dividing three sets of chromosomes into two halves causes complications. Bryophytes (mosses, liverworts and hornworts) have a dominant gametophyte stage on which the adult sporophyte is dependent on the gametophyte for nutrition. The embryo of the sporophyte develops from the zygote within the female sex organ or archegonium, and in its early development is therefore nurtured by the gametophyte. Because this embryo-nurturing feature of the life cycle is common to all land plants they are known collectively as the Embryophytes. Most algae have dominant gametophyte generations, but in some species the gametophytes and sporophytes are morphologically similar (isomorphic). An independent sporophyte is the dominant form in all clubmosses, horsetails, ferns, gymnosperms, and angiosperms (flowering plants) that have survived to the present day. Early land plants had sporophytes that produced identical spores (isosporous or homosporous) but the ancestors of the gymnosperms evolved complex heterosporous life cycles in which the spores producing male and female gametophytes were of different sizes, the female megaspores tending to be larger, and fewer in number, than the male microspores. During the Devonian period several plant groups independently evolved heterospory and subsequently the habit of endospory, in which single megaspores were retained within the sporangia of the parent sporophyte, instead of being freely liberated into the environment as in ancestral exosporous plants. These endosporic megaspores contained within them a miniature multicellular female gametophyte complete with female sex organs or archegonia containing oocytes which were fertilised by free-swimming sperm produced by windborne miniatuarised male gametophytes in the form of pre-pollen. The resulting zygote developed into the next sporophyte generation while still retained within the pre-ovule, the single large female meiospore or megaspore contained in the modified sporangium or nucellus of the parent sporophyte. The evolution of heterospory and endospory were among the earliest steps in the evolution of seeds of the kind produced by gymnosperms and angiosperms today.	Sporophyte All land plants, and some algae, have life cycles in which a haploid gametophyte generation alternates with a diploid sporophyte, the generation of a plant or alga that has a double set of chromosomes. A multicellular sporophyte generation or phase is present in the life cycle of all land plants and in some green algae. For common flowering plants (Angiosperms), the sporophyte generation comprises almost their whole life cycle (i.e. whole green plant, roots etc), except phases of small reproductive structures (pollen and ovule). # Overview The sporophyte produces spores (hence the name), by meiosis. These meiospores develop into a gametophyte. Both the spores and the resulting gametophyte are haploid, meaning they only have one set of homologous chromosomes. The mature gametophyte produces male or female gametes (or both) by mitosis. The fusion of male and female gametes produces a diploid zygote which develops into a new sporophyte. This cycle is known as alternation of generations or alternation of phases. In the normal course of events, the zygote and sporophyte will have a full double set of chromosomes again. An exception is when a diploid and haploid gamete fuse, resulting in a triploid sporophyte, which will usually be sterile, as dividing three sets of chromosomes into two halves causes complications. Bryophytes (mosses, liverworts and hornworts) have a dominant gametophyte stage on which the adult sporophyte is dependent on the gametophyte for nutrition. The embryo of the sporophyte develops from the zygote within the female sex organ or archegonium, and in its early development is therefore nurtured by the gametophyte. Because this embryo-nurturing feature of the life cycle is common to all land plants they are known collectively as the Embryophytes. Most algae have dominant gametophyte generations, but in some species the gametophytes and sporophytes are morphologically similar (isomorphic). An independent sporophyte is the dominant form in all clubmosses, horsetails, ferns, gymnosperms, and angiosperms (flowering plants) that have survived to the present day. Early land plants had sporophytes that produced identical spores (isosporous or homosporous) but the ancestors of the gymnosperms evolved complex heterosporous life cycles in which the spores producing male and female gametophytes were of different sizes, the female megaspores tending to be larger, and fewer in number, than the male microspores. During the Devonian period several plant groups independently evolved heterospory and subsequently the habit of endospory, in which single megaspores were retained within the sporangia of the parent sporophyte, instead of being freely liberated into the environment as in ancestral exosporous plants. These endosporic megaspores contained within them a miniature multicellular female gametophyte complete with female sex organs or archegonia containing oocytes which were fertilised by free-swimming sperm produced by windborne miniatuarised male gametophytes in the form of pre-pollen. The resulting zygote developed into the next sporophyte generation while still retained within the pre-ovule, the single large female meiospore or megaspore contained in the modified sporangium or nucellus of the parent sporophyte. The evolution of heterospory and endospory were among the earliest steps in the evolution of seeds of the kind produced by gymnosperms and angiosperms today.	https://www.wikidoc.org/index.php/Sporophyte
028886637920d164ad0d69f70230b353b8362984	wikidoc	Spumavirus	Spumavirus A spumavirus or foamyvirus is a genus of the retroviridae family. Spumaviruses are exogenous viruses that have specific morphology with prominent surface spikes. The virions contain significant amounts of double-stranded full-length DNA, and assembly is rather unusual in these viruses. Normally, the envelope membrane is acquired by budding through the endoplasmic reticulum. However, in, for example, the equine foamy virus (EFV), budding from the cytoplasmic membrane occurs. Some examples of this virus are the chimpanzee foamy virus, simian foamy virus and the human foamy virus. While spumaviruses will form characteristic large vacuoles in their host cells while in vitro, there is no disease association in vivo.	Spumavirus A spumavirus or foamyvirus is a genus of the retroviridae family. Spumaviruses are exogenous viruses that have specific morphology with prominent surface spikes. The virions contain significant amounts of double-stranded full-length DNA, and assembly is rather unusual in these viruses. Normally, the envelope membrane is acquired by budding through the endoplasmic reticulum. However, in, for example, the equine foamy virus (EFV), budding from the cytoplasmic membrane occurs. Some examples of this virus are the chimpanzee foamy virus, simian foamy virus and the human foamy virus. While spumaviruses will form characteristic large vacuoles in their host cells while in vitro, there is no disease association in vivo.[1] # External links - NCBI: Spumavirus - Spumavirus at the US National Library of Medicine Medical Subject Headings (MeSH)	https://www.wikidoc.org/index.php/Spumavirus
136fe3b88fe432121d39aa91297052e7e9f2af33	wikidoc	Src (gene)	Src (gene) # Overview Src is a family of proto-oncogenic tyrosine kinases originally discovered by J. Michael Bishop and Harold E. Varmus. The discovery of Src family proteins has been instrumental to the modern understanding of cancer as a disease where normally healthy cellular signalling has gone awry. This gene is highly similar to the v-src gene of Rous sarcoma virus. This proto-oncogene may play a role in the regulation of embryonic development and cell growth. The protein encoded by this gene is a tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase. Mutations in this gene could be involved in the malignant progression of colon cancer. Two transcript variants encoding the same protein have been found for this gene. # v-src Francis Peyton Rous was credited with being the first to come up with the idea that viruses could cause cancer. In 1911 he performed an experiment where he removed a type of tumor called a fibrosarcoma from chickens, ground them up, and used centrifugation to remove cells and debris. He injected the remaining liquid into healthy chicks and found that the chicks developed sarcomas. The causative agent in the liquid was later found to be a virus that was called the Rous sarcoma virus (RSV). Later work by others showed that RSV was a type of retrovirus. Non-cancer-forming retroviruses contain 3 genes, called gag, pol, and env. Some tumor-inducing retroviruses (such as RSV), however, contain a gene called v-src (viral-sarcoma). It was found that the v-src gene in RSV is required for the formation of cancer and that the other genes have no role in oncogenesis. Src tyrosine kinases transmit integrin-dependent signals central to cell movement and proliferation. Hallmarks of v-src induced transformation are rounding of the cell and the formation of actin rich podosomes on the basal surface of the cell. These structures are correlated with increased invasiveness, a process thought to be essential for metastasis. v-src lacks the C-terminal inhibitory phosphorylation site (tyrosine-527), and is therefore constitutively active as opposed to normal src (c-src) which is only activated under certain circumstances where it is required (e.g. growth factor signaling). v-src is therefore an instructive example of an oncogene whereas c-src is a proto-oncogene. # c-src In 1979, J. Michael Bishop and Harold E. Varmus discovered that normal chickens contain a gene that is structurally closely-related to v-src. The normal cellular gene was called c-src (cellular-src). This discovery changed the current thinking about cancer from a model wherein cancer is caused by a foreign substance (a viral gene) to one where a gene that is normally present in the cell can cause cancer. It is believed that at one point an ancestral virus mistakenly incorporated the c-src gene of its cellular host. At some point, the normal gene became mutated into an abnormally-functioning oncogene, as is now observed in RSV. Once the oncogene is transfected back into a normal host, it can lead to cancer. src: The transforming (sarcoma inducing) gene of Rous sarcoma virus. The protein product is pp60vsrc, a cytoplasmic protein with tyrosine-specific protein kinase activity (EC 2.7.10.2), that associates with the cytoplasmic face of the plasma membrane. The protein consists of 3 domains, an N-terminal SH3 domain, a central SH2 domain and a Tyrosine kinase domain. The SH2 and SH3 domains cooperate in the auto-inhibition of the kinase domain. c-Src is phosphorylated on an inhibitory tyrosine near the c-terminus of the protein. This produces a binding site for the SH2 domain which, when bound, facilitates binding of the SH3 domain to a low affinity polyproline site within the linker between the SH2 domain and the Kinase domain. Binding of the SH3 domain results in misalignment of residues within the kinase domain's active site inactivating the enzyme. This allows for multiple mechanism for c-Src activation: dephosphorylation of the C-terminal tyrosine by a protein tyrosine phosphatase, binding of the SH2 domain by a competitive phospho-tyrosine residue, as seen in the case of c-Src binding to Focal Adhesion Kinase, or competitive binding of a polyproline binding site to the SH3 domain, as seen in the case of the HIV NEF protein. # Src Family Kinases The Src family includes nine members: Src, Lck, Hck, Fyn, Blk, Lyn, Fgr, Yes, and Yrk.	Src (gene) # Overview Src is a family of proto-oncogenic tyrosine kinases originally discovered by J. Michael Bishop and Harold E. Varmus. The discovery of Src family proteins has been instrumental to the modern understanding of cancer as a disease where normally healthy cellular signalling has gone awry. This gene is highly similar to the v-src gene of Rous sarcoma virus. This proto-oncogene may play a role in the regulation of embryonic development and cell growth. The protein encoded by this gene is a tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase. Mutations in this gene could be involved in the malignant progression of colon cancer. Two transcript variants encoding the same protein have been found for this gene.[1] # v-src Francis Peyton Rous was credited with being the first to come up with the idea that viruses could cause cancer. In 1911 he performed an experiment where he removed a type of tumor called a fibrosarcoma from chickens, ground them up, and used centrifugation to remove cells and debris. He injected the remaining liquid into healthy chicks and found that the chicks developed sarcomas. The causative agent in the liquid was later found to be a virus that was called the Rous sarcoma virus (RSV). Later work by others showed that RSV was a type of retrovirus. Non-cancer-forming retroviruses contain 3 genes, called gag, pol, and env. Some tumor-inducing retroviruses (such as RSV), however, contain a gene called v-src (viral-sarcoma). It was found that the v-src gene in RSV is required for the formation of cancer and that the other genes have no role in oncogenesis.[2] Src tyrosine kinases transmit integrin-dependent signals central to cell movement and proliferation. Hallmarks of v-src induced transformation are rounding of the cell and the formation of actin rich podosomes on the basal surface of the cell. These structures are correlated with increased invasiveness, a process thought to be essential for metastasis. v-src lacks the C-terminal inhibitory phosphorylation site (tyrosine-527), and is therefore constitutively active as opposed to normal src (c-src) which is only activated under certain circumstances where it is required (e.g. growth factor signaling). v-src is therefore an instructive example of an oncogene whereas c-src is a proto-oncogene. # c-src In 1979, J. Michael Bishop and Harold E. Varmus discovered that normal chickens contain a gene that is structurally closely-related to v-src.[2] The normal cellular gene was called c-src (cellular-src).[3] This discovery changed the current thinking about cancer from a model wherein cancer is caused by a foreign substance (a viral gene) to one where a gene that is normally present in the cell can cause cancer. It is believed that at one point an ancestral virus mistakenly incorporated the c-src gene of its cellular host. At some point, the normal gene became mutated into an abnormally-functioning oncogene, as is now observed in RSV. Once the oncogene is transfected back into a normal host, it can lead to cancer. src: The transforming (sarcoma inducing) gene of Rous sarcoma virus. The protein product is pp60vsrc, a cytoplasmic protein with tyrosine-specific protein kinase activity (EC 2.7.10.2), that associates with the cytoplasmic face of the plasma membrane. The protein consists of 3 domains, an N-terminal SH3 domain, a central SH2 domain and a Tyrosine kinase domain. The SH2 and SH3 domains cooperate in the auto-inhibition of the kinase domain. c-Src is phosphorylated on an inhibitory tyrosine near the c-terminus of the protein. This produces a binding site for the SH2 domain which, when bound, facilitates binding of the SH3 domain to a low affinity polyproline site within the linker between the SH2 domain and the Kinase domain. Binding of the SH3 domain results in misalignment of residues within the kinase domain's active site inactivating the enzyme. This allows for multiple mechanism for c-Src activation: dephosphorylation of the C-terminal tyrosine by a protein tyrosine phosphatase, binding of the SH2 domain by a competitive phospho-tyrosine residue, as seen in the case of c-Src binding to Focal Adhesion Kinase, or competitive binding of a polyproline binding site to the SH3 domain, as seen in the case of the HIV NEF protein. # Src Family Kinases The Src family includes nine members: Src, Lck, Hck, Fyn, Blk, Lyn, Fgr, Yes, and Yrk.	https://www.wikidoc.org/index.php/Src-family_kinase
5f23cefaf5e351e1dca831896449930417cbb7fe	wikidoc	Staged PCI	Staged PCI Synonyms and keywords: delayed PCI # Overview Staged PCI or delayed PCI is referred to the performance of a percutaneous coronary intervention (PCI) at a later date separate from the performance of the diagnostic catheterization or the performance of an initial PCI. Ad hoc PCI is defined as performance of the PCI procedure immediately following diagnostic catheterization . Same day PCI is defined as removing the patient from the cardiac catheterization laboratory following the procedure, and then performing the PCI procedure later in the day. Databases usually do not allow a distinction between "Ad hoc PCI" and "Same day PCI". As a result there is no data regarding the prevalence or the impact of same day PCI. # Historical Perspective When PCI was first developed, the risk of requiring urgent coronary artery bypass grafting (CABG) surgery was approximately 5%, and this necessitated the availability of onsite CABG. AS PCI became safer and more predictable, it was more frequently performed immediately following the diagnostic cardiac catheterization ("ad hoc PCI"). # Advantages of Staged PCI More detailed informed consent can be provided regarding the proposed revascularization procedure and the potential alternatives such as CABG. Patients who are at risk of contrast induced acute tubular necrosis (patients over age 65, patients with diabetes, patients with impaired renal function), may benefit from a staged PCI procedure by minimizing the dye load required during two separate procedures. ## Risk Factors for Contrast Induced Nephropathy Three factors have been associated with an increased risk of contrast-induced nephropathy: pre-existing renal insufficiency (such as Creatinine clearance < 60 mL/min - online calculator), pre-existing diabetes, and reduced intravascular volume. A clinical prediction rule is available to estimate probability of nephropathy (increase ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 h) based upon the following risk factors: - Systolic blood pressure <80 mm Hg - 5 points - Intraarterial balloon pump - 5 points - Congestive heart failure (Class III-IV or history of pulmonary edema) - 5 points - Age >75 y - 4 points - Hematocrit level <39% for men and <35% for women - 3 points - Diabetes - 3 points - Contrast media volume - 1 point for each 100 mL - Renal insufficiency: Serum creatinine level >1.5 g/dL - 4 points OR Estimated Glomerular filtration rate (online calculator) - Serum creatinine level >1.5 g/dL - 4 points OR - Estimated Glomerular filtration rate (online calculator) - 2 for 40–60 mL/min/1.73 m2 - 4 for 20–40 mL/min/1.73 m2 - 6 for < 20 mL/min/1.73 m2 ### Scoring: 5 or less points - Risk of CIN - 7.5 - Risk of Dialysis - 0.04% 6–10 points - Risk of CIN - 14.0 - Risk of Dialysis - 0.12% 11–16 points - Risk of CIN - 26.1* - Risk of Dialysis - 1.09% 16 points - Risk of CIN - 57.3 - Risk of Dialysis - 12.8% # Disadvantages of Staged PCI The disadvantages of staged PCI include the following: - The patient must be instrumented twice with the attendant risk of bleeding and trauma to the vessel. - The patient must return to the hospital for the procedure on a separate occasion which is inconvenient. - A payor must pay for a separate procedure. # Efficacy and Safety of Staged PCI There are no randomized trials of staged versus ad hoc PCI and only registry data is available for comparison. it should be noted that registry data does not adjust for unidentified confounders. There are seven registry is that compare ad hoc and staged PCI and there are no differences in the angiographic success rates either in the era of conventional balloon angioplasty or in the era of stenting In one registry experience, the rates of vascular complications were lower in the patients undergoing ad hoc PCI # Prevalence of Ad Hoc PCI Ad hoc PCI is currently performed in approximately 60% to 96% of patients and the proportion of patients continues to increase. # Guidelines Regarding Staged PCI Performance of PCI in a non-culprit artery at the time of a ST elevation MI (STEMI) is a class III contraindication. Only 2% of interventional cardiologist would perform a PCI in a non-culprit vessel in the setting of STEMI in a patient who is hemodynamically stable . The need for and the timing of staged PCI among patients with unstable angina (UA) or non ST elevation MI (NSTEMI) and stable angina is less clear. # Timing of a Staged PCI ## STEMI 1. In the setting of STEMI, ad hoc PCI of the culprit artery is recommended if the patient presents within 12 hours of symptoms. 2. 62% of interventional cardiologists recommend that the PCI of the non-culprit artery be performed more than 15 days after the STEMI . 3. Among STEMI patients with cardiogenic shock ad hoc PCI is appropriate. If the culprit lesion cannot be identified with certainty in the setting, then PCI of more than one lesion may be appropriate. Although PCI of a non-culprit lesion is inappropriate in the absence of cardiogenic shock and may be associated with worse outcomes, PCI of a non-culprit vessel may be appropriate if there is a flow limiting lesion and cardiogenic shock persists following PCI the culprit vessel. ## UA / NSTEMI There is less of a consensus regarding the optimal timing of a staged PCI among UA / NSTEMI patients. 55% of surveyed cardiologists recommend waiting > 2 weeks following the initial revascularization to perform the next PCI, while 22% recommended that the additional PCI be performed during the same hospitalization as the initial revascularization. ## Stable Angina Among patients with stable angina, 64% of surveyed cardiologist recommend waiting ≥ 15 days to perform the second PCI following the initial revascularization while 35% recommend performance of PCI within 2 weeks of the initial revascularization. # Clinical Scenarios Favoring Delayed Percutaneous Coronary Intervention In a SCAI consensus statement, the following scenarios may favor the performance of staged PCI: The Appropriate Use Criteria indicate that a PCI should not be performed if a patient does not have severe symptoms, if they have not undergone prior functional testing to confirm ischemia, or if they are not on optimal medical therapy. Furthermore the Appropriate Use Criteria indicate that either intravascular ultrasound (IVUS) or fractional flow reserve (FFR) can be used as substitutes for noninvasive testing if it was not performed prior to angiography to evaluate the functional significance of the target lesion. Although the appropriate use pretreated does not discuss the timing of procedures, it stands to reason that if the appropriateness of a procedures is uncertain then the procedure should be delayed until the indications are clarified. # Clinical Scenarios Favoring Ad Hoc PCI 1. The presence of an Acute Coronary Syndrome(ACS). 2.The Aprpriate Use Criteria do not explicitly discuss the timing of PCI. Patients with ongoing ischemia, and those with stable moderate/severe angina who are managed with optimal medical therapy (OMT) are deemed suitable candidates for PCI.	Staged PCI Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Synonyms and keywords: delayed PCI # Overview Staged PCI or delayed PCI is referred to the performance of a percutaneous coronary intervention (PCI) at a later date separate from the performance of the diagnostic catheterization or the performance of an initial PCI. Ad hoc PCI is defined as performance of the PCI procedure immediately following diagnostic catheterization [1]. Same day PCI is defined as removing the patient from the cardiac catheterization laboratory following the procedure, and then performing the PCI procedure later in the day. Databases usually do not allow a distinction between "Ad hoc PCI" and "Same day PCI". As a result there is no data regarding the prevalence or the impact of same day PCI. # Historical Perspective When PCI was first developed, the risk of requiring urgent coronary artery bypass grafting (CABG) surgery was approximately 5%, and this necessitated the availability of onsite CABG. AS PCI became safer and more predictable, it was more frequently performed immediately following the diagnostic cardiac catheterization ("ad hoc PCI"). # Advantages of Staged PCI More detailed informed consent can be provided regarding the proposed revascularization procedure and the potential alternatives such as CABG. Patients who are at risk of contrast induced acute tubular necrosis (patients over age 65, patients with diabetes, patients with impaired renal function), may benefit from a staged PCI procedure by minimizing the dye load required during two separate procedures. ## Risk Factors for Contrast Induced Nephropathy Three factors have been associated with an increased risk of contrast-induced nephropathy: pre-existing renal insufficiency (such as Creatinine clearance < 60 mL/min [1.00 mL/s] - online calculator), pre-existing diabetes, and reduced intravascular volume.[2][3] A clinical prediction rule is available to estimate probability of nephropathy (increase ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 h)[4] based upon the following risk factors: - Systolic blood pressure <80 mm Hg - 5 points - Intraarterial balloon pump - 5 points - Congestive heart failure (Class III-IV or history of pulmonary edema) - 5 points - Age >75 y - 4 points - Hematocrit level <39% for men and <35% for women - 3 points - Diabetes - 3 points - Contrast media volume - 1 point for each 100 mL - Renal insufficiency: Serum creatinine level >1.5 g/dL - 4 points OR Estimated Glomerular filtration rate (online calculator) - Serum creatinine level >1.5 g/dL - 4 points OR - Estimated Glomerular filtration rate (online calculator) - 2 for 40–60 mL/min/1.73 m2 - 4 for 20–40 mL/min/1.73 m2 - 6 for < 20 mL/min/1.73 m2 ### Scoring: 5 or less points - Risk of CIN - 7.5 - Risk of Dialysis - 0.04% 6–10 points - Risk of CIN - 14.0 - Risk of Dialysis - 0.12% 11–16 points - Risk of CIN - 26.1* - Risk of Dialysis - 1.09% >16 points - Risk of CIN - 57.3 - Risk of Dialysis - 12.8% # Disadvantages of Staged PCI The disadvantages of staged PCI include the following: - The patient must be instrumented twice with the attendant risk of bleeding and trauma to the vessel. - The patient must return to the hospital for the procedure on a separate occasion which is inconvenient. - A payor must pay for a separate procedure. # Efficacy and Safety of Staged PCI There are no randomized trials of staged versus ad hoc PCI and only registry data is available for comparison. it should be noted that registry data does not adjust for unidentified confounders. There are seven registry is that compare ad hoc and staged PCI and there are no differences in the angiographic success rates either in the era of conventional balloon angioplasty [5][6][7][8][9][10][11] or in the era of stenting [12][13][14][15][16][17] In one registry experience, the rates of vascular complications were lower in the patients undergoing ad hoc PCI [18] # Prevalence of Ad Hoc PCI Ad hoc PCI is currently performed in approximately 60% to 96% of patients and the proportion of patients continues to increase.[19][20][21][22][23][24][25] # Guidelines Regarding Staged PCI Performance of PCI in a non-culprit artery at the time of a ST elevation MI (STEMI) is a class III contraindication. Only 2% of interventional cardiologist would perform a PCI in a non-culprit vessel in the setting of STEMI in a patient who is hemodynamically stable [26]. The need for and the timing of staged PCI among patients with unstable angina (UA) or non ST elevation MI (NSTEMI) and stable angina is less clear. # Timing of a Staged PCI ## STEMI 1. In the setting of STEMI, ad hoc PCI of the culprit artery is recommended if the patient presents within 12 hours of symptoms.[27] 2. 62% of interventional cardiologists recommend that the PCI of the non-culprit artery be performed more than 15 days after the STEMI [28]. 3. Among STEMI patients with cardiogenic shock ad hoc PCI is appropriate.[29] If the culprit lesion cannot be identified with certainty in the setting, then PCI of more than one lesion may be appropriate. Although PCI of a non-culprit lesion is inappropriate in the absence of cardiogenic shock and may be associated with worse outcomes,[30] PCI of a non-culprit vessel may be appropriate if there is a flow limiting lesion and cardiogenic shock persists following PCI the culprit vessel. ## UA / NSTEMI There is less of a consensus regarding the optimal timing of a staged PCI among UA / NSTEMI patients. 55% of surveyed cardiologists recommend waiting > 2 weeks following the initial revascularization to perform the next PCI, while 22% recommended that the additional PCI be performed during the same hospitalization as the initial revascularization. ## Stable Angina Among patients with stable angina, 64% of surveyed cardiologist recommend waiting ≥ 15 days to perform the second PCI following the initial revascularization while 35% recommend performance of PCI within 2 weeks of the initial revascularization. # Clinical Scenarios Favoring Delayed Percutaneous Coronary Intervention In a SCAI consensus statement, the following scenarios may favor the performance of staged PCI[31]: The Appropriate Use Criteria [32] indicate that a PCI should not be performed if a patient does not have severe symptoms, if they have not undergone prior functional testing to confirm ischemia, or if they are not on optimal medical therapy. Furthermore the Appropriate Use Criteria indicate that either intravascular ultrasound (IVUS) or fractional flow reserve (FFR) can be used as substitutes for noninvasive testing if it was not performed prior to angiography to evaluate the functional significance of the target lesion. Although the appropriate use pretreated does not discuss the timing of procedures, it stands to reason that if the appropriateness of a procedures is uncertain then the procedure should be delayed until the indications are clarified. [33] # Clinical Scenarios Favoring Ad Hoc PCI 1. The presence of an Acute Coronary Syndrome(ACS). [34] 2.The Aprpriate Use Criteria do not explicitly discuss the timing of PCI. Patients with ongoing ischemia, and those with stable moderate/severe angina who are managed with optimal medical therapy (OMT) are deemed suitable candidates for PCI.[35]	https://www.wikidoc.org/index.php/Staged_PCI
fed21934be476e13a31d12ddcea32f8e416c2f31	wikidoc	Stanford V	Stanford V # Overview Stanford V is a chemotherapy regimen designed for Hodgkin's lymphoma that consists of the following: - Mechlorethamine - Doxorubicin - Vinblastine - Vincristine - Bleomycin - Etoposide - Prednisone It is a newer method than MOPP or ABVD, the two previous most common treatments for Hodgkin's lymphoma. The chemotherapy part of Stanford V treatment can last anywhere from 8 to 12 weeks, depending on the staging of the disease. In many cases, this is followed by radiation therapy for anywhere from 2 to 6 weeks to the affected areas of the body. It is believed that Stanford V is at least as effective as other methods of treatment. Stanford V is a more rigorously administered form of chemotherapy, with treatments roughly twice as fast as those of other Hodgkin's lymphoma treatments; however, this is tempered by the need for radiation therapy in most cases which is not typically required under ABVD.	Stanford V # Overview Stanford V is a chemotherapy regimen designed for Hodgkin's lymphoma that consists of the following: - Mechlorethamine - Doxorubicin - Vinblastine - Vincristine - Bleomycin - Etoposide - Prednisone It is a newer method than MOPP or ABVD, the two previous most common treatments for Hodgkin's lymphoma. The chemotherapy part of Stanford V treatment can last anywhere from 8 to 12 weeks, depending on the staging of the disease. In many cases, this is followed by radiation therapy for anywhere from 2 to 6 weeks to the affected areas of the body. It is believed that Stanford V is at least as effective as other methods of treatment. Stanford V is a more rigorously administered form of chemotherapy, with treatments roughly twice as fast as those of other Hodgkin's lymphoma treatments; however, this is tempered by the need for radiation therapy in most cases which is not typically required under ABVD. # External links - Lymphoma Information Network - PMID 11821442 - Includes table for schedule Template:Chemotherapeutic Agents Template:WH Template:WS	https://www.wikidoc.org/index.php/Stanford_V
da6c37062ba87f0f3d588f676e9cf7772e9ee0c9	wikidoc	Stanozolol	Stanozolol # Overview Stanozolol, commonly sold under the name Winstrol (oral) and Winstrol Depot (intra-muscular), was developed by Winthrop Laboratories in 1962. It is a synthetic anabolic steroid derived from testosterone, and has been approved by the FDA for human use. Unlike most injectable anabolic steroids, Stanozolol is not esterified and is sold as an aqueous suspension, or in oral tablet form. The drug has a large oral bioavailability, due to a C17 α-alkylation which allows the hormone to survive first pass liver metabolism when ingested. It is because of this that Stanozolol is also sold in tablet form. Stanozolol is usually considered a safer choice for female bodybuilders in that it rewards a great amount of anabolism for a small androgenic effect, however virilization and masculinization are still very common, even at low doses. Stanozolol has been used on both animal and human patients for a number of conditions. In humans, it has been demonstrated to be successful in treating anaemia and hereditary angioedema. Veterinarians may prescribe the drug to improve muscle growth, red blood cell production, increase bone density and stimulate the appetite of debilitated or weakened animals. Stanozolol is one of the Anabolic steroids commonly used as an ergogenic aid and is banned from use in sports competition under the auspices of the International Association of Athletics Federations (IAAF).	Stanozolol # Overview Stanozolol, commonly sold under the name Winstrol (oral) and Winstrol Depot (intra-muscular), was developed by Winthrop Laboratories in 1962. It is a synthetic anabolic steroid derived from testosterone, and has been approved by the FDA for human use. Unlike most injectable anabolic steroids, Stanozolol is not esterified and is sold as an aqueous suspension, or in oral tablet form. The drug has a large oral bioavailability, due to a C17 α-alkylation which allows the hormone to survive first pass liver metabolism when ingested. It is because of this that Stanozolol is also sold in tablet form. Stanozolol is usually considered a safer choice for female bodybuilders in that it rewards a great amount of anabolism for a small androgenic effect, however virilization and masculinization are still very common, even at low doses. Stanozolol has been used on both animal and human patients for a number of conditions. In humans, it has been demonstrated to be successful in treating anaemia and hereditary angioedema. Veterinarians may prescribe the drug to improve muscle growth, red blood cell production, increase bone density and stimulate the appetite of debilitated or weakened animals. Stanozolol is one of the Anabolic steroids commonly used as an ergogenic aid and is banned from use in sports competition under the auspices of the International Association of Athletics Federations (IAAF).	https://www.wikidoc.org/index.php/Stanozolol
40644b33977bc17f3facc54c6e92e50a8b16a6f3	wikidoc	Star anise	Star anise Star anise, star aniseed or Chinese star anise, (Chinese: 八角, pinyin: bājiǎo, lit. "eight-horn") is a spice that closely resembles anise in flavor, obtained from the star-shaped pericarp of Illicium verum, a small native evergreen tree of southwest China. The star shaped fruits are harvested just before ripening. It is widely used in Chinese cuisine, in Indian cuisine where it is a major component of garam masala, and in Indonesian cuisine. It is widely grown for commercial use in China, India, and most other countries in Asia. Star anise is an ingredient of the traditional five-spice powder of Chinese cooking. It is also one of the ingredients used to make the broth for the Vietnamese noodle soup called phở. It is used as a spice in preparation of Biryani in Andhra Pradesh, a south Indian State. Star anise contains anethole, the same ingredient which gives the unrelated anise its flavor. Recently, star anise has come into use in the West as a less expensive substitute for anise in baking as well as in liquor production, most distinctively in the production of the liquor Galliano. It is also used in the production of Sambuca and pastis. Star anise has been used in a tea as a remedy for colic and rheumatism, and the seeds are sometimes chewed after meals to aid digestion. Shikimic acid, a primary feedstock used to create the anti-flu drug Tamiflu, is produced by most autotrophic organisms, but star anise is the industrial source. Tamiflu is regarded as the most promising drug to mitigate the severity of bird flu (H5N1); however, reports indicate that some forms of the virus have already adapted to Tamiflu. In 2005, there was a temporary shortage of star anise due to its use in making Tamiflu. Late in that year, a way was found of making shikimic acid artificially. A drug company named Roche now derives some of the raw material it needs from fermenting e-coli bacteria. There is no longer any shortage of star anise and it is readily available and is relatively cheap. Star anise is grown in four provinces in China and harvested between March and May. The shikimic acid is extracted from the seeds in a ten-stage manufacturing process which takes a year. Reports say 90% of the harvest is already used by the Swiss pharmaceutical manufacturer Roche in making Tamiflu, but other reports say there is an abundance of the spice in the main regions - Fujian, Guangdong, Guangxi and Yunnan. Japanese star anise (Illicium anisatum), a similar tree, is not edible because it is highly toxic; instead, it has been burned as incense in Japan. Cases of illness, including "serious neurological effects, such as seizures", reported after using star anise tea may be a result of using this species. Japanese star anise contains anisatin, which causes severe inflammation of the kidneys, urinary tract and digestive organs.	Star anise Star anise, star aniseed or Chinese star anise, (Chinese: 八角, pinyin: bājiǎo, lit. "eight-horn") is a spice that closely resembles anise in flavor, obtained from the star-shaped pericarp of Illicium verum, a small native evergreen tree of southwest China. The star shaped fruits are harvested just before ripening. It is widely used in Chinese cuisine, in Indian cuisine where it is a major component of garam masala, and in Indonesian cuisine. It is widely grown for commercial use in China, India, and most other countries in Asia. Star anise is an ingredient of the traditional five-spice powder of Chinese cooking. It is also one of the ingredients used to make the broth for the Vietnamese noodle soup called phở. It is used as a spice in preparation of Biryani in Andhra Pradesh, a south Indian State. Star anise contains anethole, the same ingredient which gives the unrelated anise its flavor. Recently, star anise has come into use in the West as a less expensive substitute for anise in baking as well as in liquor production, most distinctively in the production of the liquor Galliano. It is also used in the production of Sambuca and pastis. Star anise has been used in a tea as a remedy for colic and rheumatism, and the seeds are sometimes chewed after meals to aid digestion. Shikimic acid, a primary feedstock used to create the anti-flu drug Tamiflu, is produced by most autotrophic organisms, but star anise is the industrial source. Tamiflu is regarded as the most promising drug to mitigate the severity of bird flu (H5N1); however, reports indicate that some forms of the virus have already adapted to Tamiflu. In 2005, there was a temporary shortage of star anise due to its use in making Tamiflu. Late in that year, a way was found of making shikimic acid artificially. A drug company named Roche now derives some of the raw material it needs from fermenting e-coli bacteria. There is no longer any shortage of star anise and it is readily available and is relatively cheap. Star anise is grown in four provinces in China and harvested between March and May. The shikimic acid is extracted from the seeds in a ten-stage manufacturing process which takes a year. Reports say 90% of the harvest is already used by the Swiss pharmaceutical manufacturer Roche in making Tamiflu, but other reports say there is an abundance of the spice in the main regions - Fujian, Guangdong, Guangxi and Yunnan. Japanese star anise (Illicium anisatum), a similar tree, is not edible because it is highly toxic; instead, it has been burned as incense in Japan. Cases of illness, including "serious neurological effects, such as seizures", reported after using star anise tea may be a result of using this species. Japanese star anise contains anisatin, which causes severe inflammation of the kidneys, urinary tract and digestive organs.	https://www.wikidoc.org/index.php/Star_anise
2f0cc8bf23718115ef764b0496be9cc5fa3644bb	wikidoc	Statistics	Statistics Statistics is a mathematical science pertaining to the collection, analysis, interpretation or explanation, and presentation of data. It is applicable to a wide variety of academic disciplines, from the physical and social sciences to the humanities. Statistics are also used for making informed decisions. Statistical methods can be used to summarize or describe a collection of data; this is called descriptive statistics. In addition, patterns in the data may be modeled in a way that accounts for randomness and uncertainty in the observations, and then used to draw inferences about the process or population being studied; this is called inferential statistics. Both descriptive and inferential statistics comprise applied statistics. There is also a discipline called mathematical statistics, which is concerned with the theoretical basis of the subject. The word statistics is also the plural of statistic (singular), which refers to the result of applying a statistical algorithm to a set of data, as in economic statistics, crime statistics, etc. # History ## Etymology The word statistics ultimately derives from the New Latin term statisticum collegium ("council of state") and the Italian word statista ("statesman" or "politician"). The German Statistik, first introduced by Gottfried Achenwall (1749), originally designated the analysis of data about the state, signifying the "science of state" (then called political arithmetic in English). It acquired the meaning of the collection and classification of data generally in the early 19th century. It was introduced into English by Sir John Sinclair. Thus, the original principal purpose of Statistik was data to be used by governmental and (often centralized) administrative bodies. The collection of data about states and localities continues, largely through national and international statistical services. In particular, censuses provide regular information about the population. ## Origins in probability The mathematical methods of statistics emerged from probability theory, which can be dated to the correspondence of Pierre de Fermat and Blaise Pascal (1654). Christiaan Huygens (1657) gave the earliest known scientific treatment of the subject. Jakob Bernoulli's Ars Conjectandi (posthumous, 1713) and Abraham de Moivre's Doctrine of Chances (1718) treated the subject as a branch of mathematics. In the modern era, the work of Kolmogorov has been instrumental in formulating the fundamental model of Probability Theory, which is used throughout statistics. The theory of errors may be traced back to Roger Cotes' Opera Miscellanea (posthumous, 1722), but a memoir prepared by Thomas Simpson in 1755 (printed 1756) first applied the theory to the discussion of errors of observation. The reprint (1757) of this memoir lays down the axioms that positive and negative errors are equally probable, and that there are certain assignable limits within which all errors may be supposed to fall; continuous errors are discussed and a probability curve is given. Pierre-Simon Laplace (1774) made the first attempt to deduce a rule for the combination of observations from the principles of the theory of probabilities. He represented the law of probability of errors by a curve. He deduced a formula for the mean of three observations. He also gave (1781) a formula for the law of facility of error (a term due to Lagrange, 1774), but one which led to unmanageable equations. Daniel Bernoulli (1778) introduced the principle of the maximum product of the probabilities of a system of concurrent errors. The method of least squares, which was used to minimize errors in data measurement, was published independently by Adrien-Marie Legendre (1805), Robert Adrain (1808), and Carl Friedrich Gauss (1809). Gauss had used the method in his famous 1801 prediction of the location of the dwarf planet Ceres. Further proofs were given by Laplace (1810, 1812), Gauss (1823), James Ivory (1825, 1826), Hagen (1837), Friedrich Bessel (1838), W. F. Donkin (1844, 1856), John Herschel (1850), and Morgan Crofton (1870). Other contributors were Ellis (1844), De Morgan (1864), Glaisher (1872), and Giovanni Schiaparelli (1875). Peters's (1856) formula for r, the probable error of a single observation, is well known. In the nineteenth century authors on the general theory included Laplace, Sylvestre Lacroix (1816), Littrow (1833), Richard Dedekind (1860), Helmert (1872), Hermann Laurent (1873), Liagre, Didion, and Karl Pearson. Augustus De Morgan and George Boole improved the exposition of the theory. Adolphe Quetelet (1796-1874), another important founder of statistics, introduced the notion of the "average man" (l'homme moyen) as a means of understanding complex social phenomena such as crime rates, marriage rates, or suicide rates. ## Statistics today During the 20th century, the creation of precise instruments for public health concerns (epidemiology, biostatistics, etc.) and economic and social purposes (unemployment rate, econometry, etc.) necessitated substantial advances in statistical practices: the Western welfare states developed after World War I had to possess specific knowledge of the "population". Today the use of statistics has broadened far beyond its origins as a service to a state or government. Individuals and organizations use statistics to understand data and make informed decisions throughout the natural and social sciences, medicine, business, and other areas. Statistics is generally regarded not as a subfield of mathematics but rather as a distinct, albeit allied, field. Many universities maintain separate mathematics and statistics departments. Statistics is also taught in departments as diverse as psychology, education, and public health. ## Important contributors to statistics - Thomas Bayes - George E. P. Box - Pafnuty Chebyshev - Sir David Cox - Gertrude Cox - George Dantzig - Rene Descartes - W. Edwards Deming - Bradley Efron - Bruno de Finetti - Sir Ronald Fisher - Sir Francis Galton - Carl Friedrich Gauss - William Sealey Gosset ("Student") - Andrey Kolmogorov - Aleksandr Lyapunov - Abraham De Moivre - Sir Isaac Newton - Jerzy Neyman - Florence Nightingale - Blaise Pascal - Karl Pearson - Adolphe Quetelet - C. R. Rao - Walter A. Shewhart - Charles Spearman - John Tukey # Conceptual overview In applying statistics to a scientific, industrial, or societal problem, one begins with a process or population to be studied. This might be a population of people in a country, of crystal grains in a rock, or of goods manufactured by a particular factory during a given period. It may instead be a process observed at various times; data collected about this kind of "population" constitute what is called a time series. For practical reasons, rather than compiling data about an entire population, one usually studies a chosen subset of the population, called a sample. Data are collected about the sample in an observational or experimental setting. The data are then subjected to statistical analysis, which serves two related purposes: description and inference. - Descriptive statistics can be used to summarize the data, either numerically or graphically, to describe the sample. Basic examples of numerical descriptors include the mean and standard deviation. Graphical summarizations include various kinds of charts and graphs. - Inferential statistics is used to model patterns in the data, accounting for randomness and drawing inferences about the larger population. These inferences may take the form of answers to yes/no questions (hypothesis testing), estimates of numerical characteristics (estimation), descriptions of association (correlation), or modeling of relationships (regression). Other modeling techniques include ANOVA, time series, and data mining. The concept of correlation is particularly noteworthy. Statistical analysis of a data set may reveal that two variables (that is, two properties of the population under consideration) tend to vary together, as if they are connected. For example, a study of annual income and age of death among people might find that poor people tend to have shorter lives than affluent people. The two variables are said to be correlated. However, one cannot immediately infer the existence of a causal relationship between the two variables; see correlation does not imply causation. The correlated phenomena could be caused by a third, previously unconsidered phenomenon, called a lurking variable. If the sample is representative of the population, then inferences and conclusions made from the sample can be extended to the population as a whole. A major problem lies in determining the extent to which the chosen sample is representative. Statistics offers methods to estimate and correct for randomness in the sample and in the data collection procedure, as well as methods for designing robust experiments in the first place; see experimental design. The fundamental mathematical concept employed in understanding such randomness is probability. Mathematical statistics (also called statistical theory) is the branch of applied mathematics that uses probability theory and analysis to examine the theoretical basis of statistics. The use of any statistical method is valid only when the system or population under consideration satisfies the basic mathematical assumptions of the method. Misuse of statistics can produce subtle but serious errors in description and interpretation — subtle in that even experienced professionals sometimes make such errors, and serious in that they may affect social policy, medical practice and the reliability of structures such as bridges and nuclear power plants. Even when statistics is correctly applied, the results can be difficult to interpret for a non-expert. For example, the statistical significance of a trend in the data — which measures the extent to which the trend could be caused by random variation in the sample — may not agree with one's intuitive sense of its significance. The set of basic statistical skills (and skepticism) needed by people to deal with information in their everyday lives is referred to as statistical literacy. # Statistical methods ## Experimental and observational studies A common goal for a statistical research project is to investigate causality, and in particular to draw a conclusion on the effect of changes in the values of predictors or independent variables on response or dependent variables. There are two major types of causal statistical studies, experimental studies and observational studies. In both types of studies, the effect of differences of an independent variable (or variables) on the behavior of the dependent variable are observed. The difference between the two types is in how the study is actually conducted. Each can be very effective. An experimental study involves taking measurements of the system under study, manipulating the system, and then taking additional measurements using the same procedure to determine if the manipulation may have modified the values of the measurements. In contrast, an observational study does not involve experimental manipulation. Instead data are gathered and correlations between predictors and the response are investigated. An example of an experimental study is the famous Hawthorne studies which attempted to test changes to the working environment at the Hawthorne plant of the Western Electric Company. The researchers were interested in whether increased illumination would increase the productivity of the assembly line workers. The researchers first measured productivity in the plant then modified the illumination in an area of the plant to see if changes in illumination would affect productivity. As it turns out, productivity improved under all the experimental conditions (see Hawthorne effect). However, the study is today heavily criticized for errors in experimental procedures, specifically the lack of a control group and blindedness. An example of an observational study is a study which explores the correlation between smoking and lung cancer. This type of study typically uses a survey to collect observations about the area of interest and then perform statistical analysis. In this case, the researchers would collect observations of both smokers and non-smokers, perhaps through a case-control study, and then look at the number of cases of lung cancer in each group. The basic steps for an experiment are to: - plan the research including determining information sources, research subject selection, and ethical considerations for the proposed research and method, - design the experiment concentrating on the system model and the interaction of independent and dependent variables, - summarize a collection of observations to feature their commonality by suppressing details (descriptive statistics), - reach consensus about what the observations tell us about the world we observe (statistical inference), - document and present the results of the study. ## Levels of measurement There are four types of measurements or measurement scales used in statistics. The four types or levels of measurement (nominal, ordinal, interval, and ratio) have different degrees of usefulness in statistical research. Ratio measurements, where both a zero value and distances between different measurements are defined, provide the greatest flexibility in statistical methods that can be used for analysing the data. Interval measurements have meaningful distances between measurements but no meaningful zero value (such as IQ measurements or temperature measurements in Fahrenheit). Ordinal measurements have imprecise differences between consecutive values but a meaningful order to those values. Nominal measurements have no meaningful rank order among values. Variables conforming only to nominal or ordinal measurements are sometimes called together categorical variables since they cannot reasonably be numerically measured whereas ratio and interval measurements are grouped together as quantitative or continuous variables due to their numerical nature. ## Statistical techniques Some well known statistical tests and procedures for research observations are: - Student's t-test - chi-square test - Analysis of variance (ANOVA) - Mann-Whitney U - Regression analysis - Factor Analysis - Correlation - Pearson product-moment correlation coefficient - Spearman's rank correlation coefficient # Specialized disciplines Some fields of inquiry use applied statistics so extensively that they have specialized terminology. These disciplines include: - Actuarial science - Applied information economics - Biostatistics - Business statistics - Data mining (applying statistics and pattern recognition to discover knowledge from data) - Economic statistics (Econometrics) - Energy statistics - Engineering statistics - Epidemiology - Geography and Geographic Information Systems, more specifically in Spatial analysis - Demography - Psychological statistics - Quality - Social statistics - Statistical literacy - Statistical surveys - Process analysis and chemometrics (for analysis of data from analytical chemistry and chemical engineering) - Reliability engineering - Image processing - Statistics in various sports, particularly baseball and cricket Statistics form a key basis tool in business and manufacturing as well. It is used to understand measurement systems variability, control processes (as in statistical process control or SPC), for summarizing data, and to make data-driven decisions. In these roles it is a key tool, and perhaps the only reliable tool. # Statistical computing The rapid and sustained increases in computing power starting from the second half of the 20th century have had a substantial impact on the practice of statistical science. Early statistical models were almost always from the class of linear models, but powerful computers, coupled with suitable numerical algorithms, caused a resurgence of interest in nonlinear models (especially neural networks and decision trees) and the creation of new types, such as generalised linear models and multilevel models. Increased computing power has also led to the growing popularity of computationally-intensive methods based on resampling, such as permutation tests and the bootstrap, while techniques such as Gibbs sampling have made Bayesian methods more feasible. The computer revolution has implications for the future of statistics, with a new emphasis on "experimental" and "empirical" statistics. A large number of both general and special purpose statistical packages are now available to practitioners. # Misuse There is a general perception that statistical knowledge is all-too-frequently intentionally misused, by finding ways to interpret the data that are favorable to the presenter. A famous quote, variously attributed, but thought to be from Benjamin Disraeli is, "There are three types of lies - lies, damn lies, and statistics." The well-known book How to Lie with Statistics by Darrell Huff discusses many cases of deceptive uses of statistics, focusing on misleading graphs. By choosing (or rejecting, or modifying) a certain sample, results can be manipulated; throwing out outliers is one means of doing so. This may be the result of outright fraud or of subtle and unintentional bias on the part of the researcher. Thus, Harvard President Lawrence Lowell wrote in 1909 that statistics, "like veal pies, are good if you know the person that made them, and are sure of the ingredients." As further studies contradict previously announced results, people may become wary of trusting such studies. One might read a study that says (for example) "doing X reduces high blood pressure", followed by a study that says "doing X does not affect high blood pressure", followed by a study that says "doing X actually worsens high blood pressure". Often the studies were conducted on different groups with different protocols, or a small-sample study that promised intriguing results has not held up to further scrutiny in a large-sample study. However, many readers may not have noticed these distinctions, or the media may have oversimplified this vital contextual information, and the public's distrust of statistics is thereby increased. However, deeper criticisms come from the fact that the hypothesis testing approach, widely used and in many cases required by law or regulation, forces one hypothesis to be 'favored' (the null hypothesis), and can also seem to exaggerate the importance of minor differences in large studies. A difference that is highly statistically significant can still be of no practical significance. In the fields of psychology and medicine, especially with regard to the approval of new drug treatments by the Food and Drug Administration, criticism of the hypothesis testing approach has increased in recent years. One response has been a greater emphasis on the p-value over simply reporting whether a hypothesis was rejected at the given level of significance \alpha. Here again, however, this summarises the evidence for an effect but not the size of the effect. One increasingly common approach is to report confidence intervals instead, since these indicate both the size of the effect and the uncertainty surrounding it. This aids in interpreting the results, as the confidence interval for a given \alpha simultaneously indicates both statistical significance and effect size. Note that both the p-value and confidence interval approaches are based on the same fundamental calculations as those entering into the corresponding hypothesis test. The results are stated in a more detailed format, rather than the yes-or-no finality of the hypothesis test, but use the same underlying statistical methodology. A truly different approach is to use Bayesian methods. This approach has been criticized as well, however. The strong desire to see good drugs approved and harmful or useless drugs restricted remain conflicting tensions (type I and type II errors in the language of hypothesis testing). In his book Statistics As Principled Argument, Robert P. Abelson articulates the position that statistics serves as a standardized means of settling disputes between scientists who could otherwise each argue the merits of their own positions ad infinitum. From this point of view, statistics is principally a form of rhetoric. This can be taken as a positive or a negative, but as with any means of settling a dispute, statistical methods can succeed only as long as both sides accept the approach and agree on the method to be used.	Statistics Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Statistics is a mathematical science pertaining to the collection, analysis, interpretation or explanation, and presentation of data. It is applicable to a wide variety of academic disciplines, from the physical and social sciences to the humanities. Statistics are also used for making informed decisions. Statistical methods can be used to summarize or describe a collection of data; this is called descriptive statistics. In addition, patterns in the data may be modeled in a way that accounts for randomness and uncertainty in the observations, and then used to draw inferences about the process or population being studied; this is called inferential statistics. Both descriptive and inferential statistics comprise applied statistics. There is also a discipline called mathematical statistics, which is concerned with the theoretical basis of the subject. The word statistics is also the plural of statistic (singular), which refers to the result of applying a statistical algorithm to a set of data, as in economic statistics, crime statistics, etc. # History ## Etymology The word statistics ultimately derives from the New Latin term statisticum collegium ("council of state") and the Italian word statista ("statesman" or "politician"). The German Statistik, first introduced by Gottfried Achenwall (1749), originally designated the analysis of data about the state, signifying the "science of state" (then called political arithmetic in English). It acquired the meaning of the collection and classification of data generally in the early 19th century. It was introduced into English by Sir John Sinclair. Thus, the original principal purpose of Statistik was data to be used by governmental and (often centralized) administrative bodies. The collection of data about states and localities continues, largely through national and international statistical services. In particular, censuses provide regular information about the population. ## Origins in probability The mathematical methods of statistics emerged from probability theory, which can be dated to the correspondence of Pierre de Fermat and Blaise Pascal (1654). Christiaan Huygens (1657) gave the earliest known scientific treatment of the subject. Jakob Bernoulli's Ars Conjectandi (posthumous, 1713) and Abraham de Moivre's Doctrine of Chances (1718) treated the subject as a branch of mathematics.[1] In the modern era, the work of Kolmogorov has been instrumental in formulating the fundamental model of Probability Theory, which is used throughout statistics. The theory of errors may be traced back to Roger Cotes' Opera Miscellanea (posthumous, 1722), but a memoir prepared by Thomas Simpson in 1755 (printed 1756) first applied the theory to the discussion of errors of observation. The reprint (1757) of this memoir lays down the axioms that positive and negative errors are equally probable, and that there are certain assignable limits within which all errors may be supposed to fall; continuous errors are discussed and a probability curve is given. Pierre-Simon Laplace (1774) made the first attempt to deduce a rule for the combination of observations from the principles of the theory of probabilities. He represented the law of probability of errors by a curve. He deduced a formula for the mean of three observations. He also gave (1781) a formula for the law of facility of error (a term due to Lagrange, 1774), but one which led to unmanageable equations. Daniel Bernoulli (1778) introduced the principle of the maximum product of the probabilities of a system of concurrent errors. The method of least squares, which was used to minimize errors in data measurement, was published independently by Adrien-Marie Legendre (1805), Robert Adrain (1808), and Carl Friedrich Gauss (1809). Gauss had used the method in his famous 1801 prediction of the location of the dwarf planet Ceres. Further proofs were given by Laplace (1810, 1812), Gauss (1823), James Ivory (1825, 1826), Hagen (1837), Friedrich Bessel (1838), W. F. Donkin (1844, 1856), John Herschel (1850), and Morgan Crofton (1870). Other contributors were Ellis (1844), De Morgan (1864), Glaisher (1872), and Giovanni Schiaparelli (1875). Peters's (1856) formula for <math>r</math>, the probable error of a single observation, is well known. In the nineteenth century authors on the general theory included Laplace, Sylvestre Lacroix (1816), Littrow (1833), Richard Dedekind (1860), Helmert (1872), Hermann Laurent (1873), Liagre, Didion, and Karl Pearson. Augustus De Morgan and George Boole improved the exposition of the theory. Adolphe Quetelet (1796-1874), another important founder of statistics, introduced the notion of the "average man" (l'homme moyen) as a means of understanding complex social phenomena such as crime rates, marriage rates, or suicide rates. ## Statistics today During the 20th century, the creation of precise instruments for public health concerns (epidemiology, biostatistics, etc.) and economic and social purposes (unemployment rate, econometry, etc.) necessitated substantial advances in statistical practices: the Western welfare states developed after World War I had to possess specific knowledge of the "population". Today the use of statistics has broadened far beyond its origins as a service to a state or government. Individuals and organizations use statistics to understand data and make informed decisions throughout the natural and social sciences, medicine, business, and other areas. Statistics is generally regarded not as a subfield of mathematics but rather as a distinct, albeit allied, field. Many universities maintain separate mathematics and statistics departments. Statistics is also taught in departments as diverse as psychology, education, and public health. ## Important contributors to statistics Template:Col-start - Thomas Bayes - George E. P. Box - Pafnuty Chebyshev - Sir David Cox - Gertrude Cox - George Dantzig - Rene Descartes - W. Edwards Deming - Bradley Efron - Bruno de Finetti - Sir Ronald Fisher - Sir Francis Galton - Carl Friedrich Gauss - William Sealey Gosset ("Student") - Andrey Kolmogorov - Aleksandr Lyapunov - Abraham De Moivre - Sir Isaac Newton - Jerzy Neyman - Florence Nightingale - Blaise Pascal - Karl Pearson - Adolphe Quetelet - C. R. Rao - Walter A. Shewhart - Charles Spearman - John Tukey # Conceptual overview In applying statistics to a scientific, industrial, or societal problem, one begins with a process or population to be studied. This might be a population of people in a country, of crystal grains in a rock, or of goods manufactured by a particular factory during a given period. It may instead be a process observed at various times; data collected about this kind of "population" constitute what is called a time series. For practical reasons, rather than compiling data about an entire population, one usually studies a chosen subset of the population, called a sample. Data are collected about the sample in an observational or experimental setting. The data are then subjected to statistical analysis, which serves two related purposes: description and inference. - Descriptive statistics can be used to summarize the data, either numerically or graphically, to describe the sample. Basic examples of numerical descriptors include the mean and standard deviation. Graphical summarizations include various kinds of charts and graphs. - Inferential statistics is used to model patterns in the data, accounting for randomness and drawing inferences about the larger population. These inferences may take the form of answers to yes/no questions (hypothesis testing), estimates of numerical characteristics (estimation), descriptions of association (correlation), or modeling of relationships (regression). Other modeling techniques include ANOVA, time series, and data mining. The concept of correlation is particularly noteworthy. Statistical analysis of a data set may reveal that two variables (that is, two properties of the population under consideration) tend to vary together, as if they are connected. For example, a study of annual income and age of death among people might find that poor people tend to have shorter lives than affluent people. The two variables are said to be correlated. However, one cannot immediately infer the existence of a causal relationship between the two variables; see correlation does not imply causation. The correlated phenomena could be caused by a third, previously unconsidered phenomenon, called a lurking variable. If the sample is representative of the population, then inferences and conclusions made from the sample can be extended to the population as a whole. A major problem lies in determining the extent to which the chosen sample is representative. Statistics offers methods to estimate and correct for randomness in the sample and in the data collection procedure, as well as methods for designing robust experiments in the first place; see experimental design. The fundamental mathematical concept employed in understanding such randomness is probability. Mathematical statistics (also called statistical theory) is the branch of applied mathematics that uses probability theory and analysis to examine the theoretical basis of statistics. The use of any statistical method is valid only when the system or population under consideration satisfies the basic mathematical assumptions of the method. Misuse of statistics can produce subtle but serious errors in description and interpretation — subtle in that even experienced professionals sometimes make such errors, and serious in that they may affect social policy, medical practice and the reliability of structures such as bridges and nuclear power plants. Even when statistics is correctly applied, the results can be difficult to interpret for a non-expert. For example, the statistical significance of a trend in the data — which measures the extent to which the trend could be caused by random variation in the sample — may not agree with one's intuitive sense of its significance. The set of basic statistical skills (and skepticism) needed by people to deal with information in their everyday lives is referred to as statistical literacy. # Statistical methods ## Experimental and observational studies A common goal for a statistical research project is to investigate causality, and in particular to draw a conclusion on the effect of changes in the values of predictors or independent variables on response or dependent variables. There are two major types of causal statistical studies, experimental studies and observational studies. In both types of studies, the effect of differences of an independent variable (or variables) on the behavior of the dependent variable are observed. The difference between the two types is in how the study is actually conducted. Each can be very effective. An experimental study involves taking measurements of the system under study, manipulating the system, and then taking additional measurements using the same procedure to determine if the manipulation may have modified the values of the measurements. In contrast, an observational study does not involve experimental manipulation. Instead data are gathered and correlations between predictors and the response are investigated. An example of an experimental study is the famous Hawthorne studies which attempted to test changes to the working environment at the Hawthorne plant of the Western Electric Company. The researchers were interested in whether increased illumination would increase the productivity of the assembly line workers. The researchers first measured productivity in the plant then modified the illumination in an area of the plant to see if changes in illumination would affect productivity. As it turns out, productivity improved under all the experimental conditions (see Hawthorne effect). However, the study is today heavily criticized for errors in experimental procedures, specifically the lack of a control group and blindedness. An example of an observational study is a study which explores the correlation between smoking and lung cancer. This type of study typically uses a survey to collect observations about the area of interest and then perform statistical analysis. In this case, the researchers would collect observations of both smokers and non-smokers, perhaps through a case-control study, and then look at the number of cases of lung cancer in each group. The basic steps for an experiment are to: - plan the research including determining information sources, research subject selection, and ethical considerations for the proposed research and method, - design the experiment concentrating on the system model and the interaction of independent and dependent variables, - summarize a collection of observations to feature their commonality by suppressing details (descriptive statistics), - reach consensus about what the observations tell us about the world we observe (statistical inference), - document and present the results of the study. ## Levels of measurement There are four types of measurements or measurement scales used in statistics. The four types or levels of measurement (nominal, ordinal, interval, and ratio) have different degrees of usefulness in statistical research. Ratio measurements, where both a zero value and distances between different measurements are defined, provide the greatest flexibility in statistical methods that can be used for analysing the data. Interval measurements have meaningful distances between measurements but no meaningful zero value (such as IQ measurements or temperature measurements in Fahrenheit). Ordinal measurements have imprecise differences between consecutive values but a meaningful order to those values. Nominal measurements have no meaningful rank order among values. Variables conforming only to nominal or ordinal measurements are sometimes called together categorical variables since they cannot reasonably be numerically measured whereas ratio and interval measurements are grouped together as quantitative or continuous variables due to their numerical nature. ## Statistical techniques Some well known statistical tests and procedures for research observations are: - Student's t-test - chi-square test - Analysis of variance (ANOVA) - Mann-Whitney U - Regression analysis - Factor Analysis - Correlation - Pearson product-moment correlation coefficient - Spearman's rank correlation coefficient # Specialized disciplines Some fields of inquiry use applied statistics so extensively that they have specialized terminology. These disciplines include: - Actuarial science - Applied information economics - Biostatistics - Business statistics - Data mining (applying statistics and pattern recognition to discover knowledge from data) - Economic statistics (Econometrics) - Energy statistics - Engineering statistics - Epidemiology - Geography and Geographic Information Systems, more specifically in Spatial analysis - Demography - Psychological statistics - Quality - Social statistics - Statistical literacy - Statistical surveys - Process analysis and chemometrics (for analysis of data from analytical chemistry and chemical engineering) - Reliability engineering - Image processing - Statistics in various sports, particularly baseball and cricket Statistics form a key basis tool in business and manufacturing as well. It is used to understand measurement systems variability, control processes (as in statistical process control or SPC), for summarizing data, and to make data-driven decisions. In these roles it is a key tool, and perhaps the only reliable tool. # Statistical computing The rapid and sustained increases in computing power starting from the second half of the 20th century have had a substantial impact on the practice of statistical science. Early statistical models were almost always from the class of linear models, but powerful computers, coupled with suitable numerical algorithms, caused a resurgence of interest in nonlinear models (especially neural networks and decision trees) and the creation of new types, such as generalised linear models and multilevel models. Increased computing power has also led to the growing popularity of computationally-intensive methods based on resampling, such as permutation tests and the bootstrap, while techniques such as Gibbs sampling have made Bayesian methods more feasible. The computer revolution has implications for the future of statistics, with a new emphasis on "experimental" and "empirical" statistics. A large number of both general and special purpose statistical packages are now available to practitioners. # Misuse There is a general perception that statistical knowledge is all-too-frequently intentionally misused, by finding ways to interpret the data that are favorable to the presenter. A famous quote, variously attributed, but thought to be from Benjamin Disraeli[2] is, "There are three types of lies - lies, damn lies, and statistics." The well-known book How to Lie with Statistics by Darrell Huff discusses many cases of deceptive uses of statistics, focusing on misleading graphs. By choosing (or rejecting, or modifying) a certain sample, results can be manipulated; throwing out outliers is one means of doing so. This may be the result of outright fraud or of subtle and unintentional bias on the part of the researcher. Thus, Harvard President Lawrence Lowell wrote in 1909 that statistics, "like veal pies, are good if you know the person that made them, and are sure of the ingredients." As further studies contradict previously announced results, people may become wary of trusting such studies. One might read a study that says (for example) "doing X reduces high blood pressure", followed by a study that says "doing X does not affect high blood pressure", followed by a study that says "doing X actually worsens high blood pressure". Often the studies were conducted on different groups with different protocols, or a small-sample study that promised intriguing results has not held up to further scrutiny in a large-sample study. However, many readers may not have noticed these distinctions, or the media may have oversimplified this vital contextual information, and the public's distrust of statistics is thereby increased. However, deeper criticisms come from the fact that the hypothesis testing approach, widely used and in many cases required by law or regulation, forces one hypothesis to be 'favored' (the null hypothesis), and can also seem to exaggerate the importance of minor differences in large studies. A difference that is highly statistically significant can still be of no practical significance. In the fields of psychology and medicine, especially with regard to the approval of new drug treatments by the Food and Drug Administration, criticism of the hypothesis testing approach has increased in recent years. One response has been a greater emphasis on the p-value over simply reporting whether a hypothesis was rejected at the given level of significance <math>\alpha</math>. Here again, however, this summarises the evidence for an effect but not the size of the effect. One increasingly common approach is to report confidence intervals instead, since these indicate both the size of the effect and the uncertainty surrounding it. This aids in interpreting the results, as the confidence interval for a given <math>\alpha</math> simultaneously indicates both statistical significance and effect size. Note that both the p-value and confidence interval approaches are based on the same fundamental calculations as those entering into the corresponding hypothesis test. The results are stated in a more detailed format, rather than the yes-or-no finality of the hypothesis test, but use the same underlying statistical methodology. A truly different approach is to use Bayesian methods. This approach has been criticized as well, however. The strong desire to see good drugs approved and harmful or useless drugs restricted remain conflicting tensions (type I and type II errors in the language of hypothesis testing). In his book Statistics As Principled Argument, Robert P. Abelson articulates the position that statistics serves as a standardized means of settling disputes between scientists who could otherwise each argue the merits of their own positions ad infinitum. From this point of view, statistics is principally a form of rhetoric. This can be taken as a positive or a negative, but as with any means of settling a dispute, statistical methods can succeed only as long as both sides accept the approach and agree on the method to be used.	https://www.wikidoc.org/index.php/Statistical
e056afa012606c3a46ec9b42e08e264dcd121a4c	wikidoc	Stereotypy	Stereotypy A stereotypy (Template:PronEng) (plural stereotypies) is a repetitive or ritualistic movement, posture, or utterance, found in patients with mental retardation, autism spectrum disorders, tardive dyskinesia and stereotypic movement disorder. Stereotypies may be simple movements such as body rocking, or complex, such as self-caressing, crossing and uncrossing of legs, and marching in place. Several causes have been hypothesized for stereotypy, and several treatment options are available. # Proposed causes There are several possible explanations for stereotypy, and different stereotyped behaviors may have different explanations. A popular explanation is stimming, which hypothesizes that a particular stereotyped behavior has a function related to sensory input. Other explanations include hypotheses that stereotypy discharges tension or expresses frustration, that it communicates a need for attention or reinforcement or sensory stimulation, that it is learned or neuropathological or some combination of the two, or that it is normal behavior with no particular explanation needed. # Treatment Treatment options include replacing the repetitive behavior with a more socially acceptable behavior, exercise, or medications. Where sensory integration dysfunction is involved, sensory integration therapy may be used. When gauged to be appropriate, some behavioral specialists allow a child to engage in self-stimulatory behavior as positive reinforcement in interventions such as Applied Behavior Analysis. # In animals Stereotypies also occur in non-human animals. It is considered an abnormal behavior and is sometimes seen in captive animals, particularly those held in small enclosures with little opportunity to engage in more normal behaviors. These behaviors may be maladaptive, involving self-injury or reduced reproductive success. They can be induced by confinement; for example, cats pace in zoo cages. Pregnant sows whose feed is restricted bite at their stalls' bars, and chew without anything in their mouths. In laboratory rats and mice, grooming is the most common activity other than sleep, and grooming stereotypies have been used to investigate several animal models of anxiety and depression. Examples of stereotypical behaviors include pacing, rocking, swimming in circles, excessive sleeping, self-mutilation (including feather picking and excessive grooming), and mouthing cage bars. Stereotypies are seen in many species, including primates, birds, and carnivores. Up to 40% of elephants in zoos display stereotypical behaviors. Stereotypic behaviour in giraffes is also common; they resort to excessive tongue use on inanimate objects, due to a subconscious response to suckle milk from their mother, which many human-reared giraffes and other captive animals do not experience. Stereotypical behaviors are thought to be caused ultimately by artificial environments that do not allow animals to satisfy their normal behavioral needs. Rather than refer to the behavior as abnormal, it has been suggested that it be described as "behavior indicative of an abnormal environment." Stereotypies are correlated with altered behavioral response selection in the basal ganglia. Stereotypical behavior in laboratory animals can confound behavioral research. It is also seen as a sign of psychological distress in animals, and therefore is an animal welfare issue. Stereotypical behavior can sometimes be reduced or eliminated by environmental enrichment, including larger and more stimulating enclosures, training, and introductions of stimuli (such as objects, sounds, or scents) to the animal's environment. The enrichment must be varied to remain effective for any length of time. Housing social animals such as primates with other members of their species is also helpful. But once the behavior is established, it is sometimes impossible to eliminate due to alterations in the brain.	Stereotypy A stereotypy (Template:PronEng) (plural stereotypies) is a repetitive or ritualistic movement, posture, or utterance, found in patients with mental retardation, autism spectrum disorders, tardive dyskinesia and stereotypic movement disorder. Stereotypies may be simple movements such as body rocking, or complex, such as self-caressing, crossing and uncrossing of legs, and marching in place.[1] Several causes have been hypothesized for stereotypy, and several treatment options are available. # Proposed causes There are several possible explanations for stereotypy, and different stereotyped behaviors may have different explanations. A popular explanation is stimming, which hypothesizes that a particular stereotyped behavior has a function related to sensory input. Other explanations include hypotheses that stereotypy discharges tension or expresses frustration, that it communicates a need for attention or reinforcement or sensory stimulation, that it is learned or neuropathological or some combination of the two, or that it is normal behavior with no particular explanation needed.[2] # Treatment Treatment options include replacing the repetitive behavior with a more socially acceptable behavior, exercise, or medications. Where sensory integration dysfunction is involved, sensory integration therapy may be used. When gauged to be appropriate, some behavioral specialists allow a child to engage in self-stimulatory behavior as positive reinforcement in interventions such as Applied Behavior Analysis.[citation needed] # In animals Stereotypies also occur in non-human animals. It is considered an abnormal behavior and is sometimes seen in captive animals, particularly those held in small enclosures with little opportunity to engage in more normal behaviors. These behaviors may be maladaptive, involving self-injury or reduced reproductive success.[3] They can be induced by confinement; for example, cats pace in zoo cages.[4] Pregnant sows whose feed is restricted bite at their stalls' bars, and chew without anything in their mouths.[5] In laboratory rats and mice, grooming is the most common activity other than sleep, and grooming stereotypies have been used to investigate several animal models of anxiety and depression.[6] Examples of stereotypical behaviors include pacing, rocking, swimming in circles, excessive sleeping, self-mutilation (including feather picking and excessive grooming), and mouthing cage bars. Stereotypies are seen in many species, including primates, birds, and carnivores. Up to 40% of elephants in zoos display stereotypical behaviors.[7] Stereotypic behaviour in giraffes is also common; they resort to excessive tongue use on inanimate objects, due to a subconscious response to suckle milk from their mother, which many human-reared giraffes and other captive animals do not experience.[8] Stereotypical behaviors are thought to be caused ultimately by artificial environments that do not allow animals to satisfy their normal behavioral needs. Rather than refer to the behavior as abnormal, it has been suggested that it be described as "behavior indicative of an abnormal environment."[9] Stereotypies are correlated with altered behavioral response selection in the basal ganglia.[3] Stereotypical behavior in laboratory animals can confound behavioral research.[3] It is also seen as a sign of psychological distress in animals, and therefore is an animal welfare issue. Stereotypical behavior can sometimes be reduced or eliminated by environmental enrichment, including larger and more stimulating enclosures, training, and introductions of stimuli (such as objects, sounds, or scents) to the animal's environment. The enrichment must be varied to remain effective for any length of time. Housing social animals such as primates with other members of their species is also helpful. But once the behavior is established, it is sometimes impossible to eliminate due to alterations in the brain.[9]	https://www.wikidoc.org/index.php/Stereotypy
5d84fa9e6e93089d2d1a40e35107acffca7be319	wikidoc	Stop codon	Stop codon In the genetic code, a stop codon (or termination codon) is a nucleotide triplet within messenger RNA that signals a termination of translation. Proteins are unique sequences of amino acids, and most codons in messenger RNA correspond to the addition of an amino acid to a growing protein chain — stop codons signal the termination of this process, releasing the amino acid chain. In the standard genetic code, there are three stop codons: UAG ("amber"), UAA ("ochre"), and UGA ("opal" or "umber"); several variations to this most common set are known. Nonsense mutations are changes in DNA sequence which introduce a premature stop codon, causing any resulting protein to be abnormally shortened. This often causing a loss of function in the protein as critical parts of the amino acid chain are no longer created. Because of this terminology, stop codons have also been referred to as nonsense codons. # Amber, ochre, and opal nomenclature Stop codons were historically given different names as they each corresponded to a distinct class of mutants that all behaved in a similar manner. These mutants were first isolated within bacteriophages (T4 and lambda), viruses that infect the bacteria Escherichia coli. Mutations in viral genes weakened their infectious ability, sometimes creating viruses that were only able to infect and grow within certain varieties of E coli. Amber mutations were the first set of nonsense mutations be discovered, isolated by graduate student Harris Bernstein in experiments designed to resolve a debate between Richard Epstein and Charles Steinberg. Bernstein (whose last name means "amber" in German) had been offered the reward of having any discovered mutants named after himself. Amber mutations are characterized by their ability to infect certain strains of bacteria, known as amber suppressors. These bacteria carry their own mutation which allow a recovery of function in the mutant viruses. For example, a mutation in the tRNA which recognizes the amber stop codon allows translation to "read through" the codon and produce full length protein, thereby recovering the normal form of the protein and "suppressing" the amber mutation. Thus, amber mutants are an entire class of virus mutants which can grow in bacteria that contain amber suppressor mutations. The ochre mutation was the second stop codon mutation to be discovered. Given a color name to match the name of amber mutants, ochre mutant viruses had a similar property in that they recovered infectious ability within certain suppressor strains of bacteria. The set of ochre suppressors was distinct from amber suppressors, so ochre mutants were inferred to correspond to a different nucleotide triplet. Through a series of mutation experiments comparing these mutants with each other and other known amino acid codons, Sydney Brenner concluded that the amber and ochre mutations corresponded to the nucleotide triplets "UAG" and "UAA". The third and last stop codon in the standard genetic code was discovered soon after, corresponding to the nucleotide triplet "UGA". Nonsense mutations that created this premature stop codon were later called opal mutations or umber mutations.	Stop codon In the genetic code, a stop codon (or termination codon) is a nucleotide triplet within messenger RNA that signals a termination of translation.[1] Proteins are unique sequences of amino acids, and most codons in messenger RNA correspond to the addition of an amino acid to a growing protein chain — stop codons signal the termination of this process, releasing the amino acid chain. In the standard genetic code, there are three stop codons: UAG ("amber"), UAA ("ochre"), and UGA ("opal" or "umber"); several variations to this most common set are known. Nonsense mutations are changes in DNA sequence which introduce a premature stop codon, causing any resulting protein to be abnormally shortened. This often causing a loss of function in the protein as critical parts of the amino acid chain are no longer created. Because of this terminology, stop codons have also been referred to as nonsense codons. # Amber, ochre, and opal nomenclature Stop codons were historically given different names as they each corresponded to a distinct class of mutants that all behaved in a similar manner. These mutants were first isolated within bacteriophages (T4 and lambda), viruses that infect the bacteria Escherichia coli. Mutations in viral genes weakened their infectious ability, sometimes creating viruses that were only able to infect and grow within certain varieties of E coli. Amber mutations were the first set of nonsense mutations be discovered, isolated by graduate student Harris Bernstein in experiments designed to resolve a debate between Richard Epstein and Charles Steinberg. Bernstein (whose last name means "amber" in German) had been offered the reward of having any discovered mutants named after himself.[2] Amber mutations are characterized by their ability to infect certain strains of bacteria, known as amber suppressors. These bacteria carry their own mutation which allow a recovery of function in the mutant viruses. For example, a mutation in the tRNA which recognizes the amber stop codon allows translation to "read through" the codon and produce full length protein, thereby recovering the normal form of the protein and "suppressing" the amber mutation. Thus, amber mutants are an entire class of virus mutants which can grow in bacteria that contain amber suppressor mutations. The ochre mutation was the second stop codon mutation to be discovered. Given a color name to match the name of amber mutants, ochre mutant viruses had a similar property in that they recovered infectious ability within certain suppressor strains of bacteria. The set of ochre suppressors was distinct from amber suppressors, so ochre mutants were inferred to correspond to a different nucleotide triplet. Through a series of mutation experiments comparing these mutants with each other and other known amino acid codons, Sydney Brenner concluded that the amber and ochre mutations corresponded to the nucleotide triplets "UAG" and "UAA".[3] The third and last stop codon in the standard genetic code was discovered soon after, corresponding to the nucleotide triplet "UGA".[4] Nonsense mutations that created this premature stop codon were later called opal mutations or umber mutations.	https://www.wikidoc.org/index.php/Stop_codon
31cbb0208425e21cbc6047275205fc3e6275258b	wikidoc	Strangling	Strangling # Overview Strangling is compression of the neck that leads to unconsciousness or death by causing an increasingly hypoxic state in the brain. Fatal strangling typically occurs in cases of violence, accidents, and as the mechanism of suicide in hangings. Strangling does not have to be fatal; limited or interrupted strangling is practiced in erotic asphyxia, in the choking game, and is an important technique and in many combat sports and self-defense systems (see Chokehold for further reading). Strangling can be divided into three general types according to the mechanism used: - Hanging — Suspension from a cord wound around the neck (see the separate article Hanging) - Ligature strangulation — Strangulation without suspension using some form of cord-like object - Manual strangulation — Strangulation using the fingers or other extremity # General Strangling involves one or several mechanisms that interfere with the normal flow of oxygen into the brain: - Compression of the carotid arteries and jugular veins — causing cerebral ischemia. - Compression of the laryngopharynx, larynx, or trachea — causing asphyxia. - Stimulation of the carotid sinus reflex — causing brachycardia, hypotension, or both. Depending on the particular method of strangling, one or several of these typically occur in combination, but vascular obstruction is usually the main mechanism. Complete obstruction of blood flow to the brain is associated with irreversible neurological damage and death, but during strangulation there is still unimpeded blood flow in the vertebral arteries. Estimations have been made that significant occlusion of the carotid arteries and jugular veins occurs with a pressure of around 3.4 N/cm², while the trachea demands six times more at approximately 22 N/cm². As in all cases of strangulation, the rapidity of death can be affected by the susceptibility to carotid sinus stimulation. Carotid sinus reflex death is sometimes considered a mechanism of death in cases of strangulation, but it remains highly disputed. The reported time from application to unconsciousness varies from 7-14 seconds if effectively applied. chokeholds to one minute in some other cases, with death occurring minutes after unconsciousness. # Manual strangulation Manual strangulation (also known as "throttling" in the UK) refers to strangling with the hands, fingers, or other extremities (sometimes also with blunt objects such as batons). In violence, this type of strangling is mostly done by men against women rather than against another man, because it generally requires a large disparity in physical strength between the assailant and the victim and also because men can be over twice as big as a woman in general. Depending on how the strangling is performed, it may compress the airway, interfere with the flow of blood in the neck, or work as a combination of the two. Consequently, manual strangulation may damage the larynx,, and fracture the hyoid or other bones in the neck. In cases of airway compression, manual strangling leads to the frightening sensation of air hunger and may induce violent struggling. More technical variants of manual strangulation are referred to as chokeholds, and are extensively practiced and used in various martial arts, combat sports, self-defense systems, and in military hand-to-hand combat application. It is a mistake to refer to strangulation as "choke" or "choking". Choke means having the windpipe blocked entirely or partly by some foreign object like food. # Ligature strangulation Ligature strangulation refers to strangling with some form of cord or cloth such as rope, wire, or shoe laces, either partially or fully circumferencing the neck. Even though the mechanism of strangulation is similar, it is usually distinguished from hanging by the strangling force being something other than the person's own bodyweight. Incomplete occlusion of the carotid arteries is expected, and in cases of homicide, the victim may struggle for a period of time, with unconsciousness typically occurring in 10 to 15 seconds. Cases of ligature strangulation generally involve homicides of women, children, and the elderly, but accidents and suicides occur as well. Suicide by ligature strangulation requires that the constriction around the neck be held even after loss of consciousness, which can be accomplished with complicated knots.	Strangling # Overview Strangling is compression of the neck that leads to unconsciousness or death by causing an increasingly hypoxic state in the brain.[1] Fatal strangling typically occurs in cases of violence, accidents, and as the mechanism of suicide in hangings. Strangling does not have to be fatal; limited or interrupted strangling is practiced in erotic asphyxia, in the choking game, and is an important technique and in many combat sports and self-defense systems (see Chokehold for further reading). Strangling can be divided into three general types according to the mechanism used:[2] - Hanging — Suspension from a cord wound around the neck (see the separate article Hanging) - Ligature strangulation — Strangulation without suspension using some form of cord-like object - Manual strangulation — Strangulation using the fingers or other extremity # General Strangling involves one or several mechanisms that interfere with the normal flow of oxygen into the brain:[3] - Compression of the carotid arteries and jugular veins — causing cerebral ischemia. - Compression of the laryngopharynx, larynx, or trachea — causing asphyxia. - Stimulation of the carotid sinus reflex — causing brachycardia, hypotension, or both. Depending on the particular method of strangling, one or several of these typically occur in combination, but vascular obstruction is usually the main mechanism.[4] Complete obstruction of blood flow to the brain is associated with irreversible neurological damage and death,[5] but during strangulation there is still unimpeded blood flow in the vertebral arteries.[6] Estimations have been made that significant occlusion of the carotid arteries and jugular veins occurs with a pressure of around 3.4 N/cm², while the trachea demands six times more at approximately 22 N/cm².[7] As in all cases of strangulation, the rapidity of death can be affected by the susceptibility to carotid sinus stimulation.[4] Carotid sinus reflex death is sometimes considered a mechanism of death in cases of strangulation, but it remains highly disputed.[3][8] The reported time from application to unconsciousness varies from 7-14 seconds if effectively applied. chokeholds[9] to one minute in some other cases, with death occurring minutes after unconsciousness.[3] # Manual strangulation Manual strangulation (also known as "throttling" in the UK) refers to strangling with the hands, fingers, or other extremities (sometimes also with blunt objects such as batons). In violence, this type of strangling is mostly done by men against women rather than against another man, because it generally requires a large disparity in physical strength between the assailant and the victim and also because men can be over twice as big as a woman in general.[3] Depending on how the strangling is performed, it may compress the airway, interfere with the flow of blood in the neck, or work as a combination of the two. Consequently, manual strangulation may damage the larynx,[3], and fracture the hyoid or other bones in the neck.[4] In cases of airway compression, manual strangling leads to the frightening sensation of air hunger and may induce violent struggling.[3] More technical variants of manual strangulation are referred to as chokeholds, and are extensively practiced and used in various martial arts, combat sports, self-defense systems, and in military hand-to-hand combat application. It is a mistake to refer to strangulation as "choke" or "choking". Choke means having the windpipe blocked entirely or partly by some foreign object like food. # Ligature strangulation Ligature strangulation refers to strangling with some form of cord or cloth such as rope, wire, or shoe laces, either partially or fully circumferencing the neck.[10] Even though the mechanism of strangulation is similar, it is usually distinguished from hanging by the strangling force being something other than the person's own bodyweight.[4] Incomplete occlusion of the carotid arteries is expected, and in cases of homicide, the victim may struggle for a period of time,[4] with unconsciousness typically occurring in 10 to 15 seconds.[10] Cases of ligature strangulation generally involve homicides of women, children, and the elderly,[4] but accidents and suicides occur as well.[11] Suicide by ligature strangulation requires that the constriction around the neck be held even after loss of consciousness,[4] which can be accomplished with complicated knots.[3]	https://www.wikidoc.org/index.php/Strangling
08d34206a58e6dbfbf6572358f7f142c4280d552	wikidoc	Strawberry	Strawberry The strawberry (Fragaria) (plural strawberries) is a genus of plants in the family Rosaceae and the fruit of these plants. There are more than 20 named species and many hybrids and cultivars. The most common strawberries grown commercially are cultivars of the Garden strawberry. # Morphology The strawberry is an accessory fruit; that is, the fleshy part is derived not from the ovaries which are the "seeds" (actually achenes) but from the peg at the bottom of the hypanthium that held the ovaries. So from a technical standpoint, the seeds are the actual fruits of the plant, and the flesh of the strawberry is modified receptacle tissue. It is whitish-green as it develops and in most species turns red when ripe. # History The typical modern strawberry, of the genus Fragaria, comes from the Americas, and is a hybrid of both North and South American varieties. Interestingly, the crossbreeding was done in Europe to correct a mistake; the European horticulturists had only brought female South American plants, and were forced to cross them with the North American variety in order to get fruit and seeds. Fragaria comes from "fragans", meaning odorous, referring to the perfumed flesh of the fruit. Madam Tallien, a great figure of the French Revolution, who was nicknamed Our Lady of Thermidor, used to take baths full of strawberries to keep the full radiance of her skin. Fontenelle, centenarian writer and gourmet of the 18th century, considered his long life was due to the strawberries he used to eat. Strawberries were considered poisonous in Argentina until the mid-nineteenth century. Strawberries have a taste that varies by cultivar, and ranges from quite sweet to rather tart. Popular etymology has it that the name "straw" berry comes from gardeners' practice of mulching strawberries with straw to protect the fruits from rot (a pseudoetymology that can be found in non-linguistic sources such as the Old Farmer's Almanac 2005). However, there is no evidence that the Anglo-Saxons ever grew strawberries, and even less that they knew of this practice. There is an alternative theory that the name derives from the Anglo-Saxon verb for "strew" (meaning to spread around) which was streabergen (Strea means "strew" and Bergen means "berry" or "fruit") and thence to streberie, straiberie, strauberie, straubery, strauberry, and finally, "strawberry", the word which we use today. The name might have come from the fact that the fruit and various runners appear "strewn" along the ground. # Classification There are more than 20 different Fragaria species worldwide. Key to the classification of strawberry species is recognizing that they vary in the number of chromosomes. There are seven basic types of chromosomes that they all have in common. However, they exhibit different polyploidy. Some species are diploid, having two sets of the seven chromosomes (14 chromosomes total). Others are tetraploid (four sets, 28 chromosomes total), hexaploid (six sets, 42 chromosomes total), octoploid (eight sets, 56 chromosomes total), or decaploid (ten sets, 70 chromosomes total). As a rough rule (with exceptions), strawberry species with more chromosomes tend to be more robust and produce larger plants with larger berries (Darrow). - Fragaria daltoniana - Fragaria iinumae - Fragaria nilgerrensis - Fragaria nipponica - Fragaria nubicola - Fragaria vesca (Woodland Strawberry) - Fragaria viridis - Fragaria yezoensis - Fragaria moupinensis - Fragaria orientalis - Fragaria moschata (Musk Strawberry) - Fragaria ×ananassa (Garden Strawberry) - Fragaria chiloensis (Beach Strawberry) - Fragaria iturupensis (Iturup Strawberry) - Fragaria virginiana (Virginia Strawberry) - Fragaria ×Potentilla hybrids - Fragaria ×vescana Numerous other species have been proposed. Some are now recognized as subspecies of one of the above species (see GRIN taxonomy database). The Mock Strawberry and Barren Strawberry, which both bear resemblance to Fragaria, are closely related species in the genus Potentilla. The Strawberry tree is an unrelated species. # Production trends The FAO reports that the United States was the top producer of strawberry worldwide in 2005 followed by Spain. ## Pests A number of species of Lepidoptera feed on strawberry plants; for details see this list. ## Diseases # Uses In addition to being consumed fresh, strawberries are frozen or made into preserves. Strawberries are a popular addition to dairy products, as in strawberry flavored ice cream, milkshakes and yogurts. Strawberry pie is also popular. Strawberries can also be used as a natural acid/base indicator. # Gallery - Closeup of the surface of a strawberry Closeup of the surface of a strawberry - Strawberry flowers and developing fruit Strawberry flowers and developing fruit - Harvested strawberries Harvested strawberries - A wild strawberry plant, showing characteristic shape A wild strawberry plant, showing characteristic shape - Strawberry farms generally add hives of honeybees to improve pollination Strawberry farms generally add hives of honeybees to improve pollination - A very large strawberry. A very large strawberry. - Assorted chocolate-covered strawberries Assorted chocolate-covered strawberries - Strawberry farm in DaHu, Taiwan Strawberry farm in DaHu, Taiwan - Green strawberry late May 2007 Seattle, Washington Green strawberry late May 2007 Seattle, Washington	Strawberry Template:Tfd The strawberry (Fragaria) (plural strawberries) is a genus of plants in the family Rosaceae and the fruit of these plants. There are more than 20 named species and many hybrids and cultivars. The most common strawberries grown commercially are cultivars of the Garden strawberry. # Morphology The strawberry is an accessory fruit; that is, the fleshy part is derived not from the ovaries which are the "seeds" (actually achenes) but from the peg at the bottom of the hypanthium that held the ovaries. So from a technical standpoint, the seeds are the actual fruits of the plant, and the flesh of the strawberry is modified receptacle tissue. It is whitish-green as it develops and in most species turns red when ripe. # History The typical modern strawberry, of the genus Fragaria, comes from the Americas, and is a hybrid of both North and South American varieties. Interestingly, the crossbreeding was done in Europe to correct a mistake; the European horticulturists had only brought female South American plants, and were forced to cross them with the North American variety in order to get fruit and seeds. Fragaria comes from "fragans", meaning odorous, referring to the perfumed flesh of the fruit. Madam Tallien, a great figure of the French Revolution, who was nicknamed Our Lady of Thermidor, used to take baths full of strawberries to keep the full radiance of her skin. Fontenelle, centenarian writer and gourmet of the 18th century, considered his long life was due to the strawberries he used to eat. Strawberries were considered poisonous in Argentina until the mid-nineteenth century. Strawberries have a taste that varies by cultivar, and ranges from quite sweet to rather tart. Popular etymology has it that the name "straw" berry comes from gardeners' practice of mulching strawberries with straw to protect the fruits from rot (a pseudoetymology that can be found in non-linguistic sources such as the Old Farmer's Almanac 2005). However, there is no evidence that the Anglo-Saxons ever grew strawberries, and even less that they knew of this practice. There is an alternative theory that the name derives from the Anglo-Saxon verb for "strew" (meaning to spread around) which was streabergen (Strea means "strew" and Bergen means "berry" or "fruit") and thence to streberie, straiberie, strauberie, straubery, strauberry, and finally, "strawberry", the word which we use today. The name might have come from the fact that the fruit and various runners appear "strewn" along the ground. # Classification There are more than 20 different Fragaria species worldwide. Key to the classification of strawberry species is recognizing that they vary in the number of chromosomes. There are seven basic types of chromosomes that they all have in common. However, they exhibit different polyploidy. Some species are diploid, having two sets of the seven chromosomes (14 chromosomes total). Others are tetraploid (four sets, 28 chromosomes total), hexaploid (six sets, 42 chromosomes total), octoploid (eight sets, 56 chromosomes total), or decaploid (ten sets, 70 chromosomes total). As a rough rule (with exceptions), strawberry species with more chromosomes tend to be more robust and produce larger plants with larger berries (Darrow). - Fragaria daltoniana - Fragaria iinumae - Fragaria nilgerrensis - Fragaria nipponica - Fragaria nubicola - Fragaria vesca (Woodland Strawberry) - Fragaria viridis - Fragaria yezoensis - Fragaria moupinensis - Fragaria orientalis - Fragaria moschata (Musk Strawberry) - Fragaria ×ananassa (Garden Strawberry) - Fragaria chiloensis (Beach Strawberry) - Fragaria iturupensis (Iturup Strawberry) - Fragaria virginiana (Virginia Strawberry) - Fragaria ×Potentilla hybrids - Fragaria ×vescana Numerous other species have been proposed. Some are now recognized as subspecies of one of the above species (see GRIN taxonomy database). The Mock Strawberry and Barren Strawberry, which both bear resemblance to Fragaria, are closely related species in the genus Potentilla. The Strawberry tree is an unrelated species. # Production trends The FAO reports that the United States was the top producer of strawberry worldwide in 2005 followed by Spain. ## Pests A number of species of Lepidoptera feed on strawberry plants; for details see this list. ## Diseases # Uses In addition to being consumed fresh, strawberries are frozen or made into preserves. Strawberries are a popular addition to dairy products, as in strawberry flavored ice cream, milkshakes and yogurts. Strawberry pie is also popular. Strawberries can also be used as a natural acid/base indicator. # Gallery - Closeup of the surface of a strawberry Closeup of the surface of a strawberry - Strawberry flowers and developing fruit Strawberry flowers and developing fruit - Harvested strawberries Harvested strawberries - A wild strawberry plant, showing characteristic shape A wild strawberry plant, showing characteristic shape - Strawberry farms generally add hives of honeybees to improve pollination Strawberry farms generally add hives of honeybees to improve pollination - A very large strawberry. A very large strawberry. - Assorted chocolate-covered strawberries Assorted chocolate-covered strawberries - Strawberry farm in DaHu, Taiwan Strawberry farm in DaHu, Taiwan - Green strawberry late May 2007 Seattle, Washington Green strawberry late May 2007 Seattle, Washington	https://www.wikidoc.org/index.php/Strawberry
7d1c2f1e80f9a487c5f48f6378d9675806a56954	wikidoc	Stretching	Stretching # Overview Stretching is a form of physical exercise in which a specific skeletal muscle (or muscle group) is deliberately elongated to its fullest length (often by abduction from the torso) in order to improve the muscle's felt elasticity and reaffirm comfortable muscle tone. (Weerapong et al 189–206) The result is a feeling of increased muscle control, flexibility and range of motion. Stretching is also used therapeutically to to alleviate cramps. Stretching, in its most basic form, is a natural and instinctive activity; it is performed by both animals and humans. It can be accompanied by yawning. Stretching often occurs instinctively after waking from sleep, after long periods of inactivity, or after exiting confined spaces. Many athletes stretch deliberately before or after exercise in order to increase performance and reduce injury. Whether this is helpful, has no effect, or even has detrimental effects is in dispute. While common, it may not be beneficial for all athletic activities. # Possible Benefits In the literature described by Michael Yessis, there are many beneficial stretches that can improve Range of Motion (ROM) in athletes, especially runners. In his review, he cites benefits of stretching: - may improve ROM - reduce risk of injury - prevent post-exercise muscle soreness - slow delayed-onset muscle soreness (DOMS) To gain these benefits, Yessis describes different forms of stretching along with their individual benefits. He suggests that one stretching exercise may not be enough to prevent all types of injury. Therefore, multiple stretching exercises should be used to gain the full effects of stretching. Research by Sharman et al. sought to find what techniques elongate muscles through "proprioceptive neuromuscular facilitation" (PNF) stretching. They used around seventy sources to compile their data. In this review, PNF stretching yielded the greatest change in range of motion (ROM), especially short-term benefits. Ballistic stretching was also beneficial in comparison; however, PNF techniques emphasize active flexibility and therefore get better results. Reasoning behind the biomechanical benefit of PNF stretching points to muscular reflex relaxation found in the musculotendinous unit being stretched. More common findings in literature suggest that PNF benefits are due to influence on the joint where the stretch is felt. It has been suggested in some studies that overstretching or stretching to a point where pain is felt is inappropriate and detrimental. Effects on performance, both short and long-term, may include predisposition to injury and possible nerve damage (Yessis 8-18). Other findings in research conclude that active stretching routines will reduce muscle-tendon viscosity and increase muscle compliancy and elasticity. In sports activities where there are little or no short-stretching cycles, (bicycling, jogging, etc.) stretching routines may be detrimental to athletic performance and have no effect on reducing injuries (Witvrouw et al. 443-449). In J.C. Andersen’s compilation of lower extremity stretching research, the effects of stretching before and after exercise were reviewed for evidence of muscle soreness. The seven articles referenced in his research came from sources such as MEDLINE and CINAHL. All data used came from studies that used static stretching programs and included average healthy participants between ages eighteen and forty. The results of Andersen’s research are somewhat limited, due to the nature of the literature he selected; however, his findings suggest that stretching has no beneficial effects on injury reduction. Two to five percent reductions in injury levels lead Anderson to believe stretching routines will not have impact on injury prevention or post-exercise soreness. Also, the concept that stretching decreases risk of injury in active muscles is negated by claims in the literature reviewed. Stretching as observed in the research found increased complaisance in relaxed muscle groups. This idea, in conjunction with stretch tolerance and stretch variability, does not encourage stretching to prevent injuries. The conclusion claims more research is needed to finalize evidence on the benefits of stretching (Andersen 218-220). A study constructed by Nelson et al. set out to find the correlation between pre-exercise static stretching and its effects on muscle strength endurance. Two experiments were designed to find the initial links between pre-exercise stretching and muscle endurance. Results of the study found both stretching experiments to reduce effectiveness of muscle strength endurance by up to thirty percent. They suggest that pre-exercise stretching induces a fatigue-like state in muscles which would clearly inhibit performance if the muscle is not at full potential. Smaller amounts of research included state that stretching may cause ischemia in muscles, which reduces oxygen levels and the ability to remove metabolic waste. Higher levels of metabolic waste create a catalyst that contracts muscles. This may cause muscle injury in individual performance. Other theories included claim active static stretching increases inflow of Ca2+ from extra cellular spaces into the muscles being stretched. The increase of Ca2+ reduced the muscle twitch tension by up to sixty percent. Reasoning behind this claims that increased levels of Ca2+ in resting muscles predisposes individuals to fatigue quicker than individuals who did not stretch (Nelson, Kokkonen, and Arnall 338-343). # Flexibility A study done by LaRoche and Connolly was designed to see whether stretching reduces frequency of sports-related injuries and increases individual performance. The study, conducted over a four-week period, involved male participants between the ages of eighteen and sixty who were not actively training. Participants were randomly assigned to three different stretching groups which included ballistic, static, and control groups. The study used a custom-built device to test the individual’s maximal hamstring resistance. To see what stretching method worked best, participants first needed to experience Delayed Onset Muscle Soreness (DOMS). This was done by having individuals use a hamstring curl machine, doing three sets of fifteen repetitions with a one-minute break between sets. Stretching was done before and after exercise, only three days a week for a four-week period. Warm ups were a mandatory requirement before stretching. The results of the study found that both ballistic and static stretching yielded a large increase in individual range of motion (ROM). This is thought to be from an increase in stretch tolerance as opposed to actual muscle elongation. The study also found that ballistic stretching seemed to have the same effects as static stretching without any perceived negative effects. Although there was an increased range of motion due to stretching, there was no change in DOMS or muscle soreness (LaRoche and Connolly 1000-1007). # Uncertainty For many, the idea of stretching means that injuries become less common and athletic performance is enhanced. Multifactorial claims in literature essentially discredit generally accepted ideas of stretching. In terms of genetic ability, some people are more flexible than others; this includes gender differences where women are generally more flexible than men. In this sense, some people are more predisposed to injuries than others. In addition to genetics, some studies found that stretching does not increase range of motion. Instead it increases individual stretch tolerance and may become detrimental to athletic performance. Still, other studies are nonspecific about what their research really found. Some measure capsular mobility as opposed to the joint-muscle compliance. Overwhelming research concludes that pre-exercise stretching, especially for those who do not use short bursts of muscular activity, may result in a reduction in performance of up to five percent. At best, literature shows that weeks of regular stretching exercises, in conjunction with warm ups, may help athletes reduce injury by up to five percent. This small percent may help athletes who use short bursts of energy such as sprinters improve their fifty-yard running speed by fractions of a second. Other sports that use continuous movements, such as cycling, should not expect the same benefits. Regardless of research, athletes, especially runners, continue to stretch, attempting to reduce injuries and increase their performance. More detailed studies and research are needed to find all possible neurological effects of stretching (Shrier 22-26). Research by Weerapong et al. was designed to find the effects of stretching on the body. In their research, they used ninety-nine peer-reviewed and scholarly sources to compile their data. Their sources came from three online databases which included PubMed, SPORT Discuss, and ProQuest 5000 International. The criteria for research looked for average healthy participants where no bias was placed on age, gender or physical abilities. All claims considered in the research were picked if they researched the long and short-term effects of stretching, while suggesting what effects stretching had on events such as injury occurrence, sport performance, and muscle soreness. Results of the study found that it is very common in literature to suggest stretching as a possible mechanism to prevent onset of injury and muscle soreness. This idea, however, while very common, does not specifically explain how stretching affects muscle properties on individual performance. Their findings suggest that common stretching methods, like static and ballistic stretches, decrease muscle performance and have inconclusive evidence to support the notion of injury reduction. Their research questions whether flexibility will reduce incidence of injury. A large number of their sources claim flexibility does not reduce incidence of injury; therefore, increasing range of motion is not needed. Their conclusion states that more research is needed to find the best stretching techniques that improve performance and reduce risk of injury (Weerapong, Hume, and Kolt 189-206). A study done by Witvrouw et al. was done to find what relationship stretching has with injury prevention. Over forty sources of relevant literature were used in their review. Initially the documentation of stretching claimed to promote better physical performance and reduce risk of injury. The number of suggested ideas in recent literature makes the relationship between stretching and its effects ambiguous. Results of the research were two different findings, each of which has a different consideration based on individual activity: - They claim the reason behind conflicting data is due to the different levels of observed sports activity. - In activities where stretch-shortening cycles (SSC) are more prevalent, such as sprinting and jumping, the muscle-tendon units need to store and use more elastic energy - In activities which do not require as much SSC such as jogging, a more elastic muscle-tendon unit is not needed. # Physiology Studies have shed light on what has turned out to be a fascinating and huge protein with skeletal muscle—aptly named, titin. A seminal study performed by Magid and Law, demonstrated convincingly that the origin of passive muscle tension (which occurs during stretching) is actually within the myofibrils themselves, not extracellular as had previously been supposed. # Summary There are many recent studies and researched literature that have inconclusive evidence or contradict with other sources. More detailed evidence, especially pertaining to time, intensity, and repetition of stretches are needed. Stretching may be able to help athletic performance in some situations, but the most recent literature claims that pre-exercise stretching is detrimental to performance. Not all possible outlets of stretching have been explored; therefore, no specific claim can be made about the benefits of stretching. # Footnotes - ↑ Yessis, Michael (2006), "Runners Need Active Stretching", AMAA Journal Winter, 18 (2): 8–18.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} - ↑ (Witvrouw et al. 443-449) - ↑ Muscle Physiology - Types of Contractions	Stretching Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Stretching is a form of physical exercise in which a specific skeletal muscle (or muscle group) is deliberately elongated to its fullest length (often by abduction from the torso) in order to improve the muscle's felt elasticity and reaffirm comfortable muscle tone. (Weerapong et al 189–206) The result is a feeling of increased muscle control, flexibility and range of motion. Stretching is also used therapeutically to to alleviate cramps. Stretching, in its most basic form, is a natural and instinctive activity; it is performed by both animals and humans. It can be accompanied by yawning. Stretching often occurs instinctively after waking from sleep, after long periods of inactivity, or after exiting confined spaces. Many athletes stretch deliberately before or after exercise in order to increase performance and reduce injury. Whether this is helpful, has no effect, or even has detrimental effects is in dispute. While common, it may not be beneficial for all athletic activities. # Possible Benefits In the literature described by Michael Yessis, there are many beneficial stretches that can improve Range of Motion (ROM) in athletes, especially runners. In his review[1], he cites benefits of stretching: - may improve ROM - reduce risk of injury - prevent post-exercise muscle soreness - slow delayed-onset muscle soreness (DOMS) To gain these benefits, Yessis describes different forms of stretching along with their individual benefits. He suggests that one stretching exercise may not be enough to prevent all types of injury. Therefore, multiple stretching exercises should be used to gain the full effects of stretching. Research by Sharman et al. sought to find what techniques elongate muscles through "proprioceptive neuromuscular facilitation" (PNF) stretching. They used around seventy sources to compile their data. In this review, PNF stretching yielded the greatest change in range of motion (ROM), especially short-term benefits. Ballistic stretching was also beneficial in comparison; however, PNF techniques emphasize active flexibility and therefore get better results. Reasoning behind the biomechanical benefit of PNF stretching points to muscular reflex relaxation found in the musculotendinous unit being stretched. More common findings in literature suggest that PNF benefits are due to influence on the joint where the stretch is felt. It has been suggested in some studies that overstretching or stretching to a point where pain is felt is inappropriate and detrimental. Effects on performance, both short and long-term, may include predisposition to injury and possible nerve damage (Yessis 8-18). Other findings in research conclude that active stretching routines will reduce muscle-tendon viscosity and increase muscle compliancy and elasticity. In sports activities where there are little or no short-stretching cycles, (bicycling, jogging, etc.) stretching routines may be detrimental to athletic performance and have no effect on reducing injuries (Witvrouw et al. 443-449). In J.C. Andersen’s compilation of lower extremity stretching research, the effects of stretching before and after exercise were reviewed for evidence of muscle soreness. The seven articles referenced in his research came from sources such as MEDLINE and CINAHL. All data used came from studies that used static stretching programs and included average healthy participants between ages eighteen and forty. The results of Andersen’s research are somewhat limited, due to the nature of the literature he selected; however, his findings suggest that stretching has no beneficial effects on injury reduction. Two to five percent reductions in injury levels lead Anderson to believe stretching routines will not have impact on injury prevention or post-exercise soreness. Also, the concept that stretching decreases risk of injury in active muscles is negated by claims in the literature reviewed. Stretching as observed in the research found increased complaisance in relaxed muscle groups. This idea, in conjunction with stretch tolerance and stretch variability, does not encourage stretching to prevent injuries. The conclusion claims more research is needed to finalize evidence on the benefits of stretching (Andersen 218-220). A study constructed by Nelson et al. set out to find the correlation between pre-exercise static stretching and its effects on muscle strength endurance. Two experiments were designed to find the initial links between pre-exercise stretching and muscle endurance. Results of the study found both stretching experiments to reduce effectiveness of muscle strength endurance by up to thirty percent. They suggest that pre-exercise stretching induces a fatigue-like state in muscles which would clearly inhibit performance if the muscle is not at full potential. Smaller amounts of research included state that stretching may cause ischemia in muscles, which reduces oxygen levels and the ability to remove metabolic waste. Higher levels of metabolic waste create a catalyst that contracts muscles. This may cause muscle injury in individual performance. Other theories included claim active static stretching increases inflow of Ca2+ from extra cellular spaces into the muscles being stretched. The increase of Ca2+ reduced the muscle twitch tension by up to sixty percent. Reasoning behind this claims that increased levels of Ca2+ in resting muscles predisposes individuals to fatigue quicker than individuals who did not stretch (Nelson, Kokkonen, and Arnall 338-343). # Flexibility A study done by LaRoche and Connolly was designed to see whether stretching reduces frequency of sports-related injuries and increases individual performance. The study, conducted over a four-week period, involved male participants between the ages of eighteen and sixty who were not actively training. Participants were randomly assigned to three different stretching groups which included ballistic, static, and control groups. The study used a custom-built device to test the individual’s maximal hamstring resistance. To see what stretching method worked best, participants first needed to experience Delayed Onset Muscle Soreness (DOMS). This was done by having individuals use a hamstring curl machine, doing three sets of fifteen repetitions with a one-minute break between sets. Stretching was done before and after exercise, only three days a week for a four-week period. Warm ups were a mandatory requirement before stretching. The results of the study found that both ballistic and static stretching yielded a large increase in individual range of motion (ROM). This is thought to be from an increase in stretch tolerance as opposed to actual muscle elongation. The study also found that ballistic stretching seemed to have the same effects as static stretching without any perceived negative effects. Although there was an increased range of motion due to stretching, there was no change in DOMS or muscle soreness (LaRoche and Connolly 1000-1007). # Uncertainty For many, the idea of stretching means that injuries become less common and athletic performance is enhanced. Multifactorial claims in literature essentially discredit generally accepted ideas of stretching. In terms of genetic ability, some people are more flexible than others; this includes gender differences where women are generally more flexible than men. In this sense, some people are more predisposed to injuries than others. In addition to genetics, some studies found that stretching does not increase range of motion. Instead it increases individual stretch tolerance and may become detrimental to athletic performance. Still, other studies are nonspecific about what their research really found. Some measure capsular mobility as opposed to the joint-muscle compliance. Overwhelming research concludes that pre-exercise stretching, especially for those who do not use short bursts of muscular activity, may result in a reduction in performance of up to five percent. At best, literature shows that weeks of regular stretching exercises, in conjunction with warm ups, may help athletes reduce injury by up to five percent. This small percent may help athletes who use short bursts of energy such as sprinters improve their fifty-yard running speed by fractions of a second. Other sports that use continuous movements, such as cycling, should not expect the same benefits. Regardless of research, athletes, especially runners, continue to stretch, attempting to reduce injuries and increase their performance. More detailed studies and research are needed to find all possible neurological effects of stretching (Shrier 22-26). Research by Weerapong et al. was designed to find the effects of stretching on the body. In their research, they used ninety-nine peer-reviewed and scholarly sources to compile their data. Their sources came from three online databases which included PubMed, SPORT Discuss, and ProQuest 5000 International. The criteria for research looked for average healthy participants where no bias was placed on age, gender or physical abilities. All claims considered in the research were picked if they researched the long and short-term effects of stretching, while suggesting what effects stretching had on events such as injury occurrence, sport performance, and muscle soreness. Results of the study found that it is very common in literature to suggest stretching as a possible mechanism to prevent onset of injury and muscle soreness. This idea, however, while very common, does not specifically explain how stretching affects muscle properties on individual performance. Their findings suggest that common stretching methods, like static and ballistic stretches, decrease muscle performance and have inconclusive evidence to support the notion of injury reduction. Their research questions whether flexibility will reduce incidence of injury. A large number of their sources claim flexibility does not reduce incidence of injury; therefore, increasing range of motion is not needed. Their conclusion states that more research is needed to find the best stretching techniques that improve performance and reduce risk of injury (Weerapong, Hume, and Kolt 189-206). A study done by Witvrouw et al. was done to find what relationship stretching has with injury prevention. Over forty sources of relevant literature were used in their review. Initially the documentation of stretching claimed to promote better physical performance and reduce risk of injury. The number of suggested ideas in recent literature makes the relationship between stretching and its effects ambiguous. Results of the research were two different findings[2], each of which has a different consideration based on individual activity: - They claim the reason behind conflicting data is due to the different levels of observed sports activity. - In activities where stretch-shortening cycles (SSC) are more prevalent, such as sprinting and jumping, the muscle-tendon units need to store and use more elastic energy - In activities which do not require as much SSC such as jogging, a more elastic muscle-tendon unit is not needed. # Physiology Studies have shed light on what has turned out to be a fascinating and huge protein with skeletal muscle—aptly named, titin. A seminal study performed by Magid and Law, demonstrated convincingly that the origin of passive muscle tension (which occurs during stretching) is actually within the myofibrils themselves, not extracellular as had previously been supposed.[3] # Summary There are many recent studies and researched literature that have inconclusive evidence or contradict with other sources. More detailed evidence, especially pertaining to time, intensity, and repetition of stretches are needed. Stretching may be able to help athletic performance in some situations, but the most recent literature claims that pre-exercise stretching is detrimental to performance. Not all possible outlets of stretching have been explored; therefore, no specific claim can be made about the benefits of stretching. # Footnotes - ↑ Yessis, Michael (2006), "Runners Need Active Stretching", AMAA Journal Winter, 18 (2): 8–18.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} - ↑ (Witvrouw et al. 443-449) - ↑ Muscle Physiology - Types of Contractions	https://www.wikidoc.org/index.php/Stretching
adddf0d5e2162b8dc081f60758752b9b9cc4b4ee	wikidoc	Vorinostat	Vorinostat # 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 Vorinostat is a histone deacetylase inhibitor that is FDA approved for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. Common adverse reactions include diarrhea, fatigue, nausea, thrombocytopenia, anorexia and dysgeusia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Vorinostat is indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. - Dosage: 400 mg orally once daily with food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Vorinostat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vorinostat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness 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 Vorinostat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vorinostat in pediatric patients. # Contraindications None # Warnings - Pulmonary embolism occurred in 5% (4/86) of patients receiving vorinostat, and deep vein thrombosis has also been reported. Monitor for signs and symptoms of these events, particularly in patients with a prior history of thromboembolic events. - Treatment with vorinostat can cause dose-related thrombocytopenia and anemia. Monitor blood counts every 2 weeks during the first 2 months of therapy and monthly thereafter. Adjust dosage or discontinue treatment with vorinostat as clinically appropriate. - Gastrointestinal disturbances, including nausea, vomiting and diarrhea, have been reported and may require the use of antiemetic and antidiarrheal medications. Fluid and electrolytes should be replaced to prevent dehydration. Pre-existing nausea, vomiting, and diarrhea should be adequately controlled before beginning therapy with vorinostat. - Hyperglycemia has been observed in patients receiving vorinostat and was severe in 5% (4/86) of patients. Monitor serum glucose every 2 weeks during the first 2 months of therapy and monthly thereafter. - Obtain chemistry tests, including serum electrolytes, creatinine, magnesium, and calcium, every 2 weeks during the first 2 months of therapy and monthly thereafter. Correct hypokalemia and hypomagnesemia prior to administration of vorinostat. Monitor potassium and magnesium more frequently in symptomatic patients (e.g., patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms). - Severe thrombocytopenia leading to gastrointestinal bleeding has been reported with concomitant use of vorinostat and other HDAC inhibitors (e.g., valproic acid). Monitor platelet counts more frequently. # Adverse Reactions ## Clinical Trials Experience The most common drug-related adverse reactions can be classified into 4 symptom complexes: gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease, vomiting, constipation), constitutional symptoms (fatigue, chills), hematologic abnormalities (thrombocytopenia, anemia), and taste disorders (dysgeusia, dry mouth). The most common serious drug-related adverse reactions were pulmonary embolism and anemia. 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 vorinostat was evaluated in 107 CTCL patients in two single arm clinical studies in which 86 patients received 400 mg once daily. The data described below reflect exposure to vorinostat 400 mg once daily in the 86 patients for a median number of 97.5 days on therapy (range 2 to 480+ days). Seventeen (19.8%) patients were exposed beyond 24 weeks and 8 (9.3%) patients were exposed beyond 1 year. The population of CTCL patients studied was 37 to 83 years of age, 47.7% female, 52.3% male, and 81.4% white, 16.3% black, and 1.2% Asian or multi-racial. TABLE 1 summarizes the frequency of CTCL patients with specific adverse reactions, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 3.0). The frequencies of more severe thrombocytopenia, anemia and fatigue were increased at doses higher than 400 mg once daily of vorinostat. The most common serious adverse reactions in the 86 CTCL patients in two clinical trials were pulmonary embolism reported in 4.7% (4/86) of patients, squamous cell carcinoma reported in 3.5% (3/86) of patients and anemia reported in 2.3% (2/86) of patients. There were single events of cholecystitis, death (of unknown cause), deep vein thrombosis, enterococcal infection, exfoliative dermatitis, gastrointestinal hemorrhage, infection, lobar pneumonia, myocardial infarction, ischemic stroke, pelviureteric obstruction, sepsis, spinal cord injury, streptococcal bacteremia, syncope, T-cell lymphoma, thrombocytopenia and ureteric obstruction. Of the CTCL patients who received the 400-mg once daily dose, 9.3% (8/86) of patients discontinued vorinostat due to adverse reactions. These adverse reactions, regardless of causality, included anemia, angioneurotic edema, asthenia, chest pain, exfoliative dermatitis, death, deep vein thrombosis, ischemic stroke, lethargy, pulmonary embolism, and spinal cord injury. Of the CTCL patients who received the 400-mg once daily dose, 10.5% (9/86) of patients required a dose modification of vorinostat due to adverse reactions. These adverse reactions included increased serum creatinine, decreased appetite, hypokalemia, leukopenia, nausea, neutropenia, thrombocytopenia and vomiting. The median time to the first adverse reactions resulting in dose reduction was 42 days (range 17 to 263 days). Laboratory abnormalities were reported in all of the 86 CTCL patients who received the 400-mg once-daily dose. Increased serum glucose was reported as a laboratory abnormality in 69% (59/86) of CTCL patients who received the 400-mg once daily dose; only 4 of these abnormalities were severe (Grade 3). Increased serum glucose was reported as an adverse reaction in 8.1% (7/86) of CTCL patients who received the 400-mg once daily dose. Transient increases in serum creatinine were detected in 46.5% (40/86) of CTCL patients who received the 400-mg once daily dose. Of these laboratory abnormalities, 34 were NCI CTCAE Grade 1, 5 were Grade 2, and 1 was Grade 3. Proteinuria was detected as a laboratory abnormality (51.4%) in 38 of 74 patients tested. The clinical significance of this finding is unknown. Based on reports of dehydration as a serious drug-related adverse reaction in clinical trials, patients were instructed to drink at least 2 L/day of fluids for adequate hydration. The frequencies of individual adverse reactions were substantially higher in the non-CTCL population. Drug-related serious adverse reactions reported in the non-CTCL population which were not observed in the population included single events of blurred vision, asthenia, hyponatremia, tumor hemorrhage, Guillain-Barré syndrome, renal failure, urinary retention, cough, hemoptysis, hypertension, and vasculitis. In patients recovering from bowel surgery and treated perioperatively with vorinostat, anastomotic healing complications including fistulas, perforations, and abscess formation have occurred. ## Postmarketing Experience There is limited information regarding Vorinostat Postmarketing Experience in the drug label. # Drug Interactions ### Coumarin-Derivative Anticoagulants - Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving vorinostat concomitantly with coumarin-derivative anticoagulants. Physicians should monitor PT and INR more frequently in patients concurrently administered vorinostat and coumarin derivatives. ### Other HDAC Inhibitors - Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of vorinostat and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Vorinostat can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of vorinostat in pregnant women. Results of animal studies indicate that vorinostat crosses the placenta and is found in fetal plasma at levels up to 50% of maternal concentrations. Doses up to 50 and 150 mg/kg/day were tested in rats and rabbits, respectively (~0.5 times the human exposure based on AUC0-24 hours). Treatment-related, developmental effects including decreased mean live fetal weights, incomplete ossifications of the skull, thoracic vertebra, sternebra, and skeletal variations (cervical ribs, supernumerary ribs, vertebral count and sacral arch variations) in rats at the highest dose of vorinostat tested. Reductions in mean live fetal weight and an elevated incidence of incomplete ossification of the metacarpals were seen in rabbits dosed at 150 mg/kg/day. The no observed effect levels (NOELs) for these findings were 15 and 50 mg/kg/day (<0.1 times the human exposure based on AUC) in rats and rabbits, respectively. A dose-related increase in the incidence of malformations of the gall bladder was noted in all drug treatment groups in rabbits versus the concurrent control. 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. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vorinostat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Vorinostat during labor and delivery. ### Nursing Mothers It is not known whether this drug 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 vorinostat, 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 safety and effectiveness of vorinostat in pediatric patients have not been established. ### Geriatic Use Of the total number of patients with in trials (N=107), 46 % were 65 years of age and over, while 15 % were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals should be considered, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender Based upon an exploratory analysis of limited data, gender do not appear to have meaningful effects on the pharmacokinetics of vorinostat. ### Race Based upon an exploratory analysis of limited data, race do not appear to have meaningful effects on the pharmacokinetics of vorinostat. ### Renal Impairment Vorinostat was not evaluated in patients with renal impairment. However, renal excretion does not play a role in the elimination of vorinostat. Patients with pre-existing renal impairment should be treated with caution. ### Hepatic Impairment Vorinostat was studied in 42 patients with non-CTCL cancer and varying degrees of hepatic impairment after single and multiple-dose administration. Compared to patients with normal liver function, AUC increases of 50 to 66% were observed in patients with hepatic impairment. The incidence of Grade 3 or 4 thrombocytopenia increased in patients with mild (bilirubin of 1 to 1.5 × ULN and AST ULN) and moderate (bilirubin 1.5 to ≤ 3 × ULN) hepatic impairment treated daily at doses of 300 and 200 mg respectively. Patients with severe hepatic impairment (bilirubin > 3 × ULN) have not been treated at doses greater than 200 mg a day. Reduce the initial dose of vorinostat in patients with bilirubin 1 to 3 × ULN or AST > ULN. ### Females of Reproductive Potential and Males Effects on the female reproductive system were identified in the oral fertility study when females were dosed for 14 days prior to mating through gestational day 7. Doses of 15, 50 and 150 mg/kg/day to rats resulted in approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC. Dose dependent increases in corpora lutea were noted at ≥15 mg/kg/day, which resulted in increased peri-implantation losses were noted at ≥50 mg/kg/day. At 150 mg/kg/day, there were increases in the incidences of dead fetuses and in resorptions. No effects on reproductive performance were observed in male rats dosed (20, 50, 150 mg/kg/day; approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC), for 70 days prior to mating with untreated females. ### Immunocompromised Patients There is no FDA guidance one the use of Vorinostat in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - Obtain chemistry tests, including serum electrolytes, creatinine, magnesium, and calcium, every 2 weeks during the first 2 months of therapy and monthly thereafter. - Correct hypokalemia and hypomagnesemia prior to administration of vorinostat. - Monitor potassium and magnesium more frequently in symptomatic patients (e.g., patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms). # IV Compatibility There is limited information regarding the compatibility of Vorinostat and IV administrations. # Overdosage - No specific information is available on the treatment of overdosage of vorinostat. - In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. It is not known if vorinostat is dialyzable. # Pharmacology ## Mechanism of Action Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC50<86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity allows for the accumulation of acetyl groups on the histone lysine residues resulting in an open chromatin structure and transcriptional activation. In vitro, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized. ## Structure The empirical formula is C14H20N2O3. The molecular weight is 264.32 and the structural formula is: ## Pharmacodynamics A randomized, partially-blind, placebo-controlled, 2-period crossover study was performed to assess the effects of a single 800-mg dose of vorinostat on the QTc interval in 24 patients with advanced cancer. This study was conducted to assess the impact of vorinostat on ventricular repolarization. The upper bound of the 90% confidence interval of the placebo-adjusted mean QTc interval change-from-baseline was less than 10 msec at every time point through 24 hours. Based on these study results, administration of a single supratherapeutic 800-mg dose of vorinostat does not appear to prolong the QTc interval in patients with advanced cancer; however the study did not include a positive control to demonstrate assay sensitivity. In the fasted state, oral administration of a single 800-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of 8.6±5.7 μM∙hr and 1.7±0.67 μM and 2.1 (0.5-6) hours, respectively. In clinical studies in patients with CTCL, three of 86 CTCL patients exposed to 400 mg once daily had Grade 1 (>450-470 msec) or 2 (>470-500 msec or increase of >60 msec above baseline) clinical adverse reactions of QTc prolongation. In a retrospective analysis of three Phase 1 and two Phase 2 studies, 116 patients had a baseline and at least one follow-up ECG. Four patients had Grade 2 (>470-500 msec or increase of >60 msec above baseline) and 1 patient had Grade 3 (>500 msec) QTc prolongation. In 49 non-CTCL patients from 3 clinical trials who had complete evaluation of QT interval, 2 had QTc measurements of >500 msec and 1 had a QTc prolongation of >60 msec. ## Pharmacokinetics The pharmacokinetics of vorinostat were evaluated in 23 patients with relapsed or refractory advanced cancer. After oral administration of a single 400-mg dose of vorinostat with a high-fat meal, the mean ± standard deviation area under the curve (AUC) and peak serum concentration (Cmax) and the median (range) time to maximum concentration (Tmax) were 5.5±1.8 µM∙hr, 1.2±0.62 µM and 4 (2-10) hours, respectively. In the fasted state, oral administration of a single 400-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of 4.2±1.9 µM∙hr and 1.2±0.35 µM and 1.5 (0.5-10) hours, respectively. Therefore, oral administration of vorinostat with a high-fat meal resulted in an increase (33%) in the extent of absorption and a modest decrease in the rate of absorption (Tmax delayed 2.5 hours) compared to the fasted state. However, these small effects are not expected to be clinically meaningful. In clinical trials of patients with , vorinostat was taken with food. At steady state in the fed-state, oral administration of multiple 400-mg doses of vorinostat resulted in a mean AUC and Cmax and a median Tmax of 6.0±2.0 µM∙hr, 1.2±0.53 µM and 4 (0.5-14) hours, respectively. Vorinostat is approximately 71% bound to human plasma proteins over the range of concentrations of 0.5 to 50 µg/mL. The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively. In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. The mean urinary recovery of two pharmacologically inactive metabolites at steady state was 16±5.8% of vorinostat dose as the O‑glucuronide of vorinostat, and 36±8.6% of vorinostat dose as 4-anilino-4-oxobutanoic acid. Total urinary recovery of vorinostat and these two metabolites averaged 52±13.3% of vorinostat dose. The mean terminal half-life (t½) was ~2.0 hours for both vorinostat and the O-glucuronide metabolite, while that of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours. ## Nonclinical Toxicology Carcinogenicity studies have not been performed with vorinostat. Vorinostat was mutagenic in vitro in the bacterial reverse mutation assays (Ames test), caused chromosomal aberrations in vitro in Chinese hamster ovary(CHO) cells and increased the incidence of micro-nucleated erythrocytes when administered to mice (Mouse Micronucleus Assay). # Clinical Studies In two open-label clinical studies, patients with refractory have been evaluated to determine their response rate to oral vorinostat. One study was a single-arm clinical study and the other assessed several dosing regimens. In both studies, patients were treated until disease progression or intolerable toxicity. In an open-label, single-arm, multicenter non-randomized study, 74 patients with advanced CTCL were treated with vorinostat at a dose of 400 mg once daily. The primary endpoint was response rate to oral vorinostat in the treatment of skin disease in patients with advanced CTCL (Stage IIB and higher) who had progressive, persistent, or recurrent disease on or following two systemic therapies. Enrolled patients should have received, been intolerant to or not a candidate for bexarotene. Extent of skin disease was quantitatively assessed by investigators using a modified Severity Weighted Assessment Tool (SWAT). The investigator measured the percentage total body surface area (%TBSA) involvement separately for patches, plaques, and tumors within 12 body regions using the patient's palm as a "ruler". The total %TBSA for each lesion type was multiplied by a severity weighting factor (1=patch, 2=plaque and 4=tumor) and summed to derive the SWAT score. Efficacy was measured as either a Complete Clinical Response (CCR) defined as no evidence of disease, or Partial Response (PR) defined as a ≥50% decrease in SWAT skin assessment score compared to baseline. Both CCR and PR had to be maintained for at least 4 weeks. Secondary efficacy endpoints included response duration, time to progression, and time to objective response. The population had been exposed to a median of three prior therapies (range 1 to 12). TABLE 2 summarizes the demographic and disease characteristics of the Study 1 population. The overall objective response rate was 29.7% (22/74, 95% CI ) in all patients treated with vorinostat. In patients with Stage IIB and higher CTCL, the overall objective response rate was 29.5% (18/61). One patient with Stage IIB CTCL achieved a CCR. Median times to response were 55 and 56 days (range 28 to 171 days), respectively in the overall population and in patients with Stage IIB and higher CTCL. However, in rare cases it took up to 6 months for patients to achieve an objective response to vorinostat. The median response duration was not reached since the majority of responses continued at the time of analysis, but was estimated to exceed 6 months for both the overall population and in patients with Stage IIB and higher CTCL. When end of response was defined as a 50% increase in SWAT score from the nadir, the estimated median response duration was 168 days and the median time to tumor progression was 202 days. Using a 25% increase in SWAT score from the nadir as criterion for tumor progression, the estimated median time-to-progression was 148 days for the overall population and 169 days in the 61 patients with Stage IIB and higher CTCL. Response to any previous systemic therapy does not appear to be predictive of response to vorinostat. In an open-label, non-randomized study, vorinostat was evaluated to determine the response rate for patients with CTCL who were refractory or intolerant to at least one treatment. In this study, 33 patients were assigned to one of 3 cohorts: Cohort 1, 400 mg once daily; Cohort 2, 300 mg twice daily 3 days/week; or Cohort 3, 300 mg twice daily for 14 days followed by a 7-day rest (induction). In Cohort 3, if at least a partial response was not observed then patients were dosed with a maintenance regimen of 200 mg twice daily. The primary efficacy endpoint, objective response, was measured by the 7‑point Physician's Global Assessment (PGA) scale. The investigator assessed improvement or worsening in overall disease compared to baseline based on overall clinical impression. Index and non-index cutaneous lesions as well as cutaneous tumors, lymph nodes and all other disease manifestations were also assessed and included in the overall clinical impression. CCR required 100% clearing of all findings, and PR required at least 50% improvement in disease findings. The median age was 67.0 years (range 26.0 to 82.0). Fifty-five percent of patients were male, and 45% of patients were female. Fifteen percent of patients had Stage IA, IB, or IIA CTCL and 85% of patients had Stage IIB, III, IVA, or IVB CTCL. The median number of prior systemic therapies was 4 (range 0.0 to 11.0). In all patients treated, the objective response was 24.2% (8/33) in the overall population, 25% (7/28) in patients with Stage IIB or higher disease and 36.4% (4/11) in patients with Sezary syndrome. The overall response rates were 30.8%, 9.1% and 33.3% in Cohort 1, Cohort 2 and Cohort 3, respectively. The 300 mg twice daily regimen had higher toxicity with no additional clinical benefit over the 400 mg once daily regimen. No CCR was observed. Among the 8 patients who responded to study treatment, the median time to response was 83.5 days (range 25 to 153 days). The median response duration was 106 days (range 66 to 136 days). Median time to progression was 211.5 days (range 94 to 255 days). # How Supplied - Vorinostat capsules, 100 mg - Bottle with 120 capsules. - NDC 0006-0568-40. ## Storage Store at 20-25°C (68-77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be instructed to drink at least 2 L/day of fluid to prevent dehydration and should promptly report excessive vomiting or diarrhea to their physician. Patients should be instructed about the signs of deep vein thrombosis and should consult their physician should any evidence of deep vein thrombosis develop. Patients receiving vorinostat should seek immediate medical attention if unusual bleeding occurs. vorinostat capsules should not be opened or crushed. - Patients should be instructed to read the patient insert carefully. # Precautions with Alcohol Alcohol-Vorinostat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Zolinza # Look-Alike Drug Names There is limited information regarding Vorinostat Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Vorinostat Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]; Aparna Vuppala, M.B.B.S. [3] # 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 Vorinostat is a histone deacetylase inhibitor that is FDA approved for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. Common adverse reactions include diarrhea, fatigue, nausea, thrombocytopenia, anorexia and dysgeusia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Vorinostat is indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. - Dosage: 400 mg orally once daily with food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Vorinostat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vorinostat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness 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 Vorinostat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Vorinostat in pediatric patients. # Contraindications None # Warnings - Pulmonary embolism occurred in 5% (4/86) of patients receiving vorinostat, and deep vein thrombosis has also been reported. Monitor for signs and symptoms of these events, particularly in patients with a prior history of thromboembolic events. - Treatment with vorinostat can cause dose-related thrombocytopenia and anemia. Monitor blood counts every 2 weeks during the first 2 months of therapy and monthly thereafter. Adjust dosage or discontinue treatment with vorinostat as clinically appropriate. - Gastrointestinal disturbances, including nausea, vomiting and diarrhea, have been reported and may require the use of antiemetic and antidiarrheal medications. Fluid and electrolytes should be replaced to prevent dehydration. Pre-existing nausea, vomiting, and diarrhea should be adequately controlled before beginning therapy with vorinostat. - Hyperglycemia has been observed in patients receiving vorinostat and was severe in 5% (4/86) of patients. Monitor serum glucose every 2 weeks during the first 2 months of therapy and monthly thereafter. - Obtain chemistry tests, including serum electrolytes, creatinine, magnesium, and calcium, every 2 weeks during the first 2 months of therapy and monthly thereafter. Correct hypokalemia and hypomagnesemia prior to administration of vorinostat. Monitor potassium and magnesium more frequently in symptomatic patients (e.g., patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms). - Severe thrombocytopenia leading to gastrointestinal bleeding has been reported with concomitant use of vorinostat and other HDAC inhibitors (e.g., valproic acid). Monitor platelet counts more frequently. # Adverse Reactions ## Clinical Trials Experience The most common drug-related adverse reactions can be classified into 4 symptom complexes: gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease, vomiting, constipation), constitutional symptoms (fatigue, chills), hematologic abnormalities (thrombocytopenia, anemia), and taste disorders (dysgeusia, dry mouth). The most common serious drug-related adverse reactions were pulmonary embolism and anemia. 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 vorinostat was evaluated in 107 CTCL patients in two single arm clinical studies in which 86 patients received 400 mg once daily. The data described below reflect exposure to vorinostat 400 mg once daily in the 86 patients for a median number of 97.5 days on therapy (range 2 to 480+ days). Seventeen (19.8%) patients were exposed beyond 24 weeks and 8 (9.3%) patients were exposed beyond 1 year. The population of CTCL patients studied was 37 to 83 years of age, 47.7% female, 52.3% male, and 81.4% white, 16.3% black, and 1.2% Asian or multi-racial. TABLE 1 summarizes the frequency of CTCL patients with specific adverse reactions, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 3.0). The frequencies of more severe thrombocytopenia, anemia and fatigue were increased at doses higher than 400 mg once daily of vorinostat. The most common serious adverse reactions in the 86 CTCL patients in two clinical trials were pulmonary embolism reported in 4.7% (4/86) of patients, squamous cell carcinoma reported in 3.5% (3/86) of patients and anemia reported in 2.3% (2/86) of patients. There were single events of cholecystitis, death (of unknown cause), deep vein thrombosis, enterococcal infection, exfoliative dermatitis, gastrointestinal hemorrhage, infection, lobar pneumonia, myocardial infarction, ischemic stroke, pelviureteric obstruction, sepsis, spinal cord injury, streptococcal bacteremia, syncope, T-cell lymphoma, thrombocytopenia and ureteric obstruction. Of the CTCL patients who received the 400-mg once daily dose, 9.3% (8/86) of patients discontinued vorinostat due to adverse reactions. These adverse reactions, regardless of causality, included anemia, angioneurotic edema, asthenia, chest pain, exfoliative dermatitis, death, deep vein thrombosis, ischemic stroke, lethargy, pulmonary embolism, and spinal cord injury. Of the CTCL patients who received the 400-mg once daily dose, 10.5% (9/86) of patients required a dose modification of vorinostat due to adverse reactions. These adverse reactions included increased serum creatinine, decreased appetite, hypokalemia, leukopenia, nausea, neutropenia, thrombocytopenia and vomiting. The median time to the first adverse reactions resulting in dose reduction was 42 days (range 17 to 263 days). Laboratory abnormalities were reported in all of the 86 CTCL patients who received the 400-mg once-daily dose. Increased serum glucose was reported as a laboratory abnormality in 69% (59/86) of CTCL patients who received the 400-mg once daily dose; only 4 of these abnormalities were severe (Grade 3). Increased serum glucose was reported as an adverse reaction in 8.1% (7/86) of CTCL patients who received the 400-mg once daily dose. Transient increases in serum creatinine were detected in 46.5% (40/86) of CTCL patients who received the 400-mg once daily dose. Of these laboratory abnormalities, 34 were NCI CTCAE Grade 1, 5 were Grade 2, and 1 was Grade 3. Proteinuria was detected as a laboratory abnormality (51.4%) in 38 of 74 patients tested. The clinical significance of this finding is unknown. Based on reports of dehydration as a serious drug-related adverse reaction in clinical trials, patients were instructed to drink at least 2 L/day of fluids for adequate hydration. The frequencies of individual adverse reactions were substantially higher in the non-CTCL population. Drug-related serious adverse reactions reported in the non-CTCL population which were not observed in the population included single events of blurred vision, asthenia, hyponatremia, tumor hemorrhage, Guillain-Barré syndrome, renal failure, urinary retention, cough, hemoptysis, hypertension, and vasculitis. In patients recovering from bowel surgery and treated perioperatively with vorinostat, anastomotic healing complications including fistulas, perforations, and abscess formation have occurred. ## Postmarketing Experience There is limited information regarding Vorinostat Postmarketing Experience in the drug label. # Drug Interactions ### Coumarin-Derivative Anticoagulants - Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving vorinostat concomitantly with coumarin-derivative anticoagulants. Physicians should monitor PT and INR more frequently in patients concurrently administered vorinostat and coumarin derivatives. ### Other HDAC Inhibitors - Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of vorinostat and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Vorinostat can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of vorinostat in pregnant women. Results of animal studies indicate that vorinostat crosses the placenta and is found in fetal plasma at levels up to 50% of maternal concentrations. Doses up to 50 and 150 mg/kg/day were tested in rats and rabbits, respectively (~0.5 times the human exposure based on AUC0-24 hours). Treatment-related, developmental effects including decreased mean live fetal weights, incomplete ossifications of the skull, thoracic vertebra, sternebra, and skeletal variations (cervical ribs, supernumerary ribs, vertebral count and sacral arch variations) in rats at the highest dose of vorinostat tested. Reductions in mean live fetal weight and an elevated incidence of incomplete ossification of the metacarpals were seen in rabbits dosed at 150 mg/kg/day. The no observed effect levels (NOELs) for these findings were 15 and 50 mg/kg/day (<0.1 times the human exposure based on AUC) in rats and rabbits, respectively. A dose-related increase in the incidence of malformations of the gall bladder was noted in all drug treatment groups in rabbits versus the concurrent control. 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. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vorinostat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Vorinostat during labor and delivery. ### Nursing Mothers It is not known whether this drug 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 vorinostat, 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 safety and effectiveness of vorinostat in pediatric patients have not been established. ### Geriatic Use Of the total number of patients with in trials (N=107), 46 % were 65 years of age and over, while 15 % were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals should be considered, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender Based upon an exploratory analysis of limited data, gender do not appear to have meaningful effects on the pharmacokinetics of vorinostat. ### Race Based upon an exploratory analysis of limited data, race do not appear to have meaningful effects on the pharmacokinetics of vorinostat. ### Renal Impairment Vorinostat was not evaluated in patients with renal impairment. However, renal excretion does not play a role in the elimination of vorinostat. Patients with pre-existing renal impairment should be treated with caution. ### Hepatic Impairment Vorinostat was studied in 42 patients with non-CTCL cancer and varying degrees of hepatic impairment after single and multiple-dose administration. Compared to patients with normal liver function, AUC increases of 50 to 66% were observed in patients with hepatic impairment. The incidence of Grade 3 or 4 thrombocytopenia increased in patients with mild (bilirubin of 1 to 1.5 × ULN and AST < ULN, or bilirubin ≤ ULN and AST > ULN) and moderate (bilirubin 1.5 to ≤ 3 × ULN) hepatic impairment treated daily at doses of 300 and 200 mg respectively. Patients with severe hepatic impairment (bilirubin > 3 × ULN) have not been treated at doses greater than 200 mg a day. Reduce the initial dose of vorinostat in patients with bilirubin 1 to 3 × ULN or AST > ULN. ### Females of Reproductive Potential and Males Effects on the female reproductive system were identified in the oral fertility study when females were dosed for 14 days prior to mating through gestational day 7. Doses of 15, 50 and 150 mg/kg/day to rats resulted in approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC. Dose dependent increases in corpora lutea were noted at ≥15 mg/kg/day, which resulted in increased peri-implantation losses were noted at ≥50 mg/kg/day. At 150 mg/kg/day, there were increases in the incidences of dead fetuses and in resorptions. No effects on reproductive performance were observed in male rats dosed (20, 50, 150 mg/kg/day; approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC), for 70 days prior to mating with untreated females. ### Immunocompromised Patients There is no FDA guidance one the use of Vorinostat in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - Obtain chemistry tests, including serum electrolytes, creatinine, magnesium, and calcium, every 2 weeks during the first 2 months of therapy and monthly thereafter. - Correct hypokalemia and hypomagnesemia prior to administration of vorinostat. - Monitor potassium and magnesium more frequently in symptomatic patients (e.g., patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms). # IV Compatibility There is limited information regarding the compatibility of Vorinostat and IV administrations. # Overdosage - No specific information is available on the treatment of overdosage of vorinostat. - In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. It is not known if vorinostat is dialyzable. # Pharmacology ## Mechanism of Action Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC50<86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity allows for the accumulation of acetyl groups on the histone lysine residues resulting in an open chromatin structure and transcriptional activation. In vitro, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized. ## Structure The empirical formula is C14H20N2O3. The molecular weight is 264.32 and the structural formula is: ## Pharmacodynamics A randomized, partially-blind, placebo-controlled, 2-period crossover study was performed to assess the effects of a single 800-mg dose of vorinostat on the QTc interval in 24 patients with advanced cancer. This study was conducted to assess the impact of vorinostat on ventricular repolarization. The upper bound of the 90% confidence interval of the placebo-adjusted mean QTc interval change-from-baseline was less than 10 msec at every time point through 24 hours. Based on these study results, administration of a single supratherapeutic 800-mg dose of vorinostat does not appear to prolong the QTc interval in patients with advanced cancer; however the study did not include a positive control to demonstrate assay sensitivity. In the fasted state, oral administration of a single 800-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of 8.6±5.7 μM∙hr and 1.7±0.67 μM and 2.1 (0.5-6) hours, respectively. In clinical studies in patients with CTCL, three of 86 CTCL patients exposed to 400 mg once daily had Grade 1 (>450-470 msec) or 2 (>470-500 msec or increase of >60 msec above baseline) clinical adverse reactions of QTc prolongation. In a retrospective analysis of three Phase 1 and two Phase 2 studies, 116 patients had a baseline and at least one follow-up ECG. Four patients had Grade 2 (>470-500 msec or increase of >60 msec above baseline) and 1 patient had Grade 3 (>500 msec) QTc prolongation. In 49 non-CTCL patients from 3 clinical trials who had complete evaluation of QT interval, 2 had QTc measurements of >500 msec and 1 had a QTc prolongation of >60 msec. ## Pharmacokinetics The pharmacokinetics of vorinostat were evaluated in 23 patients with relapsed or refractory advanced cancer. After oral administration of a single 400-mg dose of vorinostat with a high-fat meal, the mean ± standard deviation area under the curve (AUC) and peak serum concentration (Cmax) and the median (range) time to maximum concentration (Tmax) were 5.5±1.8 µM∙hr, 1.2±0.62 µM and 4 (2-10) hours, respectively. In the fasted state, oral administration of a single 400-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of 4.2±1.9 µM∙hr and 1.2±0.35 µM and 1.5 (0.5-10) hours, respectively. Therefore, oral administration of vorinostat with a high-fat meal resulted in an increase (33%) in the extent of absorption and a modest decrease in the rate of absorption (Tmax delayed 2.5 hours) compared to the fasted state. However, these small effects are not expected to be clinically meaningful. In clinical trials of patients with , vorinostat was taken with food. At steady state in the fed-state, oral administration of multiple 400-mg doses of vorinostat resulted in a mean AUC and Cmax and a median Tmax of 6.0±2.0 µM∙hr, 1.2±0.53 µM and 4 (0.5-14) hours, respectively. Vorinostat is approximately 71% bound to human plasma proteins over the range of concentrations of 0.5 to 50 µg/mL. The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively. In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. The mean urinary recovery of two pharmacologically inactive metabolites at steady state was 16±5.8% of vorinostat dose as the O‑glucuronide of vorinostat, and 36±8.6% of vorinostat dose as 4-anilino-4-oxobutanoic acid. Total urinary recovery of vorinostat and these two metabolites averaged 52±13.3% of vorinostat dose. The mean terminal half-life (t½) was ~2.0 hours for both vorinostat and the O-glucuronide metabolite, while that of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours. ## Nonclinical Toxicology Carcinogenicity studies have not been performed with vorinostat. Vorinostat was mutagenic in vitro in the bacterial reverse mutation assays (Ames test), caused chromosomal aberrations in vitro in Chinese hamster ovary(CHO) cells and increased the incidence of micro-nucleated erythrocytes when administered to mice (Mouse Micronucleus Assay). # Clinical Studies In two open-label clinical studies, patients with refractory have been evaluated to determine their response rate to oral vorinostat. One study was a single-arm clinical study and the other assessed several dosing regimens. In both studies, patients were treated until disease progression or intolerable toxicity. In an open-label, single-arm, multicenter non-randomized study, 74 patients with advanced CTCL were treated with vorinostat at a dose of 400 mg once daily. The primary endpoint was response rate to oral vorinostat in the treatment of skin disease in patients with advanced CTCL (Stage IIB and higher) who had progressive, persistent, or recurrent disease on or following two systemic therapies. Enrolled patients should have received, been intolerant to or not a candidate for bexarotene. Extent of skin disease was quantitatively assessed by investigators using a modified Severity Weighted Assessment Tool (SWAT). The investigator measured the percentage total body surface area (%TBSA) involvement separately for patches, plaques, and tumors within 12 body regions using the patient's palm as a "ruler". The total %TBSA for each lesion type was multiplied by a severity weighting factor (1=patch, 2=plaque and 4=tumor) and summed to derive the SWAT score. Efficacy was measured as either a Complete Clinical Response (CCR) defined as no evidence of disease, or Partial Response (PR) defined as a ≥50% decrease in SWAT skin assessment score compared to baseline. Both CCR and PR had to be maintained for at least 4 weeks. Secondary efficacy endpoints included response duration, time to progression, and time to objective response. The population had been exposed to a median of three prior therapies (range 1 to 12). TABLE 2 summarizes the demographic and disease characteristics of the Study 1 population. The overall objective response rate was 29.7% (22/74, 95% CI [19.7 to 41.5%]) in all patients treated with vorinostat. In patients with Stage IIB and higher CTCL, the overall objective response rate was 29.5% (18/61). One patient with Stage IIB CTCL achieved a CCR. Median times to response were 55 and 56 days (range 28 to 171 days), respectively in the overall population and in patients with Stage IIB and higher CTCL. However, in rare cases it took up to 6 months for patients to achieve an objective response to vorinostat. The median response duration was not reached since the majority of responses continued at the time of analysis, but was estimated to exceed 6 months for both the overall population and in patients with Stage IIB and higher CTCL. When end of response was defined as a 50% increase in SWAT score from the nadir, the estimated median response duration was 168 days and the median time to tumor progression was 202 days. Using a 25% increase in SWAT score from the nadir as criterion for tumor progression, the estimated median time-to-progression was 148 days for the overall population and 169 days in the 61 patients with Stage IIB and higher CTCL. Response to any previous systemic therapy does not appear to be predictive of response to vorinostat. In an open-label, non-randomized study, vorinostat was evaluated to determine the response rate for patients with CTCL who were refractory or intolerant to at least one treatment. In this study, 33 patients were assigned to one of 3 cohorts: Cohort 1, 400 mg once daily; Cohort 2, 300 mg twice daily 3 days/week; or Cohort 3, 300 mg twice daily for 14 days followed by a 7-day rest (induction). In Cohort 3, if at least a partial response was not observed then patients were dosed with a maintenance regimen of 200 mg twice daily. The primary efficacy endpoint, objective response, was measured by the 7‑point Physician's Global Assessment (PGA) scale. The investigator assessed improvement or worsening in overall disease compared to baseline based on overall clinical impression. Index and non-index cutaneous lesions as well as cutaneous tumors, lymph nodes and all other disease manifestations were also assessed and included in the overall clinical impression. CCR required 100% clearing of all findings, and PR required at least 50% improvement in disease findings. The median age was 67.0 years (range 26.0 to 82.0). Fifty-five percent of patients were male, and 45% of patients were female. Fifteen percent of patients had Stage IA, IB, or IIA CTCL and 85% of patients had Stage IIB, III, IVA, or IVB CTCL. The median number of prior systemic therapies was 4 (range 0.0 to 11.0). In all patients treated, the objective response was 24.2% (8/33) in the overall population, 25% (7/28) in patients with Stage IIB or higher disease and 36.4% (4/11) in patients with Sezary syndrome. The overall response rates were 30.8%, 9.1% and 33.3% in Cohort 1, Cohort 2 and Cohort 3, respectively. The 300 mg twice daily regimen had higher toxicity with no additional clinical benefit over the 400 mg once daily regimen. No CCR was observed. Among the 8 patients who responded to study treatment, the median time to response was 83.5 days (range 25 to 153 days). The median response duration was 106 days (range 66 to 136 days). Median time to progression was 211.5 days (range 94 to 255 days). # How Supplied - Vorinostat capsules, 100 mg - Bottle with 120 capsules. - NDC 0006-0568-40. ## Storage Store at 20-25°C (68-77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be instructed to drink at least 2 L/day of fluid to prevent dehydration and should promptly report excessive vomiting or diarrhea to their physician. Patients should be instructed about the signs of deep vein thrombosis and should consult their physician should any evidence of deep vein thrombosis develop. Patients receiving vorinostat should seek immediate medical attention if unusual bleeding occurs. vorinostat capsules should not be opened or crushed. - Patients should be instructed to read the patient insert carefully. # Precautions with Alcohol Alcohol-Vorinostat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Zolinza [1] # Look-Alike Drug Names There is limited information regarding Vorinostat Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Suberoylanilide_hydroxamic_acid
f88b9245aabca57a9d3d32d23ab4c6d15f061aa4	wikidoc	Sublingual	Sublingual Sublingual, literally 'under the tongue', from Latin, refers to a pharmacological route of administration in which certain drugs are entered directly into the bloodstream via absorption under the tongue. Many pharmaceuticals are prepared for sublingual administration. These commonly include cardiovascular drugs, steroids, barbiturates, some enzymes and increasingly frequently, certain vitamins and minerals. # Principle The principle behind sublingual administration is fairly simple. When a chemical comes in contact with the mucous membrane, or buccal mucosa, it diffuses into the epithelium beneath the tongue. This region contains a high density of blood vessels, and as a result, via diffusion, the substance quickly enters the venous circulation, which returns to the heart and then travels to the systemic arterial circulation. In contrast, substances absorbed by the bowel are subject to "first pass metabolism" in the liver before they are distributed to the rest of the body. In theory, sublingual routes of administration have certain advantages over simple oral administration. This route is often faster, and entering a drug into one's body sublingually ensures that the substance will only come in contact with the enzymes in saliva prior to entry into the bloodstream. Drugs otherwise orally administered must instead survive the incredibly hostile environment of the gastrointestinal tract. This may mean a much greater percentage of the original substance is degraded either by the myriad of enzymes in the GI tract, such as monoamine oxidase, or the strong acids it contains. Additionally, after GI absorption, the drug is sent to the liver where the drug may be extensively metabolized; this is known as the first pass effect of drug metabolism. Due to the degradative qualities of the stomach and intestine, or the solubility of the GI tract, certain substances, such as salvinorin A may only be administered orally via the sublingual route. Because of its size and relative fragility, salvinorin A cannot pass the GI tract intact and must instead be absorbed across a mucous membrane. # Substance Almost any form of substance is appropriate for sublingual administration, so long as in that form the substance can readily enter into solution with the saliva in the mouth. Chemicals prepared as powders, solutions, or even aerosol sprays may all make use of this method. However, a number of factors, such as pH, molecular weight, and lipid solubility (to name just a few) of a substance may determine whether the route is practical or not. Based on these properties, it is entirely possible that a drug, which will readily become a solution with saliva, simply diffuses too slowly (or not at all) in the buccal mucosa to be effective. # Psychoactives In addition to Salvinorin A, other psychoactives may too be applied sublingually. LSD, MDMA, morphine, alprazolam and many other drugs including the psychedelic tryptamines and phenethylamines are all viable candidates for administration via this route. Most often, the drug in question is powdered and placed in the mouth (often directly under the tongue). If held there long enough, the drug will diffuse into the blood stream, bypassing the GI tract. This is definitely a preferred method to simple oral administration, because MAO is known to oxidize many drugs (especially the tryptamines such as DMT) and because this route translates the chemical directly to the brain, where most psychoactives act. However, this method is severely limited because only a small amount of the substance can be entered in this way, and often a large amount remains to be swallowed. Also, many alkaloids have a repulsive taste which makes them difficult to hold in the mouth. # Allergens Allergens may also be applied under the tongue, and the FDA is reviewing this method of allergen immunotherapy but it is not yet approved in the US. Roder published recent work showing sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care. # Footnotes - ↑ Roder (2007). "". J Allergy Clin Immunol. 119 (4): 892–8. PMID 17321581..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}	Sublingual Sublingual, literally 'under the tongue', from Latin, refers to a pharmacological route of administration in which certain drugs are entered directly into the bloodstream via absorption under the tongue. Many pharmaceuticals are prepared for sublingual administration. These commonly include cardiovascular drugs, steroids, barbiturates, some enzymes and increasingly frequently, certain vitamins and minerals. # Principle The principle behind sublingual administration is fairly simple. When a chemical comes in contact with the mucous membrane, or buccal mucosa, it diffuses into the epithelium beneath the tongue. This region contains a high density of blood vessels, and as a result, via diffusion, the substance quickly enters the venous circulation, which returns to the heart and then travels to the systemic arterial circulation. In contrast, substances absorbed by the bowel are subject to "first pass metabolism" in the liver before they are distributed to the rest of the body. In theory, sublingual routes of administration have certain advantages over simple oral administration. This route is often faster, and entering a drug into one's body sublingually ensures that the substance will only come in contact with the enzymes in saliva prior to entry into the bloodstream. Drugs otherwise orally administered must instead survive the incredibly hostile environment of the gastrointestinal tract. This may mean a much greater percentage of the original substance is degraded either by the myriad of enzymes in the GI tract, such as monoamine oxidase, or the strong acids it contains. Additionally, after GI absorption, the drug is sent to the liver where the drug may be extensively metabolized; this is known as the first pass effect of drug metabolism. Due to the degradative qualities of the stomach and intestine, or the solubility of the GI tract, certain substances, such as salvinorin A may only be administered orally via the sublingual route. Because of its size and relative fragility, salvinorin A cannot pass the GI tract intact and must instead be absorbed across a mucous membrane. # Substance Almost any form of substance is appropriate for sublingual administration, so long as in that form the substance can readily enter into solution with the saliva in the mouth. Chemicals prepared as powders, solutions, or even aerosol sprays may all make use of this method. However, a number of factors, such as pH, molecular weight, and lipid solubility (to name just a few) of a substance may determine whether the route is practical or not. Based on these properties, it is entirely possible that a drug, which will readily become a solution with saliva, simply diffuses too slowly (or not at all) in the buccal mucosa to be effective. # Psychoactives In addition to Salvinorin A, other psychoactives may too be applied sublingually. LSD, MDMA, morphine, alprazolam and many other drugs including the psychedelic tryptamines and phenethylamines are all viable candidates for administration via this route. Most often, the drug in question is powdered and placed in the mouth (often directly under the tongue). If held there long enough, the drug will diffuse into the blood stream, bypassing the GI tract. This is definitely a preferred method to simple oral administration, because MAO is known to oxidize many drugs (especially the tryptamines such as DMT) and because this route translates the chemical directly to the brain, where most psychoactives act. However, this method is severely limited because only a small amount of the substance can be entered in this way, and often a large amount remains to be swallowed. Also, many alkaloids have a repulsive taste which makes them difficult to hold in the mouth. # Allergens Allergens may also be applied under the tongue, and the FDA is reviewing this method of allergen immunotherapy but it is not yet approved in the US. Roder published recent work showing sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care.[1] # Footnotes - ↑ Roder (2007). "[sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care]". J Allergy Clin Immunol. 119 (4): 892–8. PMID 17321581..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} # External links - More info on the sublingual absorption of xanax - Sublingual+Drug+Administration at the US National Library of Medicine Medical Subject Headings (MeSH) de:Sublingual nl:Sublinguale toediening	https://www.wikidoc.org/index.php/Sublingual
1b93c9c294e5e8e49b79b588a79244e75dd3df8b	wikidoc	Sufentanil	Sufentanil # 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 Sufentanil is a analgesic opioid that is FDA approved for the {{{indicationType}}} of analgesia in labor, epidural; adjunct, general anesthesia. Common adverse reactions include cardiovascular: bradyarrhythmia (3% to 9% ), hypotension (3% to 9% ), dermatologic: pruritus (25% ), gastrointestinal: nausea (3% to 9% ), vomiting (3% to 9% ), musculoskeletal: muscle rigidity, chest wall (3% to 9% ), neurologic: somnolence (3% to 9% ). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosage should be individualized - Analgesia in labor, epidural; adjunct: (epidural use) 10-15 mcg sufentanil administered with 10 mL bupivacaine 0.125% with or without epinephrine; may repeat twice at not less than 1 hr intervals until delivery; max 3 doses - General anesthesia: primary anesthetic agent, 8-30 mcg/kg IV with 100% oxygen and a muscle relaxant, then 0.5-10 mcg/kg as needed in response to signs of lightening of anesthesia; max 30 mcg/kg/procedure - General anesthesia: analgesic adjunct to balanced general anesthesia, 1-8 mcg/kg IV (approximately 1 mcg/kg/hr of estimated surgical duration); 75% given prior to intubation, then incrementally as 10-50 mcg IV as needed in response to signs of lightening of analgesia ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Sufentanil in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Sufentanil in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - General anesthesia: cardiovascular surgery (age under 12 yr) 10-25 mcg/kg with 100% oxygen, additional doses up to 25-50 mcg for maintenance of anesthesia ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Sufentanil in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Sufentanil in pediatric patients. # Contraindications - Sufentanil is contraindicated in patients with known hypersensitivity to the drug or known intolerance to other opioid agonists. # Warnings - Sufentanil should be administered only by persons specifically trained in the use of intravenous and epidural anesthetics and management of the respiratory effects of potent opioids. - An opioid antagonist, resuscitative and intubation equipment and oxygen should be readily available. - Prior to catheter insertion, the physician should be familiar with patient conditions (such as infection at the injection site, bleeding diathesis, anticoagulant therapy, etc.) which call for special evaluation of the benefit versus risk potential. - Intravenous administration or unintentional intravascular injection during epidural administration of Sufentanil may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is dose related. Administration of Sufentanil may produce muscular rigidity with a more rapid onset of action than that seen with fentanyl. Sufentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. As with fentanyl, muscular rigidity has been reported to occur or recur infrequently in the extended postoperative period. The incidence of muscular rigidity associated with intravenous Sufentanil can be reduced by: 1) administration of up to 1/4 of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent just prior to administration of Sufentanil at dosages of up to 8 mcg/kg, 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of consciousness when Sufentanil is used in anesthetic dosages (above 8 mcg/kg) titrated by slow intravenous infusion, or, 3) simultaneous administration of Sufentanil and a full paralyzing dose of a neuromuscular blocking agent when Sufentanil is used in rapidly administered anesthetic dosages (above 8 mcg/kg). - The neuromuscular blocking agents used should be compatible with the patient's cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered Sufentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. # Adverse Reactions ## Clinical Trials Experience - The most common adverse reactions of opioids are respiratory depression and skeletal muscle rigidity, particularly of the truncal muscles. Sufentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. See Clinical Pharmacology, Warnings And Precautions on the management of respiratory depression and skeletal muscle rigidity. Urinary retention has been associated with the use of epidural opioids but was not reported in the clinical trials of epidurally administered Sufentanill due to the use of indwelling catheters. The incidence of urinary retention in patients without urinary catheters receiving epidural Sufentanil is unknown; return of normal bladder activity may be delayed. - The following adverse reaction information is derived from controlled clinical trials in 320 patients who received intravenous Sufentanil during surgical anesthesia and in 340 patients who received epidural Sufentanil plus bupivacaine 0.125% for analgesia during labor and is presented below. Based on the observed frequency, none of the reactions occurring with an incidence less than 1% were observed during clinical trials of epidural Sufentanil used during labor and delivery (N=340). - In general cardiovascular and musculoskeletal adverse experiences were not observed in clinical trials of epidural Sufentanilnil. Hypotension was observed 7 times more frequently in intravenous trials than in epidural trials. The incidence of central nervous system, dermatological and gastrointestinal adverse experiences was approximately 4 to 25 times higher in studies of epidural use in labor and delivery. - Probably Causally Related: Incidence Greater than 1% - Derived from clinical trials (See preceding paragraph) - Cardiovascular: bradycardia, hypertension, hypotension. - Musculoskeletal: chest wall rigidity. - Central Nervous System: somnolence. - Dermatological: pruritus (25%). - Gastrointestinal: nausea, vomiting. - Probably Causally Related: Incidence Less than 1% - Derived from clinical trials (Adverse events reported in post-marketing surveillance, not seen in clinical trials, are italicized.) - Body as a whole: anaphylaxis. - Cardiovascular: arrhythmia, tachycardia, cardiac arrest. - Central Nervous System: chills. - Dermatological: erythema. - Musculoskeletal: skeletal muscle rigidity of neck and extremities. - Respiratory: apnea, bronchospasm, postoperative respiratory depression. - Miscellaneous: intraoperative muscle movement. ## Postmarketing Experience There is limited information regarding Sufentanil Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Sufentanil Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Sufentanil has been shown to have an embryocidal effect in rats and rabbits when given in doses 2.5 times the upper human intravenous dose for a period of 10 days to over 30 days. These effects were most probably due to maternal toxicity (decreased food consumption with increased mortality) following prolonged administration of the drug. - No evidence of teratogenic effects have been observed after administration of Sufentanil in rats or rabbits. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sufentanil in women who are pregnant. ### Labor and Delivery - The use of epidurally administered Sufentanil in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery. (See Indications and Usage and Dosage and Administration sections.) Sufentanil is not recommended for intravenous use or for use of larger epidural doses during labor and delivery because of potential risks to the newborn infant after delivery. - In clinical trials, one case of severe fetal bradycardia associated with maternal hypotension was reported within 8 minutes of maternal administration of Sufentanilnil 15 mcg plus bupivacaine 0.125% (10 mL total volume). ### Nursing Mothers - It is not known whether Sufentanil is excreted in human milk. Because fentanyl analogs are excreted in human milk, caution should be exercised when Sufentanil is administered to a nursing woman. ### Pediatric Use - The safety and efficacy of intravenous Sufentanil in pediatric patients as young as 1 day old undergoing cardiovascular surgery have been documented in a limited number of cases. The clearance of Sufentanil in healthy neonates is approximately one-half that in adults and children. The clearance rate of Sufentanil can be further reduced by up to a third in neonates with cardiovascular disease, resulting in an increase in the elimination half-life of the drug. ### Geriatic Use There is no FDA guidance on the use of Sufentanil in geriatric settings. ### Gender There is no FDA guidance on the use of Sufentanil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sufentanil with respect to specific racial populations. ### Renal Impairment - In patients with liver or kidney dysfunction, Sufentanil should be administered with caution due to the importance of these organs in the metabolism and excretion of Sufentanil ### Hepatic Impairment - In patients with liver or kidney dysfunction, Sufentanil should be administered with caution due to the importance of these organs in the metabolism and excretion of Sufentanil ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sufentanil in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sufentanil in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Sufentanil Administration in the drug label. ### Monitoring There is limited information regarding Sufentanil Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Sufentanil and IV administrations. # Overdosage - Overdosage is manifested by an extension of the pharmacological actions of Sufentanil (see CLINICAL PHARMACOLOGY) as with other potent opioid analgesics. The most serious and significant effect of overdose for both intravenous and epidural administration of Sufentanil is respiratory depression. Intravenous administration of an opioid antagonist such as naloxone should be employed as a specific antidote to manage respiratory depression. The duration of respiratory depression following overdosage with Sufentanil may be longer than the duration of action of the opioid antagonist. Administration of an opioid antagonist should not preclude more immediate countermeasures. In the event of overdosage, oxygen should be administered and ventilation assisted or controlled as indicated for hypoventilation or apnea. A patent airway must be maintained, and a nasopharyngeal airway or endotracheal tube may be indicated. If depressed respiration is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressors for the treatment of hypotension and other supportive measures may be employed. # Pharmacology ## Mechanism of Action - Sufentanil is an opioid analgesic. When used in balanced general anesthesia, Sufentanil has been reported to be as much as 10 times as potent as fentanyl. When administered intravenously as a primary anesthetic agent with 100% oxygen, Sufentanil is approximately 5 to 7 times as potent as fentanyl. - Assays of histamine in patients administered Sufentanil have shown no elevation in plasma histamine levels and no indication of histamine release. (See dosage chart for more complete information on the intravenous use of Sufentanil.) ## Structure - SUFENTA® (sufentanil citrate) is a potent opioid analgesic chemically designated as N--4-piperidinyl]-N-phenylpropanamide:2-hydroxy-1,2,3-propanetricarboxylate (1:1) with a molecular weight of 578.68. The structural formula of SUFENTA is: - SUFENTA is a sterile, preservative free, aqueous solution containing sufentanil citrate equivalent to 50 mcg per mL of sufentanil base for intravenous and epidural injection. The solution has a pH range of 3.5 to 6.0. ## Pharmacodynamics - At intravenous doses of up to 8 mcg/kg, Sufentanil is an analgesic component of general anesthesia; at intravenous doses ≥8 mcg/kg, Sufentanil produces a deep level of anesthesia. Sufentanil produces a dose related attenuation of catecholamine release, particularly norepinephrine. - At intravenous dosages of ≥8 mcg/kg, Sufentanil produces hypnosis and anesthesia without the use of additional anesthetic agents. A deep level of anesthesia is maintained at these dosages, as demonstrated by EEG patterns. Dosages of up to 25 mcg/kg attenuate the sympathetic response to surgical stress. The catecholamine response, particularly norepinephrine, is further attenuated at doses of Sufentanil of 25 to 30 mcg/kg, with hemodynamic stability and preservation of favorable myocardial oxygen balance. - Sufentanil has an immediate onset of action, with relatively limited accumulation. Rapid elimination from tissue storage sites allows for relatively more rapid recovery as compared with equipotent dosages of fentanyl. At dosages of 1 to 2 mcg/kg, recovery times are comparable to those observed with fentanyl; at dosages of >2 to 6 mcg/kg, recovery times are comparable to enflurane, isoflurane and fentanyl. Within the anesthetic dosage range of 8 to 30 mcg/kg of Sufentanil, recovery times are more rapid compared to equipotent fentanyl dosages. - The vagolytic effects of pancuronium may produce a dose dependent elevation in heart rate during Sufentanil-oxygen anesthesia. The use of moderate doses of pancuronium or of a less vagolytic neuromuscular blocking agent may be used to maintain a stable lower heart rate and blood pressure during Sufentanil-oxygen anesthesia. The vagolytic effects of pancuronium may be reduced in patients administered nitrous oxide with Sufentanil. - Preliminary data suggest that in patients administered high doses of Sufentanil, initial dosage requirements for neuromuscular blocking agents are generally lower as compared to patients given fentanyl or halothane, and comparable to patients given enflurane. - Bradycardia is infrequently seen in patients administered Sufentanil-oxygen anesthesia. The use of nitrous oxide with high doses of Sufentanil may decrease mean arterial pressure, heart rate and cardiac output. - Sufentanil at 20 mcg/kg has been shown to provide more adequate reduction in intracranial volume than equivalent doses of fentanyl, based upon requirements for furosemide and anesthesia supplementation in one study of patients undergoing craniotomy. During carotid endarterectomy, Sufentanil-nitrous oxide/oxygen produced reductions in cerebral blood flow comparable to those of enflurane-nitrous oxide/oxygen. During cardiovascular surgery, Sufentanil-oxygen produced EEG patterns similar to fentanyl-oxygen; these EEG changes were judged to be compatible with adequate general anesthesia. - The intraoperative use of Sufentanil at anesthetic dosages maintains cardiac output, with a slight reduction in systemic vascular resistance during the initial postoperative period. The incidence of postoperative hypertension, need for vasoactive agents and requirements for postoperative analgesics are generally reduced in patients administered moderate or high doses of Sufentanil as compared to patients given inhalation agents. - Skeletal muscle rigidity is related to the dose and speed of administration of Sufentanil. This muscular rigidity may occur unless preventative measures are taken (see Warnings). - Decreased respiratory drive and increased airway resistance occur with Sufentanil. The duration and degree of respiratory depression are dose related when Sufentanil is used at sub-anesthetic dosages. At high doses, a pronounced decrease in pulmonary exchange and apnea may be produced. - Onset of analgesic effect occurs within approximately 10 minutes of administration of epidural doses of Sufentanil and bupivacaine. Duration of analgesia following a single epidural injection of 10 to 15 mcg Sufentanil and bupivacaine 0.125% averaged 1.7 hours. - During labor and vaginal delivery, the addition of 10 to 15 mcg Sufentanil to 10 mL 0.125% bupivacaine provides an increase in the duration of analgesia compared to bupivacaine without an opioid. Analgesia from 15 mcg Sufentanil plus 10 mL 0.125% bupivacaine is comparable to analgesia from 10 mL of 0.25% bupivacaine alone. Apgar scores of neonates following epidural administration of both drugs to women in labor were comparable to neonates whose mothers received bupivacaine without an opioid epidurally. ## Pharmacokinetics - The pharmacokinetics of intravenous Sufentanil can be described as a three-compartment model, with a distribution time of 1.4 minutes, redistribution of 17.1 minutes and elimination half-life of 164 minutes in adults. The elimination half-life of Sufentanil is shorter (e.g. 97 +/- 42 minutes) in infants and children, and longer in neonates (e.g. 434 +/- 160 minutes) compared to that of adolescents and adults. The liver and small intestine are the major sites of biotransformation. Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug. Plasma protein binding of Sufentanil, related to the alpha acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates. - After epidural administration of incremental doses totaling 5 to 40 mcg Sufentanil during labor and delivery, maternal and neonatal Sufentanil plasma concentrations were at or near the 0.05 to 0.1 ng/mL limit of detection, and were slightly higher in mothers than in their infants. ## Nonclinical Toxicology There is limited information regarding Sufentanil Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Sufentanil Clinical Studies in the drug label. # How Supplied - SUFENTA (Sufentanil Citrate Injection, USP) is supplied as a sterile aqueous preservative-free solution for intravenous and epidural use as: ## Storage - Store at 20° to 25°C (68° to 77°F). . PROTECT FROM LIGHT. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Sufentanil Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Sufentanil 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 Sufentanil Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Sufentanil Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Sufentanil Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, 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. # Overview Sufentanil is a analgesic opioid that is FDA approved for the {{{indicationType}}} of analgesia in labor, epidural; adjunct, general anesthesia. Common adverse reactions include cardiovascular: bradyarrhythmia (3% to 9% ), hypotension (3% to 9% ), dermatologic: pruritus (25% ), gastrointestinal: nausea (3% to 9% ), vomiting (3% to 9% ), musculoskeletal: muscle rigidity, chest wall (3% to 9% ), neurologic: somnolence (3% to 9% ). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosage should be individualized - Analgesia in labor, epidural; adjunct: (epidural use) 10-15 mcg sufentanil administered with 10 mL bupivacaine 0.125% with or without epinephrine; may repeat twice at not less than 1 hr intervals until delivery; max 3 doses - General anesthesia: primary anesthetic agent, 8-30 mcg/kg IV with 100% oxygen and a muscle relaxant, then 0.5-10 mcg/kg as needed in response to signs of lightening of anesthesia; max 30 mcg/kg/procedure - General anesthesia: analgesic adjunct to balanced general anesthesia, 1-8 mcg/kg IV (approximately 1 mcg/kg/hr of estimated surgical duration); 75% given prior to intubation, then incrementally as 10-50 mcg IV as needed in response to signs of lightening of analgesia ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Sufentanil in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Sufentanil in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - General anesthesia: cardiovascular surgery (age under 12 yr) 10-25 mcg/kg with 100% oxygen, additional doses up to 25-50 mcg for maintenance of anesthesia ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Sufentanil in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Sufentanil in pediatric patients. # Contraindications - Sufentanil is contraindicated in patients with known hypersensitivity to the drug or known intolerance to other opioid agonists. # Warnings - Sufentanil should be administered only by persons specifically trained in the use of intravenous and epidural anesthetics and management of the respiratory effects of potent opioids. - An opioid antagonist, resuscitative and intubation equipment and oxygen should be readily available. - Prior to catheter insertion, the physician should be familiar with patient conditions (such as infection at the injection site, bleeding diathesis, anticoagulant therapy, etc.) which call for special evaluation of the benefit versus risk potential. - Intravenous administration or unintentional intravascular injection during epidural administration of Sufentanil may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is dose related. Administration of Sufentanil may produce muscular rigidity with a more rapid onset of action than that seen with fentanyl. Sufentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. As with fentanyl, muscular rigidity has been reported to occur or recur infrequently in the extended postoperative period. The incidence of muscular rigidity associated with intravenous Sufentanil can be reduced by: 1) administration of up to 1/4 of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent just prior to administration of Sufentanil at dosages of up to 8 mcg/kg, 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of consciousness when Sufentanil is used in anesthetic dosages (above 8 mcg/kg) titrated by slow intravenous infusion, or, 3) simultaneous administration of Sufentanil and a full paralyzing dose of a neuromuscular blocking agent when Sufentanil is used in rapidly administered anesthetic dosages (above 8 mcg/kg). - The neuromuscular blocking agents used should be compatible with the patient's cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered Sufentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. # Adverse Reactions ## Clinical Trials Experience - The most common adverse reactions of opioids are respiratory depression and skeletal muscle rigidity, particularly of the truncal muscles. Sufentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. See Clinical Pharmacology, Warnings And Precautions on the management of respiratory depression and skeletal muscle rigidity. Urinary retention has been associated with the use of epidural opioids but was not reported in the clinical trials of epidurally administered Sufentanill due to the use of indwelling catheters. The incidence of urinary retention in patients without urinary catheters receiving epidural Sufentanil is unknown; return of normal bladder activity may be delayed. - The following adverse reaction information is derived from controlled clinical trials in 320 patients who received intravenous Sufentanil during surgical anesthesia and in 340 patients who received epidural Sufentanil plus bupivacaine 0.125% for analgesia during labor and is presented below. Based on the observed frequency, none of the reactions occurring with an incidence less than 1% were observed during clinical trials of epidural Sufentanil used during labor and delivery (N=340). - In general cardiovascular and musculoskeletal adverse experiences were not observed in clinical trials of epidural Sufentanilnil. Hypotension was observed 7 times more frequently in intravenous trials than in epidural trials. The incidence of central nervous system, dermatological and gastrointestinal adverse experiences was approximately 4 to 25 times higher in studies of epidural use in labor and delivery. - Probably Causally Related: Incidence Greater than 1% - Derived from clinical trials (See preceding paragraph) - Cardiovascular: bradycardia, hypertension, hypotension. - Musculoskeletal: chest wall rigidity. - Central Nervous System: somnolence. - Dermatological: pruritus (25%). - Gastrointestinal: nausea, vomiting. - Probably Causally Related: Incidence Less than 1% - Derived from clinical trials (Adverse events reported in post-marketing surveillance, not seen in clinical trials, are italicized.) - Body as a whole: anaphylaxis. - Cardiovascular: arrhythmia, tachycardia, cardiac arrest. - Central Nervous System: chills. - Dermatological: erythema. - Musculoskeletal: skeletal muscle rigidity of neck and extremities. - Respiratory: apnea, bronchospasm, postoperative respiratory depression. - Miscellaneous: intraoperative muscle movement. ## Postmarketing Experience There is limited information regarding Sufentanil Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Sufentanil Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Sufentanil has been shown to have an embryocidal effect in rats and rabbits when given in doses 2.5 times the upper human intravenous dose for a period of 10 days to over 30 days. These effects were most probably due to maternal toxicity (decreased food consumption with increased mortality) following prolonged administration of the drug. - No evidence of teratogenic effects have been observed after administration of Sufentanil in rats or rabbits. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sufentanil in women who are pregnant. ### Labor and Delivery - The use of epidurally administered Sufentanil in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery. (See Indications and Usage and Dosage and Administration sections.) Sufentanil is not recommended for intravenous use or for use of larger epidural doses during labor and delivery because of potential risks to the newborn infant after delivery. * In clinical trials, one case of severe fetal bradycardia associated with maternal hypotension was reported within 8 minutes of maternal administration of Sufentanilnil 15 mcg plus bupivacaine 0.125% (10 mL total volume). ### Nursing Mothers - It is not known whether Sufentanil is excreted in human milk. Because fentanyl analogs are excreted in human milk, caution should be exercised when Sufentanil is administered to a nursing woman. ### Pediatric Use - The safety and efficacy of intravenous Sufentanil in pediatric patients as young as 1 day old undergoing cardiovascular surgery have been documented in a limited number of cases. The clearance of Sufentanil in healthy neonates is approximately one-half that in adults and children. The clearance rate of Sufentanil can be further reduced by up to a third in neonates with cardiovascular disease, resulting in an increase in the elimination half-life of the drug. ### Geriatic Use There is no FDA guidance on the use of Sufentanil in geriatric settings. ### Gender There is no FDA guidance on the use of Sufentanil with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sufentanil with respect to specific racial populations. ### Renal Impairment - In patients with liver or kidney dysfunction, Sufentanil should be administered with caution due to the importance of these organs in the metabolism and excretion of Sufentanil ### Hepatic Impairment - In patients with liver or kidney dysfunction, Sufentanil should be administered with caution due to the importance of these organs in the metabolism and excretion of Sufentanil ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sufentanil in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sufentanil in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Sufentanil Administration in the drug label. ### Monitoring There is limited information regarding Sufentanil Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Sufentanil and IV administrations. # Overdosage - Overdosage is manifested by an extension of the pharmacological actions of Sufentanil (see CLINICAL PHARMACOLOGY) as with other potent opioid analgesics. The most serious and significant effect of overdose for both intravenous and epidural administration of Sufentanil is respiratory depression. Intravenous administration of an opioid antagonist such as naloxone should be employed as a specific antidote to manage respiratory depression. The duration of respiratory depression following overdosage with Sufentanil may be longer than the duration of action of the opioid antagonist. Administration of an opioid antagonist should not preclude more immediate countermeasures. In the event of overdosage, oxygen should be administered and ventilation assisted or controlled as indicated for hypoventilation or apnea. A patent airway must be maintained, and a nasopharyngeal airway or endotracheal tube may be indicated. If depressed respiration is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressors for the treatment of hypotension and other supportive measures may be employed. # Pharmacology ## Mechanism of Action - Sufentanil is an opioid analgesic. When used in balanced general anesthesia, Sufentanil has been reported to be as much as 10 times as potent as fentanyl. When administered intravenously as a primary anesthetic agent with 100% oxygen, Sufentanil is approximately 5 to 7 times as potent as fentanyl. - Assays of histamine in patients administered Sufentanil have shown no elevation in plasma histamine levels and no indication of histamine release. (See dosage chart for more complete information on the intravenous use of Sufentanil.) ## Structure - SUFENTA® (sufentanil citrate) is a potent opioid analgesic chemically designated as N-[4-(methyoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide:2-hydroxy-1,2,3-propanetricarboxylate (1:1) with a molecular weight of 578.68. The structural formula of SUFENTA is: - SUFENTA is a sterile, preservative free, aqueous solution containing sufentanil citrate equivalent to 50 mcg per mL of sufentanil base for intravenous and epidural injection. The solution has a pH range of 3.5 to 6.0. ## Pharmacodynamics - At intravenous doses of up to 8 mcg/kg, Sufentanil is an analgesic component of general anesthesia; at intravenous doses ≥8 mcg/kg, Sufentanil produces a deep level of anesthesia. Sufentanil produces a dose related attenuation of catecholamine release, particularly norepinephrine. - At intravenous dosages of ≥8 mcg/kg, Sufentanil produces hypnosis and anesthesia without the use of additional anesthetic agents. A deep level of anesthesia is maintained at these dosages, as demonstrated by EEG patterns. Dosages of up to 25 mcg/kg attenuate the sympathetic response to surgical stress. The catecholamine response, particularly norepinephrine, is further attenuated at doses of Sufentanil of 25 to 30 mcg/kg, with hemodynamic stability and preservation of favorable myocardial oxygen balance. - Sufentanil has an immediate onset of action, with relatively limited accumulation. Rapid elimination from tissue storage sites allows for relatively more rapid recovery as compared with equipotent dosages of fentanyl. At dosages of 1 to 2 mcg/kg, recovery times are comparable to those observed with fentanyl; at dosages of >2 to 6 mcg/kg, recovery times are comparable to enflurane, isoflurane and fentanyl. Within the anesthetic dosage range of 8 to 30 mcg/kg of Sufentanil, recovery times are more rapid compared to equipotent fentanyl dosages. - The vagolytic effects of pancuronium may produce a dose dependent elevation in heart rate during Sufentanil-oxygen anesthesia. The use of moderate doses of pancuronium or of a less vagolytic neuromuscular blocking agent may be used to maintain a stable lower heart rate and blood pressure during Sufentanil-oxygen anesthesia. The vagolytic effects of pancuronium may be reduced in patients administered nitrous oxide with Sufentanil. - Preliminary data suggest that in patients administered high doses of Sufentanil, initial dosage requirements for neuromuscular blocking agents are generally lower as compared to patients given fentanyl or halothane, and comparable to patients given enflurane. - Bradycardia is infrequently seen in patients administered Sufentanil-oxygen anesthesia. The use of nitrous oxide with high doses of Sufentanil may decrease mean arterial pressure, heart rate and cardiac output. - Sufentanil at 20 mcg/kg has been shown to provide more adequate reduction in intracranial volume than equivalent doses of fentanyl, based upon requirements for furosemide and anesthesia supplementation in one study of patients undergoing craniotomy. During carotid endarterectomy, Sufentanil-nitrous oxide/oxygen produced reductions in cerebral blood flow comparable to those of enflurane-nitrous oxide/oxygen. During cardiovascular surgery, Sufentanil-oxygen produced EEG patterns similar to fentanyl-oxygen; these EEG changes were judged to be compatible with adequate general anesthesia. - The intraoperative use of Sufentanil at anesthetic dosages maintains cardiac output, with a slight reduction in systemic vascular resistance during the initial postoperative period. The incidence of postoperative hypertension, need for vasoactive agents and requirements for postoperative analgesics are generally reduced in patients administered moderate or high doses of Sufentanil as compared to patients given inhalation agents. - Skeletal muscle rigidity is related to the dose and speed of administration of Sufentanil. This muscular rigidity may occur unless preventative measures are taken (see Warnings). - Decreased respiratory drive and increased airway resistance occur with Sufentanil. The duration and degree of respiratory depression are dose related when Sufentanil is used at sub-anesthetic dosages. At high doses, a pronounced decrease in pulmonary exchange and apnea may be produced. - Onset of analgesic effect occurs within approximately 10 minutes of administration of epidural doses of Sufentanil and bupivacaine. Duration of analgesia following a single epidural injection of 10 to 15 mcg Sufentanil and bupivacaine 0.125% averaged 1.7 hours. - During labor and vaginal delivery, the addition of 10 to 15 mcg Sufentanil to 10 mL 0.125% bupivacaine provides an increase in the duration of analgesia compared to bupivacaine without an opioid. Analgesia from 15 mcg Sufentanil plus 10 mL 0.125% bupivacaine is comparable to analgesia from 10 mL of 0.25% bupivacaine alone. Apgar scores of neonates following epidural administration of both drugs to women in labor were comparable to neonates whose mothers received bupivacaine without an opioid epidurally. ## Pharmacokinetics - The pharmacokinetics of intravenous Sufentanil can be described as a three-compartment model, with a distribution time of 1.4 minutes, redistribution of 17.1 minutes and elimination half-life of 164 minutes in adults. The elimination half-life of Sufentanil is shorter (e.g. 97 +/- 42 minutes) in infants and children, and longer in neonates (e.g. 434 +/- 160 minutes) compared to that of adolescents and adults. The liver and small intestine are the major sites of biotransformation. Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug. Plasma protein binding of Sufentanil, related to the alpha acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates. - After epidural administration of incremental doses totaling 5 to 40 mcg Sufentanil during labor and delivery, maternal and neonatal Sufentanil plasma concentrations were at or near the 0.05 to 0.1 ng/mL limit of detection, and were slightly higher in mothers than in their infants. ## Nonclinical Toxicology There is limited information regarding Sufentanil Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Sufentanil Clinical Studies in the drug label. # How Supplied - SUFENTA (Sufentanil Citrate Injection, USP) is supplied as a sterile aqueous preservative-free solution for intravenous and epidural use as: ## Storage - Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. PROTECT FROM LIGHT. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Sufentanil Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Sufentanil 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 Sufentanil Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Sufentanil Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Sufenta
e11ca6aad5fd441153ec54ce0432b48da089a6d4	wikidoc	Sugammadex	Sugammadex # 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 Sugammadex is a modified gamma cyclodextrin that is FDA approved for the of reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery. Common adverse reactions include vomiting, pain, nausea, hypotension, and headache (≥10%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Sugammadex is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery. Sugammadex injection, for intravenous use, should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses and timing of Sugammadex administration should be based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred. Administer Sugammadex intravenously as a single bolus injection. The bolus injection may be given over 10 seconds, into an existing intravenous line. Sugammadex has only been administered as a single bolus injection in clinical trials. From the time of Sugammadex administration until complete recovery of neuromuscular function, monitor the patient to assure adequate ventilation and maintenance of a patent airway. Satisfactory recovery should be determined through assessment of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation. The recommended dose of Sugammadex does not depend on the anesthetic regimen. - Recommended Dosing Sugammadex can be used to reverse different levels of rocuronium- or vecuronium-induced neuromuscular blockade. - For rocuronium and vecuronium: - A dose of 4 mg/kg Sugammadex is recommended if spontaneous recovery of the twitch response has reached 1 to 2 post-tetanic counts (PTC) and there are no twitch responses to train-of-four (TOF) stimulation following rocuronium- or vecuronium-induced neuromuscular blockade. - A dose of 2 mg/kg Sugammadex is recommended if spontaneous recovery has reached the reappearance of the second twitch (T2) in response to TOF stimulation following rocuronium- or vecuronium-induced neuromuscular blockade. - For rocuronium only: - A dose of 16 mg/kg Sugammadex is recommended if there is a clinical need to reverse neuromuscular blockade soon (approximately 3 minutes) after administration of a single dose of 1.2 mg/kg of rocuronium. The efficacy of the 16 mg/kg dose of Sugammadex following administration of vecuronium has not been studied. Sugammadex dosing is based on actual body weight. - Drug Compatibility May inject Sugammadex into the intravenous line of a running infusion with the following intravenous solutions: - 0.9% sodium chloride - 5% dextrose - 0.45% sodium chloride and 2.5% dextrose - 5% dextrose in 0.9% sodium chloride - isolyte P with 5% dextrose - Ringer's lactate solution - Ringer's solution Ensure the infusion line is adequately flushed (e.g., with 0.9% sodium chloride) between administration of Sugammadex and other drugs. Do not mix Sugammadex with other products except those listed above. Sugammadex is physically incompatible with verapamil, ondansetron, and ranitidine. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever the solution and container permit. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sugammadex in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sugammadex in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and efficacy of Sugammadex 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 Sugammadex in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sugammadex in pediatric patients. # Contraindications Sugammadex is contraindicated in patients with known hypersensitivity to Sugammadex or any of its components. Hypersensitivity reactions that occurred varied from isolated skin reactions to serious systemic reactions (i.e., anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to Sugammadex. # Warnings Clinicians should be prepared for the possibility of drug hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions. Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with Sugammadex. The nature and frequency of anaphylaxis and hypersensitivity associated with Sugammadex administration were evaluated in a randomized, double-blind, placebo-controlled, parallel-group, repeat-dose study in which 375 subjects were randomized to receive 3 doses of Sugammadex IV with a 5 week washout period: 151 subjects received 4 mg/kg, 148 received 16 mg/kg and 76 received placebo. The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous Sugammadex was 0.3% (n=1 in the Sugammadex 16 mg/kg group on the first dose). Signs and symptoms included conjunctival edema, urticaria, erythema, swelling of the uvula and reduction in peak expiratory flow within 5 minutes of dose administration. The most common hypersensitivity adverse reactions reported were nausea, pruritus and urticaria and showed a dose response relationship, occurring more frequently in the 16 mg/kg group compared to the 4 mg/kg and placebo groups. Anaphylaxis has also been reported in the post-marketing setting, including at doses less than 16 mg/kg. The most commonly described clinical features in reports of anaphylaxis were dermatologic symptoms (including urticaria, rash, erythema, flushing and skin eruption); and clinically important hypotension often requiring the use of vasopressors for circulatory support. In addition prolonged hospitalization and/or the use of additional respiratory support until full recovery (re-intubation, prolonged intubation, manual or mechanical ventilation) have been noted in a number of the anaphylaxis reports. Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of Sugammadex. Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anticholinergic agents, such as atropine, should be administered if clinically significant bradycardia is observed. Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored and the ability to maintain a patent airway is assured. Even if recovery from neuromuscular blockade is complete, other drugs used in the peri- and post-operative period could depress respiratory function and therefore ventilatory support might still be required. Should neuromuscular blockade persist after Sugammadex administration or recur following extubation, take appropriate steps to provide adequate ventilation. In clinical trials, a small number of patients experienced a delayed or minimal response to the administration of Sugammadex. Thus, it is important to monitor ventilation until recovery occurs. A minimum waiting time is necessary before administration of a steroidal neuromuscular blocking agent after administration of Sugammadex. - Table 1: Re-administration of Rocuronium or Vecuronium after Reversal (up to 4 mg/kg Sugammadex) When rocuronium 1.2 mg/kg is administered within 30 minutes after reversal with Sugammadex, the onset of neuromuscular blockade may be delayed up to approximately 4 minutes and the duration of neuromuscular blockade may be shortened up to approximately 15 minutes. The recommended waiting time in patients with mild or moderate renal impairment for re-use of 0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium after reversal with up to 4 mg/kg Sugammadex should be 24 hours. If a shorter waiting time is required, the rocuronium dose for a new neuromuscular blockade should be 1.2 mg/kg. For re-administration of rocuronium or administration of vecuronium after reversal of rocuronium with 16 mg/kg Sugammadex, a waiting time of 24 hours is suggested. If neuromuscular blockade is required before the recommended waiting time has elapsed, use a nonsteroidal neuromuscular blocking agent. The onset of a depolarizing neuromuscular blocking agent might be slower than expected, because a substantial fraction of postjunctional nicotinic receptors can still be occupied by the neuromuscular blocking agent. Due to the administration of Sugammadex, certain drugs, including hormonal contraceptives, could become less effective due to a lowering of the (free) plasma concentrations. In this situation, consider the re-administration of the other drug, the administration of a therapeutically equivalent drug (preferably from a different chemical class), and/or non-pharmacological interventions as appropriate. Recurrence of neuromuscular blockade may occur due to displacement of rocuronium or vecuronium from Sugammadex by other drugs. In this situation the patient may require mechanical ventilation. Administration of the drug which caused displacement should be stopped in case of an infusion. The risk of displacement reactions will be the highest in the time period equivalent to 3 times the half-life of Sugammadex. The use of lower than recommended doses of Sugammadex may lead to an increased risk of recurrence of neuromuscular blockade after initial reversal and is not recommended. When drugs which potentiate neuromuscular blockade are used in the post-operative phase, special attention should be paid to the possibility of recurrence of neuromuscular blockade. Refer to the package insert for rocuronium or vecuronium for a list of the specific drugs which potentiate neuromuscular blockade. In case recurrence of neuromuscular blockade is observed, the patient may require mechanical ventilation. Sugammadex doses up to 16 mg/kg were associated with increases in the coagulation parameters activated partial thromboplastin time (aPTT) and prothrombin time/international normalized ratio of up to 25% for up to 1 hour in healthy volunteers. In patients undergoing major orthopedic surgery of the lower extremity who were concomitantly treated with heparin or low molecular weight heparin for thromboprophylaxis, increases in aPTT and PT(INR) of 5.5% and 3.0%, respectively, were observed in the hour following Sugammadex 4 mg/kg administration. This clinical trial did not demonstrate an increased blood loss or anemia incidence with Sugammadex compared with usual treatment. The rate of adjudicated bleeding events within 24 hours was 2.9% for Sugammadex and 4.1% for usual care. The rate of post-operative anemia was 21% for Sugammadex and 22% for usual care. The mean 24-hour drainage volume was 0.46 L for Sugammadex and 0.48 L for usual care. The need for any post-operative transfusion was 37% for Sugammadex and 39% for usual care. In vitro experiments demonstrated additional aPTT and PT(INR) prolongations for Sugammadex in combination with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban, and dabigatran up to ~25% and ~50% at Cmax levels of Sugammadex corresponding to 4 mg/kg and 16 mg/kg doses, respectively. Since bleeding risk has been studied systematically with only heparin and low molecular weight heparin thromboprophylaxis and 4 mg/kg doses of Sugammadex coagulation parameters should be carefully monitored in patients with known coagulopathies, being treated with therapeutic anticoagulation, receiving thromboprophylaxis drugs other than heparin and low molecular weight heparin, or receiving thromboprophylaxis drugs and who then receive a dose of 16 mg/kg Sugammadex. Sugammadex is not recommended for use in patients with severe renal impairment, including those requiring dialysis. With regard to the recommended waiting time for re-administration in patients with mild or moderate renal impairment, see Waiting Times for Re-administration of Neuromuscular Blocking Agents for Intubation Following Reversal with Sugammadex. When neuromuscular blockade was reversed intentionally in the middle of anesthesia in clinical trials, e.g., when investigating urgent reversal, signs of light anesthesia were noted occasionally (movement, coughing, grimacing and suckling of the tracheal tube). Sugammadex has not been studied for reversal following rocuronium or vecuronium administration in the ICU. Do not use BRIDION to reverse blockade induced by nonsteroidal neuromuscular blocking agents such as succinylcholine or benzylisoquinolinium compounds. Do not use Sugammadex to reverse neuromuscular blockade induced by steroidal neuromuscular blocking agents other than rocuronium or vecuronium. # 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 2914 subjects exposed to 2, 4, or 16 mg/kg Sugammadex and 544 to placebo in pooled Phase 1-3 studies. The population was 18 to 92 years old, 47% male and 53% female, 34% ASA (American Society of Anesthesiologists) Class 1, 51% ASA Class 2, and 14% ASA Class 3, and 82% Caucasian. Most subjects received a single dose of Sugammadex 2 mg/kg or 4 mg/kg. Adverse reactions reported in ≥10% of patients at a 2, 4, or 16 mg/kg Sugammadex dose with a rate higher than the placebo rate are: vomiting, pain, nausea, hypotension, and headache. All adverse reactions occurring in ≥2% of subjects treated with Sugammadex and more often than placebo for adult subjects who received anesthesia and/or neuromuscular blocking agent in pooled Phase 1 to 3 studies are presented in Table 2. - Table 2: Percent of Subject Exposures in Pooled Phase 1 to 3 Studies with Adverse Reactions Incidence ≥ 2% - Anaphylaxis and Hypersensitivity Hypersensitivity reactions, including anaphylaxis, have occurred in both premarketing clinical trials and in post-marketing spontaneous reports. In a dedicated hypersensitivity study in healthy volunteers, the frequency of anaphylaxis was 0.3%. These reactions varied from isolated skin reactions to serious systemic reactions (i.e., anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to Sugammadex. Symptoms associated with these reactions can include: flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia, swelling of tongue, swelling of pharynx, bronchospasm and pulmonary obstructive events. Severe hypersensitivity reactions can be fatal. A randomized, double-blind study examined the incidence of drug hypersensitivity reactions in healthy volunteers given up to 3 doses of placebo (N=76), Sugammadex 4 mg/kg (N=151) or Sugammadex 16 mg/kg (N=148). Reports of suspected hypersensitivity were adjudicated by a blinded committee. The incidence of adjudicated hypersensitivity was 1%, 7% and 9% in the placebo, Sugammadex 4 mg/kg and Sugammadex 16 mg/kg groups, respectively. There were no reports of anaphylaxis after placebo or Sugammadex 4 mg/kg. There was a single case of adjudicated anaphylaxis after the first dose of Sugammadex 16 mg/kg. The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous Sugammadex was 0.3%. There was no evidence of increased frequency or severity of hypersensitivity with repeat dosing. In a previous study of similar design, there were three adjudicated cases of anaphylaxis, all after Sugammadex 16 mg/kg (incidence 1% in the 298 healthy volunteers treated with Sugammadex). - Recurrence of Neuromuscular Blockade In clinical studies with subjects treated with rocuronium or vecuronium, where Sugammadex was administered using a dose labeled for the depth of neuromuscular blockade (N=2022), an incidence of <1% was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence. - Bronchospasm In one dedicated clinical trial and in post-marketing data, in patients with a history of pulmonary complications, bronchospasm was reported as a possibly related adverse event. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of Sugammadex. 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 Disorders: Cases of marked bradycardia and bradycardia with cardiac arrest have been observed within minutes after administration of Sugammadex. Other cardiac rhythm abnormalities have included atrial fibrillation, atrioventricular block, cardiac/cardiorespiratory arrest, ST segment changes, supraventricular tachycardia/extrasystoles, tachycardia, ventricular fibrillation, and ventricular tachycardia. - General Disorders and Administration Site Conditions: Cases of Sugammadex not having the intended effect. - Immune System Disorders: Hypersensitivity events including anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, and Type 1 hypersensitivity have been reported. - Respiratory, Thoracic, and Mediastinal Disorders: Events of laryngospasm, dyspnea, wheezing, pulmonary edema, and respiratory arrest have been reported. # Drug Interactions - Summary The information reported in the next sections is based on binding affinity between Sugammadex and other drugs, preclinical experiments, clinical studies and simulations of a pharmacokinetic-pharmacodynamic (PK-PD) model. Based on these considerations, no clinically significant pharmacodynamic interactions with other drugs are expected, with the exception of toremifene and hormonal contraceptives. - Interactions Potentially Affecting the Efficacy of Sugammadex - Toremifene For toremifene, which has a relatively high binding affinity for Sugammadex and for which relatively high plasma concentrations might be present, some displacement of vecuronium or rocuronium from the complex with Sugammadex could occur. The recovery to TOF ratio to 0.9 could therefore be delayed in patients who have received toremifene on the same day of surgery. - Interaction Potentially Affecting the Efficacy of Hormonal Contraceptives In vitro binding studies indicate that Sugammadex may bind to progestogen, thereby decreasing progestogen exposure. Therefore, the administration of a bolus dose of Sugammadex is considered to be equivalent to missing dose(s) of oral contraceptives containing an estrogen or progestogen. If an oral contraceptive is taken on the same day that Sugammadex is administered, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days. In the case of non-oral hormonal contraceptives, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days. - Interference with Laboratory Tests Sugammadex may interfere with the serum progesterone assay. Interference with this test was observed at Sugammadex plasma concentrations of 100 mcg/mL, which may be observed for up to 30 minutes after a 16 mg/kg dose. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Risk Summary There are no data on Sugammadex use in pregnant women to inform any drug-associated risks. In animal reproduction studies, there was no evidence of teratogenicity following daily intravenous administration of Sugammadex to rats and rabbits during organogenesis at exposures of up to 6 and 8 times, respectively, the maximum recommended human dose (MRHD) of 16 mg/kg. However, there was an increase in the incidence of incomplete ossification of the sternebra and reduced fetal body weights in the rabbit study at 8 times the MRHD, which is a dose level in which maternal toxicity was also observed. In a pre- and postnatal development study, Sugammadex treatment resulted in an increase in early postnatal loss, which correlated with maternal behavior (increased incidence of pup cannibalism), at exposures equivalent to the MRHD and higher. The background risk of major birth defects and miscarriage for the indicated population are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. - Data - Animal Data In an embryofetal development study in rats, pregnant animals received daily intravenous administration of Sugammadex at 0, 20, 100, and 500 mg/kg (0.2, 1, and 6-times the MRHD of 16 mg/kg/day, respectively, based on AUC comparison) during organogenesis (Gestational Days 6 - 17). No treatment-related maternal and embryofetal changes were observed. In another embryofetal development study, pregnant New Zealand white rabbits received daily intravenous administration of Sugammadex at 0, 20, 65, 200 mg/kg (0.6, 2, and 8 times the MRHD, respectively, based on AUC comparison) during organogenesis (Gestational Days 6-18). Fetal body weight decreases (10 and 14%, respectively) were observed in the offspring at maternal doses of 65 mg/kg and 200 mg/kg. In addition, incomplete ossification of sternebra, and unossified 1st metacarpal were noted at a maternal dose of 200 mg/kg/day. Maternal toxicity was also observed at 200 mg/kg. Considering the observed effects of Sugammadex on bone, it is possible that these findings may be attributable to drug. There was no evidence of teratogenicity at any dose. In a prenatal and postnatal development study, pregnant rats were administered Sugammadex intravenously at 0, 30, 120, and 500 mg/kg (0.3, 1, and 6 times the MRHD, respectively, based on AUC comparison) from Gestational Day (GD) 6 to Postnatal Day (PND) 21 (corresponding to the beginning of organogenesis through parturition and subsequent pup weaning). Postnatal loss during PND 1-4 was noted across control litters and treated litters from dams receiving Sugammadex as a result of pup cannibalization by dams. Overall incidence of affected litters was 2, 1, 4, and 3 litters, respectively, at 0, 30, 120, or 500 mg/kg/day. The reason for the increased cannibalization is not known. An effect of Sugammadex on steroidal hormones and/or pheromones cannot be ruled out. In addition, there were no drug-related effects on parturition in rats during evaluations for prenatal or postnatal development. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sugammadex in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sugammadex during labor and delivery. ### Nursing Mothers - Risk Summary No data are available regarding the presence of Sugammadex in human milk, the effects of Sugammadex on the breast fed infant, or the effects of Sugammadex on milk production. However, Sugammadex is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sugammadex and any potential adverse effects on the breastfed infant from Sugammadex or from the underlying maternal condition. - Data In a milk excretion study in rat dams following single intravenous dose of 20 mg/kg Sugammadex on Postnatal Day 9, the maximum drug level was achieved at about 30 minutes after dosing with a ratio of milk to plasma level approximately 1:1. The oral exposure via milk did not induce effects on survival, body weight and physical or the behavioral developmental parameters monitored in rats in the prenatal and postnatal development studies. ### Pediatric Use The safety and efficacy of Sugammadex in pediatric patients have not been established. - Juvenile Animal Studies In a bone deposition study, Sugammadex concentrations were significantly higher in juvenile rats compared to adult rats (13% vs. 3% of the administered dose, respectively) following a single intravenous (IV) dose at 30 mg/kg (0.3 times the MRHD based on adult AUC comparison). In a juvenile animal bone toxicity study, 7-day old rats were dosed intravenously once daily for 28 days with 0, 30, 120, and 500 mg/kg Sugammadex (approximately 0.1, 0.6, and 3 times the MRHD, respectively, by adult AUC comparison). Sugammadex at 120 and 500 mg/kg decreased ulna and femur bone lengths by approximately 3%, which did not recover after an 8-week treatment-free period. Reversible whitish discoloration and disturbance of enamel formation were also observed in the incisors at these dose levels. In molars, this effect was only observed at 500 mg/kg. The no-observed-effect-level (NOEL) was 30 mg/kg. In a second juvenile animal bone toxicity study, 7-day old rats were dosed once weekly for 8 weeks with 0, 7.5, 30, and 120 mg/kg (up to 1.2 times the MRHD of 16 mg/kg based on adult AUC comparison). No adverse effects on bone or teeth were noted. ### Geriatic Use Sugammadex has been administered in a dedicated clinical study to a total 102 geriatric patients that compared the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 mg/kg Sugammadex given at the reappearance of T2 in 65-74 year-olds (N=62) and ≥75 year-olds (N=40) compared with 18-64 year-olds (N=48). The median time to recovery of the TOF (T4/T1) ratio to 0.9 in 18-64 year-olds was 2.2 minutes; in 65-74 year-olds it was 2.5 minutes, and in ≥75 year-olds it was 3.6 minutes. For time to recovery from neuromuscular blockade induced by rocuronium following administration of 4 mg/kg Sugammadex given at 1-2 PTCs, results across clinical trials revealed a median recovery of 2.5 minutes for geriatric patients (≥65 years, N=63) versus 2.0 minutes, for adults aged 18-64 years (N=359). Hence no dose adjustment is necessary in geriatric patients with normal organ function. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Sugammadex with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sugammadex with respect to specific racial populations. ### Renal Impairment This drug is known to be substantially excreted by the kidney. Effect of mild or moderate renal impairment (creatine clearance ≥30 and ≤80 mL/min) on Sugammadex PK and PD was obtained from a study in elderly patients. Although clearance of drug decreased in elderly subjects with mild and moderate renal impairment, there was no significant difference in the ability of Sugammadex to reverse the pharmacodynamic effect of rocuronium. Hence, no dosage adjustment is necessary for mild and moderate renal impairment. Sugammadex is not recommended for use in patients with severe renal impairment (creatine clearance <30 mL/min) due to insufficient safety information combined with the prolonged and increased overall exposure in these patients. ### Hepatic Impairment Sugammadex is not metabolized nor excreted by the liver; therefore, dedicated trials in patients with hepatic impairment have not been conducted. Exercise caution when administering Sugammadex to patients with hepatic impairment accompanied by coagulopathy or severe edema. ### Females of Reproductive Potential and Males - Contraception Upon administration of Sugammadex, the efficacy of hormonal contraceptives may be reduced for up to 7 days. Advise female patients of reproductive potential using hormonal contraceptives to use an additional, non-hormonal contraceptive for the next 7 days following Sugammadex administration. ### Immunocompromised Patients There is no FDA guidance one the use of Sugammadex in patients who are immunocompromised. ### Pulmonary Patients One trial of 77 patients who were diagnosed with or have a history of pulmonary complications investigated the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 mg/kg or 4 mg/kg Sugammadex given at the first signs of recovery (reappearance of T2). The trial showed that for these patients the median time to recovery of the T4/T1 ratio to 0.9 was 2.1 minutes after a dose of 2 mg/kg Sugammadex and 1.9 minutes after a dose of 4 mg/kg Sugammadex. This is similar to the median values observed in the other trials; therefore, no dosage adjustment is necessary. # Administration and Monitoring ### Administration Sugammadex injection, for intravenous use, should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses and timing of Sugammadex administration should be based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred. Administer Sugammadex intravenously as a single bolus injection. The bolus injection may be given over 10 seconds, into an existing intravenous line. Sugammadex has only been administered as a single bolus injection in clinical trials. From the time of Sugammadex administration until complete recovery of neuromuscular function, monitor the patient to assure adequate ventilation and maintenance of a patent airway. Satisfactory recovery should be determined through assessment of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation. The recommended dose of Sugammadex does not depend on the anesthetic regimen. ### Monitoring There is limited information regarding Sugammadex Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Sugammadex and IV administrations. # Overdosage In premarketing clinical trials, one case of accidental overdose with 40 mg/kg Sugammadex was reported without significant effects. Sugammadex can be removed using hemodialysis with a high-flux filter, but not with a low-flux filter. Based upon clinical studies, Sugammadex concentrations in plasma are reduced with a high-flux filter by about 70% after a 3- to 6-hour dialysis session. # Pharmacology ## Mechanism of Action Sugammadex is a modified gamma cyclodextrin. It forms a complex with the neuromuscular blocking agents rocuronium and vecuronium, and it reduces the amount of neuromuscular blocking agent available to bind to nicotinic cholinergic receptors in the neuromuscular junction. This results in the reversal of neuromuscular blockade induced by rocuronium and vecuronium. ## Structure There is limited information regarding Sugammadex Structure in the drug label. ## Pharmacodynamics Sugammadex has been administered in doses ranging from 0.5 mg/kg to 16 mg/kg in dose response trials of rocuronium-induced blockade (0.6, 0.9, 1 and 1.2 mg/kg with and without maintenance doses) and vecuronium-induced blockade (0.1 mg/kg with or without maintenance doses) at different time points/depths of block. In these trials a clear dose-response relationship was observed. Sugammadex may contain up to 7% of the mono OH-derivative of Sugammadex. In preclinical pharmacology studies, the mono OH-derivative was demonstrated to have ~50% of the affinity as Sugammadex for rocuronium and vecuronium and that product with up to 7% of the mono OH-derivative has nearly similar efficacy in reversing rocuronium- or vecuronium-induced blockade. Although Sugammadex has greatest affinity for aminosteroid neuromuscular blocking agents such as rocuronium and vecuronium, plasma levels of endogenous or exogenous compounds with a similar steroidal structure, such as some hormones, hormonal contraceptives, and pheromones may also be reduced following administration of Sugammadex. - Cardiac Electrophysiology At a dose 2 times the maximum recommended dose, Sugammadex does not prolong the QTc interval to any clinically relevant extent. ## Pharmacokinetics The Sugammadex pharmacokinetic parameters were calculated from the total sum of non-complex-bound and complex-bound concentrations of Sugammadex. Pharmacokinetic parameters as clearance and volume of distribution are assumed to be the same for non-complex-bound and complex-bound Sugammadex in anesthetized patients. - Distribution The observed steady-state volume of distribution of Sugammadex is approximately 11 to 14 liters in adult patients with normal renal function (based on conventional, non-compartmental pharmacokinetic analysis). Neither Sugammadex nor the complex of Sugammadex and rocuronium binds to plasma proteins or erythrocytes, as was shown in vitro using male human plasma and whole blood. Sugammadex exhibits linear kinetics in the dosage range of 1 to 16 mg/kg when administered as an IV bolus dose. In nonclinical drug distribution studies, Sugammadex is retained in sites of active mineralization, such as bone and teeth, with a mean half-life of 172 and 8 days, respectively. - Metabolism In clinical studies, no metabolites of Sugammadex have been observed and only renal excretion of the unchanged product was observed as the route of elimination. - Elimination In adult anesthetized patients with normal renal function, the elimination half-life (t1/2) of Sugammadex is about 2 hours and the estimated plasma clearance is about 88 mL/min (based on compartmental pharmacokinetic analysis). A mass balance study demonstrated that >90% of the dose was excreted within 24 hours. Ninety-six percent (96%) of the dose was excreted in urine, of which at least 95% could be attributed to unchanged Sugammadex. Excretion via feces or expired air was less than 0.02% of the dose. Administration of Sugammadex to healthy volunteers resulted in increased renal elimination of rocuronium in complex. - Patients with Renal Impairment Sugammadex is known to be substantially excreted by the kidney. The half-life of Sugammadex in patients with mild, moderate and severe renal impairment is 4, 6, and 19 hours, respectively. In one study, exposure to Sugammadex was prolonged, leading to 17-fold higher overall exposure in patients with severe renal impairment. Low concentrations of sugammadex are detectable for at least 48 hours post-dose in patients with severe renal impairment. In a second study comparing subjects with moderate or severe renal impairment to subjects with normal renal function, Sugammadex clearance progressively decreased and t1/2 was progressively prolonged with declining renal function. Exposure was 2-fold and 5-fold higher in subjects with moderate and severe renal impairment, respectively. Sugammadex concentrations were no longer detectable beyond 7 days post-dose in subjects with severe renal impairment. - Age: Geriatric Population Geriatric patients may have mild or moderate renal impairment. Population pharmacokinetic analysis indicated that, beyond the effects of a decreased creatinine clearance, increased age has limited impact on Sugammadex PK parameters. - Sex No pharmacokinetic differences between male and female subjects were observed. - Race In a study in healthy Japanese and Caucasian subjects no clinically relevant differences in pharmacokinetic parameters were observed. Limited data do not indicate differences in pharmacokinetic parameters in Black or African Americans. ## Nonclinical Toxicology - Carcinogenesis Long-term animal studies to evaluate the carcinogenic potential of Sugammadex have not been conducted. - Mutagenesis Sugammadex and its mono OH-derivative tested negatively in in vitro bacterial reverse mutation assays (Ames test), in vitro chromosomal aberration assays in human peripheral blood lymphocytes, and in vivo micronucleus assays in mice and rats. - Impairment of Fertility A fertility and early embryonic development study in Sprague-Dawley rats in which male rats were treated daily for 29 days prior to mating and through the mating period and female rats were treated daily for 14 days prior to mating to Day 5 post-coitum via intravenous administration of Sugammadex at 20, 100, and 500 mg/kg (0.2, 1, and 6 times the MRHD of 16 mg/kg, respectively, based on AUC comparison) did not show adverse effects on fertility. Bone and teeth retention of Sugammadex occurred in rats after intravenous injection, with mean half-lives of 172 and 8 days, respectively. Sugammadex bound to hydroxyapatite in an in vitro study and distributed in the bone formation area where hydroxyapatite is present for mineralization in vivo. In adult rat bone toxicity studies, a single dose of Sugammadex at 2000 mg/kg (approximately 24 times the maximum recommended human dose (MRHD) of 16 mg/kg by AUC comparison) administered to adult rats caused a slight increase in bone resorption, but had no effect on teeth color. No adverse bone effects were seen following a single dose of Sugammadex at 500 mg/kg (4 times the MRHD dose of 16 mg/kg based on plasma AUC comparison). In a bone repair study, adult rats were treated with intravenous Sugammadex weekly for 6 weeks at 0, 30, 120, and 500 mg/kg (approximately 0.4, 1, and 6 times the MRHD, respectively, by AUC comparison). Based on histological data, high dose animals with post-fracture treatment, showed a statistically significant increase in callus formation and decrease in bone formation, suggesting a potential for a slight delay in the bone healing process. However there were no statistically significant effects on bone volume or bone mineral density. In juvenile animal studies, bone and teeth deposition was significantly higher in juvenile rats compared to adults. In addition, Sugammadex administered to juvenile rats daily for 4 weeks caused slight bone length decrease (approximately 3%), which did not recover after an 8-week treatment-free period, and reversible whitish discoloration of the teeth at a dose approximately 0.6 times the MRHD, while weekly administration for 8 weeks did not produce similar changes in bone and teeth at doses up to 1.2 times the MRHD. # Clinical Studies - Controlled Clinical Studies - Comparative Study of Sugammadex versus Neostigmine as a Reversal Agent for Neuromuscular Blockade Induced by Rocuronium or Vecuronium at Reappearance of T2 (Moderate Blockade) A multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study comparing Sugammadex and neostigmine enrolled 189 patients (87 women and 102 men, 95% were ASA class 1 and 2 and 99% were Caucasian, median weights were 72 kg and 76 kg and median ages were 50 years and 51 years in the rocuronium and vecuronium groups, respectively). Patients were randomly assigned to the rocuronium or vecuronium group and underwent elective surgical procedures under general anesthesia that required endotracheal intubation and maintenance of neuromuscular blockade. The surgical procedures were mainly endocrine, ocular, ENT, abdominal (gynecological, colorectal, urological), orthopedic, vascular, or dermatological. At the reappearance of T2, after the last dose of rocuronium or vecuronium, 2 mg/kg Sugammadex or 50 mcg/kg neostigmine was administered in a randomized order as a single bolus injection. The time from start of administration of Sugammadex or neostigmine to recovery of the TOF (T4/T1) ratio to 0.9 was assessed. Generally, a T4/T1 ratio ≥0.9 correlates with recovery from neuromuscular blockade. Return of the T4/T1 ratio to 0.9 after the reappearance of T2 was overall faster with Sugammadex 2 mg/kg as compared to neostigmine 50 mcg/kg in the setting of rocuronium or vecuronium-induced neuromuscular blockade (Figures 1 and 2). - Figure 1: Time (Minutes) from Administration of Sugammadex or Neostigmine at the Reappearance of T2 after Rocuronium to Recovery of the T4/T1 Ratio to 0.9 - Figure 2: Time (Minutes) from Administration of Sugammadex or Neostigmine at the Reappearance of T2 after Vecuronium to Recovery of the T4/T1 Ratio to 0.9 - Comparative Study of Sugammadex versus Neostigmine as a Reversal Agent for Neuromuscular Blockade Induced by Rocuronium or Vecuronium at 1 to 2 PTCs (Deep Blockade) A multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study comparing Sugammadex and neostigmine enrolled 157 patients (86 women and 71 men; 8% ASA class 1, 71% class 2, and 21% class 3; 79% Caucasian; median weights of 81 kg and 84 kg, and median ages of 54 years and 56 years in the rocuronium and vecuronium groups, respectively). Patients were randomly assigned to the rocuronium or vecuronium group and underwent elective surgical procedures under general anesthesia that required endotracheal intubation and maintenance of neuromuscular blockade. The surgical procedures were mainly abdominal (gynecological, colorectal, urological), orthopedic, reconstructive, or neurological. At 1 to 2 PTCs, after the last dose of rocuronium or vecuronium, 4 mg/kg Sugammadex or 70 mcg/kg neostigmine was administered in a randomized order as a single bolus injection. The time from start of administration of Sugammadex or neostigmine to recovery of the TOF (T4/T1) ratio to 0.9 was assessed, although neostigmine was not expected to reverse neuromuscular blockade at a depth of 1 to 2 PTCs. Generally, a T4/T1 ratio ≥0.9 correlates with recovery from neuromuscular blockade. Return of the T4/T1 ratio to 0.9 in patients with 1 to 2 PTCs with Sugammadex 4 mg/kg had a wider range of recovery times but the median time to recovery was comparable to the study of reversal at T2 (2.7 minutes with 25th and 75th percentiles of 2.1 and 4.3 minutes for rocuronium , and 3.3 minutes with 25th and 75th percentiles of 2.3 and 6.6 minutes for vecuronium ). There were 7 and 6 censored observations in the rocuronium and vecuronium groups, respectively. - Reversal of Neuromuscular Blockade 3 Minutes after Rocuronium 1.2 mg/kg Time to recovery from neuromuscular blockade induced by succinylcholine compared with recovery from neuromuscular blockade induced by rocuronium followed 3 minutes later with Sugammadex was assessed in a multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study. The study was conducted in 110 patients (64 women and 46 men, ASA class 1 and 2, 78% were Caucasian, median weight was 70 kg, median age was 43 years). Patients underwent elective surgical procedures under general anesthesia that required endotracheal intubation and a short duration of neuromuscular relaxation. The laparoscopic or open surgical procedures were mainly gynecological, orthopedic, or reconstructive. Return of the first twitch in a TOF (T1) to 10% of baseline was compared between Sugammadex 16 mg/kg for reversal of rocuronium 1.2 mg/kg versus spontaneous recovery from succinylcholine 1 mg/kg. Recovery to T1 of 10% of baseline (relative to the time of administration of rocuronium or succinylcholine) was overall faster in the rocuronium/Sugammadex group compared with succinylcholine alone (Table 3). - Table 3: Time (minutes) from Start of Administration of Rocuronium or Succinylcholine to Recovery of T1 to 10% of Baseline BRIDION: Sugammadex's Brand name # How Supplied - Sugammadex 2-mL single-dose vials containing 200 mg Sugammadex (100 mg/mL) Box of 10 NDC 0006-5423-12 - Sugammadex 5-mL single-dose vials containing 500 mg Sugammadex (100 mg/mL) Box of 10 NDC 0006-5423-15 The packaging of this product is not made with natural rubber latex. ## Storage Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. When not protected from light, the vial should be used within 5 days. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise females of reproductive potential using hormonal contraceptives that Sugammadex may reduce the contraceptive effect. Instruct females to use an additional, non-hormonal method of contraception for the next 7 days following Sugammadex administration # Precautions with Alcohol Alcohol-Sugammadex interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names BRIDION® # Look-Alike Drug Names There is limited information regarding Sugammadex Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Sugammadex Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [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 Sugammadex is a modified gamma cyclodextrin that is FDA approved for the of reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery. Common adverse reactions include vomiting, pain, nausea, hypotension, and headache (≥10%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Sugammadex is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery. Sugammadex injection, for intravenous use, should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses and timing of Sugammadex administration should be based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred. Administer Sugammadex intravenously as a single bolus injection. The bolus injection may be given over 10 seconds, into an existing intravenous line. Sugammadex has only been administered as a single bolus injection in clinical trials. From the time of Sugammadex administration until complete recovery of neuromuscular function, monitor the patient to assure adequate ventilation and maintenance of a patent airway. Satisfactory recovery should be determined through assessment of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation. The recommended dose of Sugammadex does not depend on the anesthetic regimen. - Recommended Dosing Sugammadex can be used to reverse different levels of rocuronium- or vecuronium-induced neuromuscular blockade. - For rocuronium and vecuronium: - A dose of 4 mg/kg Sugammadex is recommended if spontaneous recovery of the twitch response has reached 1 to 2 post-tetanic counts (PTC) and there are no twitch responses to train-of-four (TOF) stimulation following rocuronium- or vecuronium-induced neuromuscular blockade. - A dose of 2 mg/kg Sugammadex is recommended if spontaneous recovery has reached the reappearance of the second twitch (T2) in response to TOF stimulation following rocuronium- or vecuronium-induced neuromuscular blockade. - For rocuronium only: - A dose of 16 mg/kg Sugammadex is recommended if there is a clinical need to reverse neuromuscular blockade soon (approximately 3 minutes) after administration of a single dose of 1.2 mg/kg of rocuronium. The efficacy of the 16 mg/kg dose of Sugammadex following administration of vecuronium has not been studied. Sugammadex dosing is based on actual body weight. - Drug Compatibility May inject Sugammadex into the intravenous line of a running infusion with the following intravenous solutions: - 0.9% sodium chloride - 5% dextrose - 0.45% sodium chloride and 2.5% dextrose - 5% dextrose in 0.9% sodium chloride - isolyte P with 5% dextrose - Ringer's lactate solution - Ringer's solution Ensure the infusion line is adequately flushed (e.g., with 0.9% sodium chloride) between administration of Sugammadex and other drugs. Do not mix Sugammadex with other products except those listed above. Sugammadex is physically incompatible with verapamil, ondansetron, and ranitidine. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever the solution and container permit. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sugammadex in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sugammadex in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and efficacy of Sugammadex 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 Sugammadex in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sugammadex in pediatric patients. # Contraindications Sugammadex is contraindicated in patients with known hypersensitivity to Sugammadex or any of its components. Hypersensitivity reactions that occurred varied from isolated skin reactions to serious systemic reactions (i.e., anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to Sugammadex. # Warnings Clinicians should be prepared for the possibility of drug hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions. Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with Sugammadex. The nature and frequency of anaphylaxis and hypersensitivity associated with Sugammadex administration were evaluated in a randomized, double-blind, placebo-controlled, parallel-group, repeat-dose study in which 375 subjects were randomized to receive 3 doses of Sugammadex IV with a 5 week washout period: 151 subjects received 4 mg/kg, 148 received 16 mg/kg and 76 received placebo. The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous Sugammadex was 0.3% (n=1 in the Sugammadex 16 mg/kg group on the first dose). Signs and symptoms included conjunctival edema, urticaria, erythema, swelling of the uvula and reduction in peak expiratory flow within 5 minutes of dose administration. The most common hypersensitivity adverse reactions reported were nausea, pruritus and urticaria and showed a dose response relationship, occurring more frequently in the 16 mg/kg group compared to the 4 mg/kg and placebo groups. Anaphylaxis has also been reported in the post-marketing setting, including at doses less than 16 mg/kg. The most commonly described clinical features in reports of anaphylaxis were dermatologic symptoms (including urticaria, rash, erythema, flushing and skin eruption); and clinically important hypotension often requiring the use of vasopressors for circulatory support. In addition prolonged hospitalization and/or the use of additional respiratory support until full recovery (re-intubation, prolonged intubation, manual or mechanical ventilation) have been noted in a number of the anaphylaxis reports. Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of Sugammadex. Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anticholinergic agents, such as atropine, should be administered if clinically significant bradycardia is observed. Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored and the ability to maintain a patent airway is assured. Even if recovery from neuromuscular blockade is complete, other drugs used in the peri- and post-operative period could depress respiratory function and therefore ventilatory support might still be required. Should neuromuscular blockade persist after Sugammadex administration or recur following extubation, take appropriate steps to provide adequate ventilation. In clinical trials, a small number of patients experienced a delayed or minimal response to the administration of Sugammadex. Thus, it is important to monitor ventilation until recovery occurs. A minimum waiting time is necessary before administration of a steroidal neuromuscular blocking agent after administration of Sugammadex. - Table 1: Re-administration of Rocuronium or Vecuronium after Reversal (up to 4 mg/kg Sugammadex) When rocuronium 1.2 mg/kg is administered within 30 minutes after reversal with Sugammadex, the onset of neuromuscular blockade may be delayed up to approximately 4 minutes and the duration of neuromuscular blockade may be shortened up to approximately 15 minutes. The recommended waiting time in patients with mild or moderate renal impairment for re-use of 0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium after reversal with up to 4 mg/kg Sugammadex should be 24 hours. If a shorter waiting time is required, the rocuronium dose for a new neuromuscular blockade should be 1.2 mg/kg. For re-administration of rocuronium or administration of vecuronium after reversal of rocuronium with 16 mg/kg Sugammadex, a waiting time of 24 hours is suggested. If neuromuscular blockade is required before the recommended waiting time has elapsed, use a nonsteroidal neuromuscular blocking agent. The onset of a depolarizing neuromuscular blocking agent might be slower than expected, because a substantial fraction of postjunctional nicotinic receptors can still be occupied by the neuromuscular blocking agent. Due to the administration of Sugammadex, certain drugs, including hormonal contraceptives, could become less effective due to a lowering of the (free) plasma concentrations. In this situation, consider the re-administration of the other drug, the administration of a therapeutically equivalent drug (preferably from a different chemical class), and/or non-pharmacological interventions as appropriate. Recurrence of neuromuscular blockade may occur due to displacement of rocuronium or vecuronium from Sugammadex by other drugs. In this situation the patient may require mechanical ventilation. Administration of the drug which caused displacement should be stopped in case of an infusion. The risk of displacement reactions will be the highest in the time period equivalent to 3 times the half-life of Sugammadex. The use of lower than recommended doses of Sugammadex may lead to an increased risk of recurrence of neuromuscular blockade after initial reversal and is not recommended. When drugs which potentiate neuromuscular blockade are used in the post-operative phase, special attention should be paid to the possibility of recurrence of neuromuscular blockade. Refer to the package insert for rocuronium or vecuronium for a list of the specific drugs which potentiate neuromuscular blockade. In case recurrence of neuromuscular blockade is observed, the patient may require mechanical ventilation. Sugammadex doses up to 16 mg/kg were associated with increases in the coagulation parameters activated partial thromboplastin time (aPTT) and prothrombin time/international normalized ratio [PT(INR)] of up to 25% for up to 1 hour in healthy volunteers. In patients undergoing major orthopedic surgery of the lower extremity who were concomitantly treated with heparin or low molecular weight heparin for thromboprophylaxis, increases in aPTT and PT(INR) of 5.5% and 3.0%, respectively, were observed in the hour following Sugammadex 4 mg/kg administration. This clinical trial did not demonstrate an increased blood loss or anemia incidence with Sugammadex compared with usual treatment. The rate of adjudicated bleeding events within 24 hours was 2.9% for Sugammadex and 4.1% for usual care. The rate of post-operative anemia was 21% for Sugammadex and 22% for usual care. The mean 24-hour drainage volume was 0.46 L for Sugammadex and 0.48 L for usual care. The need for any post-operative transfusion was 37% for Sugammadex and 39% for usual care. In vitro experiments demonstrated additional aPTT and PT(INR) prolongations for Sugammadex in combination with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban, and dabigatran up to ~25% and ~50% at Cmax levels of Sugammadex corresponding to 4 mg/kg and 16 mg/kg doses, respectively. Since bleeding risk has been studied systematically with only heparin and low molecular weight heparin thromboprophylaxis and 4 mg/kg doses of Sugammadex coagulation parameters should be carefully monitored in patients with known coagulopathies, being treated with therapeutic anticoagulation, receiving thromboprophylaxis drugs other than heparin and low molecular weight heparin, or receiving thromboprophylaxis drugs and who then receive a dose of 16 mg/kg Sugammadex. Sugammadex is not recommended for use in patients with severe renal impairment, including those requiring dialysis. With regard to the recommended waiting time for re-administration in patients with mild or moderate renal impairment, see Waiting Times for Re-administration of Neuromuscular Blocking Agents for Intubation Following Reversal with Sugammadex. When neuromuscular blockade was reversed intentionally in the middle of anesthesia in clinical trials, e.g., when investigating urgent reversal, signs of light anesthesia were noted occasionally (movement, coughing, grimacing and suckling of the tracheal tube). Sugammadex has not been studied for reversal following rocuronium or vecuronium administration in the ICU. Do not use BRIDION to reverse blockade induced by nonsteroidal neuromuscular blocking agents such as succinylcholine or benzylisoquinolinium compounds. Do not use Sugammadex to reverse neuromuscular blockade induced by steroidal neuromuscular blocking agents other than rocuronium or vecuronium. # 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 2914 subjects exposed to 2, 4, or 16 mg/kg Sugammadex and 544 to placebo in pooled Phase 1-3 studies. The population was 18 to 92 years old, 47% male and 53% female, 34% ASA (American Society of Anesthesiologists) Class 1, 51% ASA Class 2, and 14% ASA Class 3, and 82% Caucasian. Most subjects received a single dose of Sugammadex 2 mg/kg or 4 mg/kg. Adverse reactions reported in ≥10% of patients at a 2, 4, or 16 mg/kg Sugammadex dose with a rate higher than the placebo rate are: vomiting, pain, nausea, hypotension, and headache. All adverse reactions occurring in ≥2% of subjects treated with Sugammadex and more often than placebo for adult subjects who received anesthesia and/or neuromuscular blocking agent in pooled Phase 1 to 3 studies are presented in Table 2. - Table 2: Percent of Subject Exposures in Pooled Phase 1 to 3 Studies with Adverse Reactions Incidence ≥ 2% - Anaphylaxis and Hypersensitivity Hypersensitivity reactions, including anaphylaxis, have occurred in both premarketing clinical trials and in post-marketing spontaneous reports. In a dedicated hypersensitivity study in healthy volunteers, the frequency of anaphylaxis was 0.3%. These reactions varied from isolated skin reactions to serious systemic reactions (i.e., anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to Sugammadex. Symptoms associated with these reactions can include: flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia, swelling of tongue, swelling of pharynx, bronchospasm and pulmonary obstructive events. Severe hypersensitivity reactions can be fatal. A randomized, double-blind study examined the incidence of drug hypersensitivity reactions in healthy volunteers given up to 3 doses of placebo (N=76), Sugammadex 4 mg/kg (N=151) or Sugammadex 16 mg/kg (N=148). Reports of suspected hypersensitivity were adjudicated by a blinded committee. The incidence of adjudicated hypersensitivity was 1%, 7% and 9% in the placebo, Sugammadex 4 mg/kg and Sugammadex 16 mg/kg groups, respectively. There were no reports of anaphylaxis after placebo or Sugammadex 4 mg/kg. There was a single case of adjudicated anaphylaxis after the first dose of Sugammadex 16 mg/kg. The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous Sugammadex was 0.3%. There was no evidence of increased frequency or severity of hypersensitivity with repeat dosing. In a previous study of similar design, there were three adjudicated cases of anaphylaxis, all after Sugammadex 16 mg/kg (incidence 1% in the 298 healthy volunteers treated with Sugammadex). - Recurrence of Neuromuscular Blockade In clinical studies with subjects treated with rocuronium or vecuronium, where Sugammadex was administered using a dose labeled for the depth of neuromuscular blockade (N=2022), an incidence of <1% was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence. - Bronchospasm In one dedicated clinical trial and in post-marketing data, in patients with a history of pulmonary complications, bronchospasm was reported as a possibly related adverse event. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of Sugammadex. 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 Disorders: Cases of marked bradycardia and bradycardia with cardiac arrest have been observed within minutes after administration of Sugammadex. Other cardiac rhythm abnormalities have included atrial fibrillation, atrioventricular block, cardiac/cardiorespiratory arrest, ST segment changes, supraventricular tachycardia/extrasystoles, tachycardia, ventricular fibrillation, and ventricular tachycardia. - General Disorders and Administration Site Conditions: Cases of Sugammadex not having the intended effect. - Immune System Disorders: Hypersensitivity events including anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, and Type 1 hypersensitivity have been reported. - Respiratory, Thoracic, and Mediastinal Disorders: Events of laryngospasm, dyspnea, wheezing, pulmonary edema, and respiratory arrest have been reported. # Drug Interactions - Summary The information reported in the next sections is based on binding affinity between Sugammadex and other drugs, preclinical experiments, clinical studies and simulations of a pharmacokinetic-pharmacodynamic (PK-PD) model. Based on these considerations, no clinically significant pharmacodynamic interactions with other drugs are expected, with the exception of toremifene and hormonal contraceptives. - Interactions Potentially Affecting the Efficacy of Sugammadex - Toremifene For toremifene, which has a relatively high binding affinity for Sugammadex and for which relatively high plasma concentrations might be present, some displacement of vecuronium or rocuronium from the complex with Sugammadex could occur. The recovery to TOF ratio to 0.9 could therefore be delayed in patients who have received toremifene on the same day of surgery. - Interaction Potentially Affecting the Efficacy of Hormonal Contraceptives In vitro binding studies indicate that Sugammadex may bind to progestogen, thereby decreasing progestogen exposure. Therefore, the administration of a bolus dose of Sugammadex is considered to be equivalent to missing dose(s) of oral contraceptives containing an estrogen or progestogen. If an oral contraceptive is taken on the same day that Sugammadex is administered, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days. In the case of non-oral hormonal contraceptives, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days. - Interference with Laboratory Tests Sugammadex may interfere with the serum progesterone assay. Interference with this test was observed at Sugammadex plasma concentrations of 100 mcg/mL, which may be observed for up to 30 minutes after a 16 mg/kg dose. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Risk Summary There are no data on Sugammadex use in pregnant women to inform any drug-associated risks. In animal reproduction studies, there was no evidence of teratogenicity following daily intravenous administration of Sugammadex to rats and rabbits during organogenesis at exposures of up to 6 and 8 times, respectively, the maximum recommended human dose (MRHD) of 16 mg/kg. However, there was an increase in the incidence of incomplete ossification of the sternebra and reduced fetal body weights in the rabbit study at 8 times the MRHD, which is a dose level in which maternal toxicity was also observed. In a pre- and postnatal development study, Sugammadex treatment resulted in an increase in early postnatal loss, which correlated with maternal behavior (increased incidence of pup cannibalism), at exposures equivalent to the MRHD and higher. The background risk of major birth defects and miscarriage for the indicated population are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. - Data - Animal Data In an embryofetal development study in rats, pregnant animals received daily intravenous administration of Sugammadex at 0, 20, 100, and 500 mg/kg (0.2, 1, and 6-times the MRHD of 16 mg/kg/day, respectively, based on AUC comparison) during organogenesis (Gestational Days 6 - 17). No treatment-related maternal and embryofetal changes were observed. In another embryofetal development study, pregnant New Zealand white rabbits received daily intravenous administration of Sugammadex at 0, 20, 65, 200 mg/kg (0.6, 2, and 8 times the MRHD, respectively, based on AUC comparison) during organogenesis (Gestational Days 6-18). Fetal body weight decreases (10 and 14%, respectively) were observed in the offspring at maternal doses of 65 mg/kg and 200 mg/kg. In addition, incomplete ossification of sternebra, and unossified 1st metacarpal were noted at a maternal dose of 200 mg/kg/day. Maternal toxicity was also observed at 200 mg/kg. Considering the observed effects of Sugammadex on bone, it is possible that these findings may be attributable to drug. There was no evidence of teratogenicity at any dose. In a prenatal and postnatal development study, pregnant rats were administered Sugammadex intravenously at 0, 30, 120, and 500 mg/kg (0.3, 1, and 6 times the MRHD, respectively, based on AUC comparison) from Gestational Day (GD) 6 to Postnatal Day (PND) 21 (corresponding to the beginning of organogenesis through parturition and subsequent pup weaning). Postnatal loss during PND 1-4 was noted across control litters and treated litters from dams receiving Sugammadex as a result of pup cannibalization by dams. Overall incidence of affected litters was 2, 1, 4, and 3 litters, respectively, at 0, 30, 120, or 500 mg/kg/day. The reason for the increased cannibalization is not known. An effect of Sugammadex on steroidal hormones and/or pheromones cannot be ruled out. In addition, there were no drug-related effects on parturition in rats during evaluations for prenatal or postnatal development. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sugammadex in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sugammadex during labor and delivery. ### Nursing Mothers - Risk Summary No data are available regarding the presence of Sugammadex in human milk, the effects of Sugammadex on the breast fed infant, or the effects of Sugammadex on milk production. However, Sugammadex is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sugammadex and any potential adverse effects on the breastfed infant from Sugammadex or from the underlying maternal condition. - Data In a milk excretion study in rat dams following single intravenous dose of 20 mg/kg Sugammadex on Postnatal Day 9, the maximum drug level was achieved at about 30 minutes after dosing with a ratio of milk to plasma level approximately 1:1. The oral exposure via milk did not induce effects on survival, body weight and physical or the behavioral developmental parameters monitored in rats in the prenatal and postnatal development studies. ### Pediatric Use The safety and efficacy of Sugammadex in pediatric patients have not been established. - Juvenile Animal Studies In a bone deposition study, Sugammadex concentrations were significantly higher in juvenile rats compared to adult rats (13% vs. 3% of the administered dose, respectively) following a single intravenous (IV) dose at 30 mg/kg (0.3 times the MRHD based on adult AUC comparison). In a juvenile animal bone toxicity study, 7-day old rats were dosed intravenously once daily for 28 days with 0, 30, 120, and 500 mg/kg Sugammadex (approximately 0.1, 0.6, and 3 times the MRHD, respectively, by adult AUC comparison). Sugammadex at 120 and 500 mg/kg decreased ulna and femur bone lengths by approximately 3%, which did not recover after an 8-week treatment-free period. Reversible whitish discoloration and disturbance of enamel formation were also observed in the incisors at these dose levels. In molars, this effect was only observed at 500 mg/kg. The no-observed-effect-level (NOEL) was 30 mg/kg. In a second juvenile animal bone toxicity study, 7-day old rats were dosed once weekly for 8 weeks with 0, 7.5, 30, and 120 mg/kg (up to 1.2 times the MRHD of 16 mg/kg based on adult AUC comparison). No adverse effects on bone or teeth were noted. ### Geriatic Use Sugammadex has been administered in a dedicated clinical study to a total 102 geriatric patients that compared the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 mg/kg Sugammadex given at the reappearance of T2 in 65-74 year-olds (N=62) and ≥75 year-olds (N=40) compared with 18-64 year-olds (N=48). The median time to recovery of the TOF (T4/T1) ratio to 0.9 in 18-64 year-olds was 2.2 minutes; in 65-74 year-olds it was 2.5 minutes, and in ≥75 year-olds it was 3.6 minutes. For time to recovery from neuromuscular blockade induced by rocuronium following administration of 4 mg/kg Sugammadex given at 1-2 PTCs, results across clinical trials revealed a median recovery of 2.5 minutes for geriatric patients (≥65 years, N=63) versus 2.0 minutes, for adults aged 18-64 years (N=359). Hence no dose adjustment is necessary in geriatric patients with normal organ function. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ### Gender There is no FDA guidance on the use of Sugammadex with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sugammadex with respect to specific racial populations. ### Renal Impairment This drug is known to be substantially excreted by the kidney. Effect of mild or moderate renal impairment (creatine clearance ≥30 and ≤80 mL/min) on Sugammadex PK and PD was obtained from a study in elderly patients. Although clearance of drug decreased in elderly subjects with mild and moderate renal impairment, there was no significant difference in the ability of Sugammadex to reverse the pharmacodynamic effect of rocuronium. Hence, no dosage adjustment is necessary for mild and moderate renal impairment. Sugammadex is not recommended for use in patients with severe renal impairment (creatine clearance <30 mL/min) due to insufficient safety information combined with the prolonged and increased overall exposure in these patients. ### Hepatic Impairment Sugammadex is not metabolized nor excreted by the liver; therefore, dedicated trials in patients with hepatic impairment have not been conducted. Exercise caution when administering Sugammadex to patients with hepatic impairment accompanied by coagulopathy or severe edema. ### Females of Reproductive Potential and Males - Contraception Upon administration of Sugammadex, the efficacy of hormonal contraceptives may be reduced for up to 7 days. Advise female patients of reproductive potential using hormonal contraceptives to use an additional, non-hormonal contraceptive for the next 7 days following Sugammadex administration. ### Immunocompromised Patients There is no FDA guidance one the use of Sugammadex in patients who are immunocompromised. ### Pulmonary Patients One trial of 77 patients who were diagnosed with or have a history of pulmonary complications investigated the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 mg/kg or 4 mg/kg Sugammadex given at the first signs of recovery (reappearance of T2). The trial showed that for these patients the median time to recovery of the T4/T1 ratio to 0.9 was 2.1 minutes after a dose of 2 mg/kg Sugammadex and 1.9 minutes after a dose of 4 mg/kg Sugammadex. This is similar to the median values observed in the other trials; therefore, no dosage adjustment is necessary. # Administration and Monitoring ### Administration Sugammadex injection, for intravenous use, should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses and timing of Sugammadex administration should be based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred. Administer Sugammadex intravenously as a single bolus injection. The bolus injection may be given over 10 seconds, into an existing intravenous line. Sugammadex has only been administered as a single bolus injection in clinical trials. From the time of Sugammadex administration until complete recovery of neuromuscular function, monitor the patient to assure adequate ventilation and maintenance of a patent airway. Satisfactory recovery should be determined through assessment of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation. The recommended dose of Sugammadex does not depend on the anesthetic regimen. ### Monitoring There is limited information regarding Sugammadex Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Sugammadex and IV administrations. # Overdosage In premarketing clinical trials, one case of accidental overdose with 40 mg/kg Sugammadex was reported without significant effects. Sugammadex can be removed using hemodialysis with a high-flux filter, but not with a low-flux filter. Based upon clinical studies, Sugammadex concentrations in plasma are reduced with a high-flux filter by about 70% after a 3- to 6-hour dialysis session. # Pharmacology ## Mechanism of Action Sugammadex is a modified gamma cyclodextrin. It forms a complex with the neuromuscular blocking agents rocuronium and vecuronium, and it reduces the amount of neuromuscular blocking agent available to bind to nicotinic cholinergic receptors in the neuromuscular junction. This results in the reversal of neuromuscular blockade induced by rocuronium and vecuronium. ## Structure There is limited information regarding Sugammadex Structure in the drug label. ## Pharmacodynamics Sugammadex has been administered in doses ranging from 0.5 mg/kg to 16 mg/kg in dose response trials of rocuronium-induced blockade (0.6, 0.9, 1 and 1.2 mg/kg with and without maintenance doses) and vecuronium-induced blockade (0.1 mg/kg with or without maintenance doses) at different time points/depths of block. In these trials a clear dose-response relationship was observed. Sugammadex may contain up to 7% of the mono OH-derivative of Sugammadex. In preclinical pharmacology studies, the mono OH-derivative was demonstrated to have ~50% of the affinity as Sugammadex for rocuronium and vecuronium and that product with up to 7% of the mono OH-derivative has nearly similar efficacy in reversing rocuronium- or vecuronium-induced blockade. Although Sugammadex has greatest affinity for aminosteroid neuromuscular blocking agents such as rocuronium and vecuronium, plasma levels of endogenous or exogenous compounds with a similar steroidal structure, such as some hormones, hormonal contraceptives, and pheromones may also be reduced following administration of Sugammadex. - Cardiac Electrophysiology At a dose 2 times the maximum recommended dose, Sugammadex does not prolong the QTc interval to any clinically relevant extent. ## Pharmacokinetics The Sugammadex pharmacokinetic parameters were calculated from the total sum of non-complex-bound and complex-bound concentrations of Sugammadex. Pharmacokinetic parameters as clearance and volume of distribution are assumed to be the same for non-complex-bound and complex-bound Sugammadex in anesthetized patients. - Distribution The observed steady-state volume of distribution of Sugammadex is approximately 11 to 14 liters in adult patients with normal renal function (based on conventional, non-compartmental pharmacokinetic analysis). Neither Sugammadex nor the complex of Sugammadex and rocuronium binds to plasma proteins or erythrocytes, as was shown in vitro using male human plasma and whole blood. Sugammadex exhibits linear kinetics in the dosage range of 1 to 16 mg/kg when administered as an IV bolus dose. In nonclinical drug distribution studies, Sugammadex is retained in sites of active mineralization, such as bone and teeth, with a mean half-life of 172 and 8 days, respectively. - Metabolism In clinical studies, no metabolites of Sugammadex have been observed and only renal excretion of the unchanged product was observed as the route of elimination. - Elimination In adult anesthetized patients with normal renal function, the elimination half-life (t1/2) of Sugammadex is about 2 hours and the estimated plasma clearance is about 88 mL/min (based on compartmental pharmacokinetic analysis). A mass balance study demonstrated that >90% of the dose was excreted within 24 hours. Ninety-six percent (96%) of the dose was excreted in urine, of which at least 95% could be attributed to unchanged Sugammadex. Excretion via feces or expired air was less than 0.02% of the dose. Administration of Sugammadex to healthy volunteers resulted in increased renal elimination of rocuronium in complex. - Patients with Renal Impairment Sugammadex is known to be substantially excreted by the kidney. The half-life of Sugammadex in patients with mild, moderate and severe renal impairment is 4, 6, and 19 hours, respectively. In one study, exposure to Sugammadex was prolonged, leading to 17-fold higher overall exposure in patients with severe renal impairment. Low concentrations of sugammadex are detectable for at least 48 hours post-dose in patients with severe renal impairment. In a second study comparing subjects with moderate or severe renal impairment to subjects with normal renal function, Sugammadex clearance progressively decreased and t1/2 was progressively prolonged with declining renal function. Exposure was 2-fold and 5-fold higher in subjects with moderate and severe renal impairment, respectively. Sugammadex concentrations were no longer detectable beyond 7 days post-dose in subjects with severe renal impairment. - Age: Geriatric Population Geriatric patients may have mild or moderate renal impairment. Population pharmacokinetic analysis indicated that, beyond the effects of a decreased creatinine clearance, increased age has limited impact on Sugammadex PK parameters. - Sex No pharmacokinetic differences between male and female subjects were observed. - Race In a study in healthy Japanese and Caucasian subjects no clinically relevant differences in pharmacokinetic parameters were observed. Limited data do not indicate differences in pharmacokinetic parameters in Black or African Americans. ## Nonclinical Toxicology - Carcinogenesis Long-term animal studies to evaluate the carcinogenic potential of Sugammadex have not been conducted. - Mutagenesis Sugammadex and its mono OH-derivative tested negatively in in vitro bacterial reverse mutation assays (Ames test), in vitro chromosomal aberration assays in human peripheral blood lymphocytes, and in vivo micronucleus assays in mice and rats. - Impairment of Fertility A fertility and early embryonic development study in Sprague-Dawley rats in which male rats were treated daily for 29 days prior to mating and through the mating period and female rats were treated daily for 14 days prior to mating to Day 5 post-coitum via intravenous administration of Sugammadex at 20, 100, and 500 mg/kg (0.2, 1, and 6 times the MRHD of 16 mg/kg, respectively, based on AUC comparison) did not show adverse effects on fertility. Bone and teeth retention of Sugammadex occurred in rats after intravenous injection, with mean half-lives of 172 and 8 days, respectively. Sugammadex bound to hydroxyapatite in an in vitro study and distributed in the bone formation area where hydroxyapatite is present for mineralization in vivo. In adult rat bone toxicity studies, a single dose of Sugammadex at 2000 mg/kg (approximately 24 times the maximum recommended human dose (MRHD) of 16 mg/kg by AUC comparison) administered to adult rats caused a slight increase in bone resorption, but had no effect on teeth color. No adverse bone effects were seen following a single dose of Sugammadex at 500 mg/kg (4 times the MRHD dose of 16 mg/kg based on plasma AUC comparison). In a bone repair study, adult rats were treated with intravenous Sugammadex weekly for 6 weeks at 0, 30, 120, and 500 mg/kg (approximately 0.4, 1, and 6 times the MRHD, respectively, by AUC comparison). Based on histological data, high dose animals with post-fracture treatment, showed a statistically significant increase in callus formation and decrease in bone formation, suggesting a potential for a slight delay in the bone healing process. However there were no statistically significant effects on bone volume or bone mineral density. In juvenile animal studies, bone and teeth deposition was significantly higher in juvenile rats compared to adults. In addition, Sugammadex administered to juvenile rats daily for 4 weeks caused slight bone length decrease (approximately 3%), which did not recover after an 8-week treatment-free period, and reversible whitish discoloration of the teeth at a dose approximately 0.6 times the MRHD, while weekly administration for 8 weeks did not produce similar changes in bone and teeth at doses up to 1.2 times the MRHD. # Clinical Studies - Controlled Clinical Studies - Comparative Study of Sugammadex versus Neostigmine as a Reversal Agent for Neuromuscular Blockade Induced by Rocuronium or Vecuronium at Reappearance of T2 (Moderate Blockade) A multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study comparing Sugammadex and neostigmine enrolled 189 patients (87 women and 102 men, 95% were ASA class 1 and 2 and 99% were Caucasian, median weights were 72 kg and 76 kg and median ages were 50 years and 51 years in the rocuronium and vecuronium groups, respectively). Patients were randomly assigned to the rocuronium or vecuronium group and underwent elective surgical procedures under general anesthesia that required endotracheal intubation and maintenance of neuromuscular blockade. The surgical procedures were mainly endocrine, ocular, ENT, abdominal (gynecological, colorectal, urological), orthopedic, vascular, or dermatological. At the reappearance of T2, after the last dose of rocuronium or vecuronium, 2 mg/kg Sugammadex or 50 mcg/kg neostigmine was administered in a randomized order as a single bolus injection. The time from start of administration of Sugammadex or neostigmine to recovery of the TOF (T4/T1) ratio to 0.9 was assessed. Generally, a T4/T1 ratio ≥0.9 correlates with recovery from neuromuscular blockade. Return of the T4/T1 ratio to 0.9 after the reappearance of T2 was overall faster with Sugammadex 2 mg/kg as compared to neostigmine 50 mcg/kg in the setting of rocuronium or vecuronium-induced neuromuscular blockade (Figures 1 and 2). - Figure 1: Time (Minutes) from Administration of Sugammadex or Neostigmine at the Reappearance of T2 after Rocuronium to Recovery of the T4/T1 Ratio to 0.9 - Figure 2: Time (Minutes) from Administration of Sugammadex or Neostigmine at the Reappearance of T2 after Vecuronium to Recovery of the T4/T1 Ratio to 0.9 - Comparative Study of Sugammadex versus Neostigmine as a Reversal Agent for Neuromuscular Blockade Induced by Rocuronium or Vecuronium at 1 to 2 PTCs (Deep Blockade) A multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study comparing Sugammadex and neostigmine enrolled 157 patients (86 women and 71 men; 8% ASA class 1, 71% class 2, and 21% class 3; 79% Caucasian; median weights of 81 kg and 84 kg, and median ages of 54 years and 56 years in the rocuronium and vecuronium groups, respectively). Patients were randomly assigned to the rocuronium or vecuronium group and underwent elective surgical procedures under general anesthesia that required endotracheal intubation and maintenance of neuromuscular blockade. The surgical procedures were mainly abdominal (gynecological, colorectal, urological), orthopedic, reconstructive, or neurological. At 1 to 2 PTCs, after the last dose of rocuronium or vecuronium, 4 mg/kg Sugammadex or 70 mcg/kg neostigmine was administered in a randomized order as a single bolus injection. The time from start of administration of Sugammadex or neostigmine to recovery of the TOF (T4/T1) ratio to 0.9 was assessed, although neostigmine was not expected to reverse neuromuscular blockade at a depth of 1 to 2 PTCs. Generally, a T4/T1 ratio ≥0.9 correlates with recovery from neuromuscular blockade. Return of the T4/T1 ratio to 0.9 in patients with 1 to 2 PTCs with Sugammadex 4 mg/kg had a wider range of recovery times but the median time to recovery was comparable to the study of reversal at T2 (2.7 minutes with 25th and 75th percentiles of 2.1 and 4.3 minutes for rocuronium [N=37], and 3.3 minutes with 25th and 75th percentiles of 2.3 and 6.6 minutes for vecuronium [N=47]). There were 7 and 6 censored observations in the rocuronium and vecuronium groups, respectively. - Reversal of Neuromuscular Blockade 3 Minutes after Rocuronium 1.2 mg/kg Time to recovery from neuromuscular blockade induced by succinylcholine compared with recovery from neuromuscular blockade induced by rocuronium followed 3 minutes later with Sugammadex was assessed in a multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study. The study was conducted in 110 patients (64 women and 46 men, ASA class 1 and 2, 78% were Caucasian, median weight was 70 kg, median age was 43 years). Patients underwent elective surgical procedures under general anesthesia that required endotracheal intubation and a short duration of neuromuscular relaxation. The laparoscopic or open surgical procedures were mainly gynecological, orthopedic, or reconstructive. Return of the first twitch in a TOF (T1) to 10% of baseline was compared between Sugammadex 16 mg/kg for reversal of rocuronium 1.2 mg/kg versus spontaneous recovery from succinylcholine 1 mg/kg. Recovery to T1 of 10% of baseline (relative to the time of administration of rocuronium or succinylcholine) was overall faster in the rocuronium/Sugammadex group compared with succinylcholine alone (Table 3). - Table 3: Time (minutes) from Start of Administration of Rocuronium or Succinylcholine to Recovery of T1 to 10% of Baseline BRIDION: Sugammadex's Brand name # How Supplied - Sugammadex 2-mL single-dose vials containing 200 mg Sugammadex (100 mg/mL) Box of 10 NDC 0006-5423-12 - Sugammadex 5-mL single-dose vials containing 500 mg Sugammadex (100 mg/mL) Box of 10 NDC 0006-5423-15 The packaging of this product is not made with natural rubber latex. ## Storage Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. When not protected from light, the vial should be used within 5 days. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise females of reproductive potential using hormonal contraceptives that Sugammadex may reduce the contraceptive effect. Instruct females to use an additional, non-hormonal method of contraception for the next 7 days following Sugammadex administration # Precautions with Alcohol Alcohol-Sugammadex interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names BRIDION® # Look-Alike Drug Names There is limited information regarding Sugammadex Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Sugammadex
1582b65400c597b6ca2eb200f486a17eeef69c22	wikidoc	Sugar Pine	Sugar Pine The Sugar Pine (Pinus lambertiana; family Pinaceae) is a species of pine that occurs in the mountains of Oregon and California in the western United States, and Baja California in northwestern Mexico; specifically the Sierra Nevada, the Cascade Range, the Coast Ranges, and the Sierra San Pedro Martir. This tree is the largest species of pine, commonly growing to 40-60 meters (130-200 feet) tall, exceptionally up to 81 m (265 ft) tall, and with a trunk diameter of 1.5-2.5 m (5-8 ft), exceptionally 3.5 m (11 ft). It is a member of the white pine group, Pinus subgenus Strobus, and like all members of that group, the leaves ('needles') are in fascicles (bundles) of five, with a deciduous sheath. They are 6-11 cm (2-4 inch) long. Sugar Pine is notable for having the longest cones of any conifer, mostly 25-50 cm (10-20 in) long, exceptionally up to 66 cm (26 in) long (although the cones of the Coulter pine are more massive). The seeds are 10-12 mm (0.4-0.5 in) long, with a 2-3 cm (0.75-1.2 in) long wing that aids wind dispersal. The Sugar Pine has been severely affected by the White Pine Blister Rust (Cronartium ribicola), a fungus that was accidentally introduced from Europe in 1909. A high proportion of the Sugar Pine has been killed by the blister rust, particularly in the northern part of the species' range that has experienced the rust for a longer period of time. The rust has also destroyed much of the Western White Pine and Whitebark Pine throughout their ranges. The U.S. Forest Service has a program (see link below) for developing rust-resistant Sugar Pine and Western White Pine. Seedlings of these trees have been introduced into the wild. The Sugar Pine Foundation in the Lake Tahoe Basin has been successful in finding resistant sugar pine seed trees and has demonstrated that it is important for private citizens to assist the U.S. Forest Service in restoring this species. Naturalist John Muir considered Sugar Pine to be the "king of the conifers". The name comes from the sweet resin, which Muir found preferable to maple sugar. # Folklore In the Achumawi origin belief system, Annikadel, the creator, makes one of the 'First People' by intentionally dropping a Sugar Pine seed in a place suitable for growth. One of the descendants in this ancestry is Sugarpine-Cone man, who has a handsome son named Ahsoballache. After Ahsoballache marries the daughter of To'kis the Chipmunk-woman, his grandfather insists that the new couple have a child. To this end, the grandfather breaks open a scale from a Sugar Pine cone, and secretly instructs Ahsoballache to immerse the scale's contents in spring water and hide it inside a covered basket. Ahsoballache performs the tasks that night; at the next dawn, he and his wife discover the infant Edechewe near their bed. # References and external links - Template:IUCN2006 - US Forestry Service: Pinus lambertiana - Arboretum de Villardebelle: photo of a cone - Gymnosperm Database: Pinus lambertiana - Flora of North America: Pinus lambertiana - US Forest Service, Dorena Genetic Resource Center (rust resistance program) - The Sugar Pine Foundation (Sugar Pine and Western White Pine Restoration Program) - Muir, J. (1911). My First Summer in the Sierra. cs:Borovice Lambertova no:Sukkerfuru uk:Сосна Ламберта	Sugar Pine The Sugar Pine (Pinus lambertiana; family Pinaceae) is a species of pine that occurs in the mountains of Oregon and California in the western United States, and Baja California in northwestern Mexico; specifically the Sierra Nevada, the Cascade Range, the Coast Ranges, and the Sierra San Pedro Martir. This tree is the largest species of pine, commonly growing to 40-60 meters (130-200 feet) tall, exceptionally up to 81 m (265 ft) tall, and with a trunk diameter of 1.5-2.5 m (5-8 ft), exceptionally 3.5 m (11 ft). It is a member of the white pine group, Pinus subgenus Strobus, and like all members of that group, the leaves ('needles') are in fascicles (bundles) of five, with a deciduous sheath. They are 6-11 cm (2-4 inch) long. Sugar Pine is notable for having the longest cones of any conifer, mostly 25-50 cm (10-20 in) long, exceptionally up to 66 cm (26 in) long (although the cones of the Coulter pine are more massive). The seeds are 10-12 mm (0.4-0.5 in) long, with a 2-3 cm (0.75-1.2 in) long wing that aids wind dispersal. The Sugar Pine has been severely affected by the White Pine Blister Rust (Cronartium ribicola), a fungus that was accidentally introduced from Europe in 1909. A high proportion of the Sugar Pine has been killed by the blister rust, particularly in the northern part of the species' range that has experienced the rust for a longer period of time. The rust has also destroyed much of the Western White Pine and Whitebark Pine throughout their ranges.[1] The U.S. Forest Service has a program (see link below) for developing rust-resistant Sugar Pine and Western White Pine. Seedlings of these trees have been introduced into the wild. The Sugar Pine Foundation in the Lake Tahoe Basin has been successful in finding resistant sugar pine seed trees and has demonstrated that it is important for private citizens to assist the U.S. Forest Service in restoring this species. [2] Naturalist John Muir considered Sugar Pine to be the "king of the conifers". The name comes from the sweet resin, which Muir found preferable to maple sugar.[3] # Folklore In the Achumawi origin belief system, Annikadel, the creator, makes one of the 'First People' by intentionally dropping a Sugar Pine seed in a place suitable for growth. One of the descendants in this ancestry is Sugarpine-Cone man, who has a handsome son named Ahsoballache. After Ahsoballache marries the daughter of To'kis the Chipmunk-woman, his grandfather insists that the new couple have a child. To this end, the grandfather breaks open a scale from a Sugar Pine cone, and secretly instructs Ahsoballache to immerse the scale's contents in spring water and hide it inside a covered basket. Ahsoballache performs the tasks that night; at the next dawn, he and his wife discover the infant Edechewe near their bed. # References and external links - Template:IUCN2006 - US Forestry Service: Pinus lambertiana - Arboretum de Villardebelle: photo of a cone - Gymnosperm Database: Pinus lambertiana - Flora of North America: Pinus lambertiana - US Forest Service, Dorena Genetic Resource Center (rust resistance program) - The Sugar Pine Foundation (Sugar Pine and Western White Pine Restoration Program) - Muir, J. (1911). My First Summer in the Sierra. cs:Borovice Lambertova no:Sukkerfuru uk:Сосна Ламберта	https://www.wikidoc.org/index.php/Sugar_Pine
f5b1fe26c95a0274994e37176881c95aafb31b64	wikidoc	Suggestion	Suggestion Suggestion is the name given to the psychological process by which one person may guide the thoughts, feelings or behaviour of another. For nineteenth century writers on psychology such as William James the words "suggest" and "suggestion" were used in senses very close to those which they have in common speech; one idea was said to suggest another when it brought that other idea to mind. Early scientific studies of hypnosis by scientists such as Clark Leonard Hull led to the extension of the meaning of these words in a special and technical sense (Hull, 1933). Modern scientific study of hypnosis, which has followed the pattern of Hull's work, separates two essential factors: "trance" and suggestion (Heap, 1996). The state of mind induced by "trance" is said to come about via the process of a hypnotic induction; essentially instructions and suggestions that an individual will enter a hypnotic state. Once a subject has entered hypnosis, suggestions are given which can produce the effects sought by the hypnotist. Commonly used suggestions on measures of "suggestibility" or "susceptibility" (or, for those with a different theoretical orientation, "hypnotic talent") include suggestions that one's arm is getting lighter and floating up in the air, or the suggestion that a fly is buzzing around your head. The "classic" response to an accepted suggestion that one's arm is beginning to float in the air is that the subject perceives the intended effect as happening involuntarily (Weitzenhoffer, 1980). Suggestions, however, can also have an effect in the absence of a hypnosis. These so-called "waking suggestions" are given in precisely the same way as "hypnotic suggestions" (i.e., suggestions given within hypnosis) and can produce strong changes in perceptual experience. Experiments on suggestion, in the absence of hypnosis, were conducted by early researchers such as Hull (1933). More recently, researchers such as Nicholas Spanos and Irving Kirsch have conducted experiments investigating such non-hypnotic-suggestibility and found a strong correlation between people's responses to suggestion both in- and outside hypnosis (Kirsch & Braffman, 2001). In addition to the kinds of suggestion typically delivered by researchers interested in hypnosis there are other forms of suggestibility, though not all are considered interrelated. These include: primary and secondary suggestibility (older terms for non-hypnotic and hypnotic suggestibility respectively), hypnotic suggestibility (i.e., the response to suggestion measured within hypnosis), and interrogative suggestibility (yielding to interrogative questions, and shifting responses when interrogative pressure is applied: see Gudjonsson suggestibility scale.	Suggestion Suggestion is the name given to the psychological process by which one person may guide the thoughts, feelings or behaviour of another. For nineteenth century writers on psychology such as William James the words "suggest" and "suggestion" were used in senses very close to those which they have in common speech; one idea was said to suggest another when it brought that other idea to mind. Early scientific studies of hypnosis by scientists such as Clark Leonard Hull led to the extension of the meaning of these words in a special and technical sense (Hull, 1933). Modern scientific study of hypnosis, which has followed the pattern of Hull's work, separates two essential factors: "trance" and suggestion (Heap, 1996). The state of mind induced by "trance" is said to come about via the process of a hypnotic induction; essentially instructions and suggestions that an individual will enter a hypnotic state. Once a subject has entered hypnosis, suggestions are given which can produce the effects sought by the hypnotist. Commonly used suggestions on measures of "suggestibility" or "susceptibility" (or, for those with a different theoretical orientation, "hypnotic talent") include suggestions that one's arm is getting lighter and floating up in the air, or the suggestion that a fly is buzzing around your head. The "classic" response to an accepted suggestion that one's arm is beginning to float in the air is that the subject perceives the intended effect as happening involuntarily (Weitzenhoffer, 1980). Suggestions, however, can also have an effect in the absence of a hypnosis. These so-called "waking suggestions" are given in precisely the same way as "hypnotic suggestions" (i.e., suggestions given within hypnosis) and can produce strong changes in perceptual experience. Experiments on suggestion, in the absence of hypnosis, were conducted by early researchers such as Hull (1933). More recently, researchers such as Nicholas Spanos and Irving Kirsch have conducted experiments investigating such non-hypnotic-suggestibility and found a strong correlation between people's responses to suggestion both in- and outside hypnosis (Kirsch & Braffman, 2001). In addition to the kinds of suggestion typically delivered by researchers interested in hypnosis there are other forms of suggestibility, though not all are considered interrelated. These include: primary and secondary suggestibility (older terms for non-hypnotic and hypnotic suggestibility respectively), hypnotic suggestibility (i.e., the response to suggestion measured within hypnosis), and interrogative suggestibility (yielding to interrogative questions, and shifting responses when interrogative pressure is applied: see Gudjonsson suggestibility scale.	https://www.wikidoc.org/index.php/Suggestion
a59c65219b04f7a5de64e1c6e740a1f419267713	wikidoc	Sulfa drug	Sulfa drug # Overview The term sulfa drug refers to the class of medications called sulfonamides. This class includes several antibiotics, including sulfamethoxazole, sulfasalazine, and sulfacetamide, among others. It is important to make a distinction between sulfa drugs and other sulfur-containing drugs and additives, such as sulfates and sulfites, which are chemically unrelated to the sulfonamide group, and do not cause the same hypersensitivity reactions seen in the sulfonamides. # Functions These antibiotics are used to treat pneumocystis jiroveci pneumonia, urinary tract infections, shigellosis, and certain protozoan infections. The sulfonamide chemical moiety is also present in other medications that are not antimicrobials, including thiazide diuretics (including hydrochorothiazide, metolazone, and indapamide, among others), sulfonylureas (including glipizide, glyburide, among others), and acetazolamide. Sulfasalazine, in addition to its use as an antibiotic, is also utilized in the treatment of inflammatory bowel disease. # Adverse reactions Approximately 3% of the general population have adverse reactions when treated with sulfonamide antimicrobials. Of note is the observation that patients with HIV have a much higher prevalence, at about 60%. People who have a hypersensitivity reaction to one member of the sulfonamide class are likely to have a similar reaction to others. Hypersensitivity reactions are less common in non-antibiotic sulfonamides, and, though controversial, the available evidence suggests those with hypersensitivity to sulfonamide antibiotics do not have an increased risk of hypersensitivity reaction to the non-antibiotic agents. Two regions of the sulfonamide antibiotic chemical structure are implicated in the hypersensitivity reactions associated with the class. - The first is the N1 heterocyclic ring, which causes a type I hypersensitivity reaction. - The second is the N4 amino nitrogen that, in a stereospecific process, forms reactive metabolites that cause either direct cytotoxicity or immunologic response. The non-antibiotic sulfonamides lack both of these structures. The most common manifestation of a hypersensitivity reaction to sulfa drugs are rash and hives. However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, including Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic anemia, thrombocytopenia, and fulminant hepatic necrosis, among others.	Sulfa drug Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The term sulfa drug refers to the class of medications called sulfonamides. This class includes several antibiotics, including sulfamethoxazole, sulfasalazine, and sulfacetamide, among others. It is important to make a distinction between sulfa drugs and other sulfur-containing drugs and additives, such as sulfates and sulfites, which are chemically unrelated to the sulfonamide group, and do not cause the same hypersensitivity reactions seen in the sulfonamides. # Functions These antibiotics are used to treat pneumocystis jiroveci pneumonia, urinary tract infections, shigellosis, and certain protozoan infections. The sulfonamide chemical moiety is also present in other medications that are not antimicrobials, including thiazide diuretics (including hydrochorothiazide, metolazone, and indapamide, among others), sulfonylureas (including glipizide, glyburide, among others), and acetazolamide. Sulfasalazine, in addition to its use as an antibiotic, is also utilized in the treatment of inflammatory bowel disease. # Adverse reactions Approximately 3% of the general population have adverse reactions when treated with sulfonamide antimicrobials. Of note is the observation that patients with HIV have a much higher prevalence, at about 60%[1]. People who have a hypersensitivity reaction to one member of the sulfonamide class are likely to have a similar reaction to others. Hypersensitivity reactions are less common in non-antibiotic sulfonamides, and, though controversial, the available evidence suggests those with hypersensitivity to sulfonamide antibiotics do not have an increased risk of hypersensitivity reaction to the non-antibiotic agents[2]. Two regions of the sulfonamide antibiotic chemical structure are implicated in the hypersensitivity reactions associated with the class. - The first is the N1 heterocyclic ring, which causes a type I hypersensitivity reaction. - The second is the N4 amino nitrogen that, in a stereospecific process, forms reactive metabolites that cause either direct cytotoxicity or immunologic response. The non-antibiotic sulfonamides lack both of these structures[3]. The most common manifestation of a hypersensitivity reaction to sulfa drugs are rash and hives. However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, including Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic anemia, thrombocytopenia, and fulminant hepatic necrosis, among others[4].	https://www.wikidoc.org/index.php/Sulfa_drug
3fd1c4623d37f6ffef6d58108bda831933d97c2a	wikidoc	Sulodexide	Sulodexide # Overview Sulodexide is a highly purified mixture of glycosaminoglycans composed of low molecular weight heparin (80%) and dermatan sulfate (20%). # Pharmacology The low molecular weight of both sulodexide fractions allows for extensive oral absorption compared to unfractionated heparin. The pharmacological effects of sulodexide differ substantially from other glycosaminoglycans and are mainly characterized by a prolonged half-life and reduced effect on global coagulation and bleeding parameters. Due to the presence of both glycosaminoglycan fractions, sulodexide potentiates the antiprotease activities of both antithrombin III and heparin cofactor II simultaneously. # Uses Clinically, sulodexide is used for the prophylaxis and treatment of thromboembolic diseases however recent research has also demonstrated the beneficial effects of sulodexide in animal models of reperfusion injury and the treatment of diabetic nephropathy. In combination with Melatonin, Sulodexide have been shown to be a viable treatment option for patients suffering from central or sensorineural tinnitus.	Sulodexide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Sulodexide is a highly purified mixture of glycosaminoglycans composed of low molecular weight heparin (80%) and dermatan sulfate (20%). # Pharmacology The low molecular weight of both sulodexide fractions allows for extensive oral absorption compared to unfractionated heparin. The pharmacological effects of sulodexide differ substantially from other glycosaminoglycans and are mainly characterized by a prolonged half-life and reduced effect on global coagulation and bleeding parameters.[1] Due to the presence of both glycosaminoglycan fractions, sulodexide potentiates the antiprotease activities of both antithrombin III and heparin cofactor II simultaneously.[2] # Uses Clinically, sulodexide is used for the prophylaxis and treatment of thromboembolic diseases however recent research has also demonstrated the beneficial effects of sulodexide in animal models of reperfusion injury[3] and the treatment of diabetic nephropathy.[4][5][6] In combination with Melatonin, Sulodexide have been shown to be a viable treatment option for patients suffering from central or sensorineural tinnitus.[7][8]	https://www.wikidoc.org/index.php/Sulodexide
0ebf523b13e4dc01074f7c6c46af43d0dfad917c	wikidoc	Sunglasses	Sunglasses Sunglasses or sun glasses are a visual aid, variously termed spectacles or glasses, which feature lenses that are coloured or darkened to prevent strong light from reaching the eyes. Many people find direct sunlight too bright to be comfortable, especially when reading from paper in direct sunlight. In outdoor activities like riding, skiing and flying, the eye can receive more light than usual. It has been recommended to wear these kind of glasses whenever outside to protect the eyes from ultraviolet radiation, which can lead to the development of a cataract. Sunglasses have also been associated with celebrities and film actors primarily due to the desire to mask identity, but in part due to the lighting involved in production typically being stronger than natural light and uncomfortable to the naked eye. Since the 1950s sunglasses have been popular as a fashion statement, especially on the beach. # Uses Hiding one's eyes has implications in face-to-face communication: It can hide weeping, being one of the signs of mourning, makes eye contact impossible which can be intimidating, like in the stereotype of the guardian of a chain gang as depicted in Cool Hand Luke, or can show detachment, which is considered cool in some circles. Darkened sunglasses of particular shapes may be in vogue as a fashion accessory. Note that normal glasses are very rarely worn without a practical purpose — curiously, they can project an image of uncool nerdiness that sunglasses do not have. The impact on nonverbal communication and the cool image are among the reasons for wearing sunglasses by night or indoors. People may also wear sunglasses to hide dilated or contracted pupils or bloodshot eyes (which would reveal drug use), recent physical abuse, or to compensate for increased photosensitivity. Fashion trends are another reason for wearing sunglasses, particularly designer sunglasses. People with severe visual impairment, such as the blind, often wear sunglasses in order to avoid making others uncomfortable — not seeing eyes may be better than seeing eyes which seem to look in the wrong direction. Those whose eyes have an abnormal appearance (for example due to cataract) or which jerk uncontrollably (nystagmus) may also do so. ## Visual clarity and comfort Sunglasses can improve visual comfort and visual clarity by protecting the eye from glare. Various types of disposable sunglasses are dispensed to patients after receiving mydriatic eye drops during eye examinations. ## Protection Excessive exposure to ultraviolet radiation (UV) can cause short-term and long-term ocular problems such as photokeratitis, snow blindness, cataracts, pterygium, and various eye cancers. Medical experts often advise the public on the importance of wearing sunglasses to protect the eyes from UV. In the European Union, a CE mark identifies glasses fulfilling quality regulations. In the preparation for solar eclipses, health authorities often warn against looking at the sun through sunglasses alone. There is no demonstrated correlation between high prices and increased UV protection. A 1995 study reported that "Expensive brands and polarizing sunglasses do not guarantee optimal UVA protection." The Australian Competition and Consumer Commission has also reported that "onsumers cannot rely on price as an indicator of quality". One unscientific survey even found a $6.95 pair of generic glasses with slightly better protection than Salvatore Ferragamo shades. More recently, High energy visible light (HEV) has been implicated as a cause of age-related macular degeneration, and some manufacturers design to block it. Sunglasses may be especially important for children, as their ocular lenses are thought to transmit far more HEV light than adults (lenses "yellow" with age). Some sunglasses also pass ANSI Z87.1 requirements for basic impact and high impact protection. These are voluntary standards, so not all sunglasses comply, nor are manufacturers required to comply. In the basic impact test, a 1 in (2.54 cm) steel ball is dropped on the lens from 50 in (127 cm). In the high velocity test, a 1/4 in (6.35mm) steel ball is shot at the lens at 150 ft/s (45.72 m/s). In both tests, no part of the lens can touch the eye. ## Standards There are three sunglass standards. The Australian Standard is AS 1067. The five sunglass ratings under this standard are based on the amount of light they absorb, 0 to 4, with “0” providing some protection from UV radiation and sunglare, and “4” a high level of protection. The US standard is ANSI Z80.3-1972. According to the ANSI Z80.3-2001 standard, the compliable lens should have a UVB (280 to 315nm) transmittance of no more than one per cent and a UVA (315 to 380nm) transmittance of no more than 0.5 times of the visual light transmittance The European standard is EN 1836:2005. The four ratings are 0 for insufficient UV protection, 1 for sufficient UV protection, 2 for good UV protection and 3 for full UV protection. # Water sunglasses Water sunglasses, also known as surfing sunglasses, surf goggles and water eyewear consist of eyewear specially adapted to be used in turbulent water, such as the surf. Features normally available include a) shatter proof & impact resistant lenses b) strap or other fixing to keep glasses in place during sporting activities c) buoyancy to stop them from sinking should they be displaced from the wearer d) nose cushion e) vent or other method to eliminate fogging Many sports utilize these sunglasses including surfing, windsurfing, kiteboarding, wakeboarding, kayaking, jet skiing, Bodyboarding, and water skiing. # Construction ## Lens The color of the lens can vary by style, fashion, and purpose, but for general use, green, grey, yellow, or brown is recommended to avoid or minimize color distortion which would be dangerous when, for instance, driving a car. Gray lenses are considered neutral because they do not enhance contrast or distort colors. Brown and green lenses cause some minimal color distortion, but have contrast-enhancing properties. Red lenses are good for medium and lower light conditions because they are good at enhancing contrast but causes color distortion. Orange and yellow lenses have the best contrast enhancement at depth perception but cause color distortion. Yellow lenses are commonly used by golfers and shooters for its contrast enhancement and depth perception properties. Blue and purple lenses offer no real benefits and are mainly cosmetic. Clear lenses are used typically to protect the eyes from impact, debris, dust, or chemicals. Some sunglasses with interchangeable lens have optional clear lenses to protect the eyes during low light or night time activities. Debates exist as to whether "blue blocking" or amber tinted lenses may have a protective effect. Blue blocking sunglasses typically also block some light of other colors to function well in full sunlight. Some low blue glasses are for use inside at night to avoid suppression of the sleep promoting hormone melatonin. They provide enough light so normal evening activities can continue. Some models, such as those by Costa Del Mar, have polarized lenses (made from Polaroid or a similar material) to reduce glare caused by light reflected from polarizing surfaces such as water (see Brewster's angle for how this works) as well as by polarized diffuse sky radiation (skylight). This can be especially useful when fishing, as the ability to see beneath the surface of the water is crucial. Some models use a gradation where the top of the lens (where the sky is viewed) is darker and the bottom is transparent. A mirrored coating can also be applied to the lens. This mirrored coating reflects some of the light when it hits the lens before it is transmitted through the lens making it useful in bright conditions. These mirrored coatings can be made any color by the manufacturer for styling and fashion purposes. The color of the mirrored surface is irrelevant to the color of the lens. For example, a gray lens can have a blue mirror coating, and a brown lens can have a silver coating. Sunglasses of this type are sometimes called mirrorshades. A mirror does not get hot in the sunlight and prevents scattering in the lens bulk. Any of the above features: color, polarization, gradation, and mirroring, can be combined into a set of lenses for a pair of sunglasses. With the introduction of office computing, ergonomists can recommend mildly tinted glasses for display operators to increase contrast. Corrective lenses can be darkened to serve the same purpose, or secondary clip-on dark lenses can be placed in front of the regular lenses. Some lenses gradually darken with bright light and lighten in darkness. These are known as photochromic lenses. Sunglass lenses are made from either glass or plastic. Plastic lenses are typically made from acrylic, polycarbonate, or CR-39. Glass lenses have the best optical clarity and scratch resistance, but are heavier than plastic lenses. They can also shatter or break on impact. Plastic lenses are lighter than glass lenses, but are more prone to scratching. They do however, offer more resistance to shattering than glass. Polycarbonate lenses are the lightest, and are also almost shatterproof, making them good for impact protection. CR-39 lenses are the most common plastic lenses, due to their low weight, high scratch resistance, low transparency for ultraviolet and infrared radiation, and other advantageous properties. For sunglasses that also include vision correction, see also corrective lens. ## Frames Frames are generally made from plastic, nylon, a metal or metal alloy. Nylon frames are usually used in sports because they are light weight and flexible. They are able to bend slightly and return to their original shape instead of breaking when pressure is applied to them. This flex can also help the glasses grip better on the wearer's face. Metal frames are usually more rigid than nylon frames thus they can be more easily damaged when participating in sporty activities, but this is not to say that they cannot be used for such activities. Because metal frames are more rigid, some models have spring loaded hinges to help them grip the wearer's face better. The end of the ear pieces and the bridge over the nose can be textured or have a rubber or plastic material to hold better. The end of the ear pieces are usually curved so that they wrap around the ear; however, some models have straight ear pieces. Oakley, for example, has straight ear pieces on all their glasses. Frames can be made to hold the lenses in several different ways. There are three common styles: full frame, half frame, and frameless. Full frame glasses have the frame go all around the lenses. Half frames go around only half the lens, typically the frames attach to the top of the lenses and on the side near the top. Frameless glasses have no frame around the lenses and the ear stems are attached directly to the lenses. There are two styles of frameless glasses: those that have a piece of frame material connecting the two lenses together, and those that are a single lens with ear stems on each side. Some sports-oriented sunglasses have interchangeable lens options. Lenses can be easily removed and swapped with a different lens, usually a different colored lens. The purpose of this is to allow the wearer to easily change lenses when light conditions or activities change. The reason for this is because the cost of a set of lenses is less than the cost of a separate pair of glasses and carrying extra lenses is less bulky than carrying multiple pairs of glasses. It also allows easy replacement of a set of lenses if they are damaged. The most common type of sunglasses with interchangeable lenses have a single lens or shield that covers both eyes. Styles that use two lenses also exist, but are less common. ## Nose Bridge Nose bridges allow support between the lens and the face. Nose bridges also prevent pressure marks caused by the weight of the lens or frame on the cheeks. People with large noses may need a low nose bridge on their sunglasses. People with medium noses may need a low or medium nose bridge. People with small noses may need sunglasses with high nose bridges to allow clearance. # Fashion ## Oversized sunglasses Oversize sunglasses are often used for humorous purposes, and look like a pair of sunglasses that is extremely large for the face. They usually come in bright colors with colored lenses and can be purchased cheaply. Over recent years however, moderately oversized sunglasses have become a fashion trend. There are many variations, such as the 'Onassis', discussed below, and Dior white sunglasses. ## Onassis glasses Onassis glasses or "Jackie O's" are very large sunglasses worn by women. This style of sunglasses is said to kind mimic the kind most famously worn by Jacqueline Kennedy Onassis. While originally worn by Onassis in the 1960's, the glasses eventually became popular with younger American girls around the year 2003. Big sunglasses have maintained their popularity through 2007. They have also expanded their demographic reach to adult women throughout the world. Modern day celebrities use these to hide from paparazzi. ## Mirrorshades Mirrorshades are sunglasses with a mirrored coating on the surface. Their popularity with police officers in the United States has earned them the nickname "cop shades". The two most popular styles for these are dual lenses set in metal frames (which are often confused with Aviators), and "Wraparound" (a single, smooth, semi-circular lense that covers both eyes and much of the same area of the face covered by protective goggles, combined with a minimal plastic frame and single piece of plastic serving as a nosepick). Wraparound sunglasses are also quite popular in the world of extreme sports. ## Aviators Aviators are sunglasses with an oversized teardrop-shaped lens and thin metal frames. This design first appeared in 1936 by Ray Ban for issue to U.S. military aviators. Their popularity with pilots, military and law enforcement personnel in the United States has never wavered. As a fashion statement, models of aviator sunglasses are often made in mirrored, colored, degregated, and wrap-around styles. In addition to pilots, Aviator-style sunglasses gained popularity with young people in the late 1960's and continued to be very popular through the 70's and early 80's. Aviators again became popular in the first decade of the 2000's, along with renewed interest in retro-fashion. ## Wayfarers First introduced by Ray-Ban, the Wayfarer design popularized since the 1950s by Hollywood celebrities such as James Dean is thought to be the bestselling sunglasses design to date. ## Teashades 'Teashades' (sometimes also called '"John Lennon glasses" or "Ozzy Glasses", after Ozzy Osbourne') were a type of Psychedelic art wire-rim sunglasses that were often worn, usually for purely aesthetic reasons, by members of the 60's drug counterculture, as well as by opponents of segregation. Rockstars such as Mick Jagger, John Lennon, Ozzy Osbourne, and Janis Joplin all wore teashades. The original teashade design was made up of medium-sized, perfectly round lenses, supported by pads on the bridge of the nose and a thin wire frame. When teashades became popular in the late 1960's, they were often elaborated; lenses were elaborately colored, mirrored, and degregated, and often of excessively large size, and the wire earpieces were sometimes exaggerated. A uniquely-colored or darkened glass lens was usually preferred. The term has now fallen into disuse, although references can still be found in literature of the time. Teashades are briefly referenced during a police training seminar in Hunter S. Thompson's Fear and Loathing in Las Vegas. ## Glacier Glasses Sunglasses with round lenses and leather blinders that protect the eyes by blocking the sun's rays around the edges of the lenses. Because they provide extra protection from bright sun and light reflected by snow and ice, they are often used when traveling across glaciers or snowfields. # History ## Precursors It is said that the Roman emperor Nero Rushawa liked to watch gladiator fights with emeralds. These, however, appear to have worked rather like mirrors. Flat panes of Smoky quartz which offered no corrective powers but did protect the eyes from glare were used in China in the 12th century or possibly earlier. Contemporary documents describe the use of such crystals by judges in Chinese courts to conceal their facial expressions while questioning witnesses. James Ayscough began experimenting with tinted lenses in spectacles in the mid-18th century. These were not "sunglasses" as such; Ayscough believed blue- or green-tinted glass could correct for specific vision impairments. Protection from the sun's rays was not a concern of his. ## Modern developments In the early 1900s, the use of sunglasses started to become more widespread, especially among the pioneering stars of silent movies. But early movie stars did not wear sunglasses as much to avoid being recognized than to protect their eyes from the harshly bright lighting of some early film studios, often taking their sunglasses off only when stepping in front of the camera to shoot a scene. Inexpensive mass-produced sunglasses were introduced to America by Sam Foster in 1929. Foster found a ready market on the beaches of Atlantic City, New Jersey, where he began selling sunglasses under the name Foster Grant from a Woolworth on the Boardwalk. Sunglasses first became polarized in 1936, when Edwin H. Land began experimenting with making lenses with his patented Polaroid filter. In 2004, Oakley developed Thump, sunglasses with built-in digital audio player. This design has been copied by a number of smaller companies. # Other names for sunglasses There are also various words referring to eyepieces with darkened lenses: - Glares is a term popular in India if the glass is dark. If it is light then Coolers - Sun spectacles is a term used by some opticians. - Spekkies is a term used predominantly in southern Australia. - Sun specs (also sunspecs) is the shortened form of the above term. - Sunglasses is a term in common usage in Britain and North America, and it is also used when preceded by "pair of". - Sun-shades can also refer to the sun-shading eyepiece-type, although the term is not exclusive to these. Also in use is the derivative abbreviation, shades. - Dark glasses (also preceded by pair of) - generic term in common usage. - Sunnies is Australian and New Zealand Slang - Specs is a common name for sunglasses in North America. - Smoked spectacles usually refers to the darkened eyepieces worn by blind people. - Solar Shields Usually refers to the models of sunglasses with large lenses. - Stunna shades - Shades - Hater blockers - Locs (also maddoggers) is a term for very dark lensed sunglasses. - Cheaters	Sunglasses Sunglasses or sun glasses are a visual aid, variously termed spectacles or glasses, which feature lenses that are coloured or darkened to prevent strong light from reaching the eyes. Many people find direct sunlight too bright to be comfortable, especially when reading from paper in direct sunlight. In outdoor activities like riding, skiing and flying, the eye can receive more light than usual. It has been recommended to wear these kind of glasses whenever outside to protect the eyes from ultraviolet radiation, which can lead to the development of a cataract. Sunglasses have also been associated with celebrities and film actors primarily due to the desire to mask identity, but in part due to the lighting involved in production typically being stronger than natural light and uncomfortable to the naked eye. Since the 1950s sunglasses have been popular as a fashion statement, especially on the beach. # Uses Hiding one's eyes has implications in face-to-face communication: It can hide weeping, being one of the signs of mourning, makes eye contact impossible which can be intimidating, like in the stereotype of the guardian of a chain gang as depicted in Cool Hand Luke, or can show detachment, which is considered cool in some circles. Darkened sunglasses of particular shapes may be in vogue as a fashion accessory. Note that normal glasses are very rarely worn without a practical purpose — curiously, they can project an image of uncool nerdiness that sunglasses do not have. The impact on nonverbal communication and the cool image are among the reasons for wearing sunglasses by night or indoors. People may also wear sunglasses to hide dilated or contracted pupils or bloodshot eyes (which would reveal drug use), recent physical abuse, or to compensate for increased photosensitivity. Fashion trends are another reason for wearing sunglasses, particularly designer sunglasses. People with severe visual impairment, such as the blind, often wear sunglasses in order to avoid making others uncomfortable — not seeing eyes may be better than seeing eyes which seem to look in the wrong direction. Those whose eyes have an abnormal appearance (for example due to cataract) or which jerk uncontrollably (nystagmus) may also do so. ## Visual clarity and comfort Sunglasses can improve visual comfort and visual clarity by protecting the eye from glare.[1] Various types of disposable sunglasses are dispensed to patients after receiving mydriatic eye drops during eye examinations. ## Protection Excessive exposure to ultraviolet radiation (UV) can cause short-term and long-term ocular problems such as photokeratitis, snow blindness, cataracts, pterygium, and various eye cancers.[2] Medical experts often advise the public on the importance of wearing sunglasses to protect the eyes from UV[2]. In the European Union, a CE mark identifies glasses fulfilling quality regulations. In the preparation for solar eclipses, health authorities often warn against looking at the sun through sunglasses alone. There is no demonstrated correlation between high prices and increased UV protection. A 1995 study reported that "Expensive brands and polarizing sunglasses do not guarantee optimal UVA protection." [3] The Australian Competition and Consumer Commission has also reported that "[c]onsumers cannot rely on price as an indicator of quality".[4] One unscientific survey even found a $6.95 pair of generic glasses with slightly better protection than Salvatore Ferragamo shades.[5] More recently, High energy visible light (HEV) has been implicated as a cause of age-related macular degeneration[6][7], and some manufacturers design to block it. Sunglasses may be especially important for children, as their ocular lenses are thought to transmit far more HEV light than adults (lenses "yellow" with age). Some sunglasses also pass ANSI Z87.1 requirements for basic impact and high impact protection. These are voluntary standards, so not all sunglasses comply, nor are manufacturers required to comply. In the basic impact test, a 1 in (2.54 cm) steel ball is dropped on the lens from 50 in (127 cm). In the high velocity test, a 1/4 in (6.35mm) steel ball is shot at the lens at 150 ft/s (45.72 m/s). In both tests, no part of the lens can touch the eye. ## Standards There are three sunglass standards.[8] The Australian Standard is AS 1067. The five sunglass ratings under this standard are based on the amount of light they absorb, 0 to 4, with “0” providing some protection from UV radiation and sunglare, and “4” a high level of protection. The US standard is ANSI Z80.3-1972. According to the ANSI Z80.3-2001 standard, the compliable lens should have a UVB (280 to 315nm) transmittance of no more than one per cent and a UVA (315 to 380nm) transmittance of no more than 0.5 times of the visual light transmittance The European standard is EN 1836:2005. The four ratings are 0 for insufficient UV protection, 1 for sufficient UV protection, 2 for good UV protection and 3 for full UV protection. # Water sunglasses Water sunglasses, also known as surfing sunglasses, surf goggles and water eyewear consist of eyewear specially adapted to be used in turbulent water, such as the surf. Features normally available include a) shatter proof & impact resistant lenses b) strap or other fixing to keep glasses in place during sporting activities c) buoyancy to stop them from sinking should they be displaced from the wearer d) nose cushion e) vent or other method to eliminate fogging Many sports utilize these sunglasses including surfing, windsurfing, kiteboarding, wakeboarding, kayaking, jet skiing, Bodyboarding, and water skiing. # Construction ## Lens The color of the lens can vary by style, fashion, and purpose, but for general use, green, grey, yellow, or brown is recommended to avoid or minimize color distortion which would be dangerous when, for instance, driving a car. Gray lenses are considered neutral because they do not enhance contrast or distort colors. Brown and green lenses cause some minimal color distortion, but have contrast-enhancing properties. Red lenses are good for medium and lower light conditions because they are good at enhancing contrast but causes color distortion. Orange and yellow lenses have the best contrast enhancement at depth perception but cause color distortion. Yellow lenses are commonly used by golfers and shooters for its contrast enhancement and depth perception properties. Blue and purple lenses offer no real benefits and are mainly cosmetic. Clear lenses are used typically to protect the eyes from impact, debris, dust, or chemicals. Some sunglasses with interchangeable lens have optional clear lenses to protect the eyes during low light or night time activities. Debates exist as to whether "blue blocking" or amber tinted lenses may have a protective effect.[9] Blue blocking sunglasses typically also block some light of other colors to function well in full sunlight. Some low blue glasses are for use inside at night to avoid suppression of the sleep promoting hormone melatonin. They provide enough light so normal evening activities can continue. Some models, such as those by Costa Del Mar, have polarized lenses (made from Polaroid or a similar material) to reduce glare caused by light reflected from polarizing surfaces such as water (see Brewster's angle for how this works) as well as by polarized diffuse sky radiation (skylight). This can be especially useful when fishing, as the ability to see beneath the surface of the water is crucial. Some models use a gradation where the top of the lens (where the sky is viewed) is darker and the bottom is transparent. A mirrored coating can also be applied to the lens. This mirrored coating reflects some of the light when it hits the lens before it is transmitted through the lens making it useful in bright conditions. These mirrored coatings can be made any color by the manufacturer for styling and fashion purposes. The color of the mirrored surface is irrelevant to the color of the lens. For example, a gray lens can have a blue mirror coating, and a brown lens can have a silver coating. Sunglasses of this type are sometimes called mirrorshades. A mirror does not get hot in the sunlight and prevents scattering in the lens bulk. Any of the above features: color, polarization, gradation, and mirroring, can be combined into a set of lenses for a pair of sunglasses. With the introduction of office computing, ergonomists can recommend mildly tinted glasses for display operators to increase contrast. Corrective lenses can be darkened to serve the same purpose, or secondary clip-on dark lenses can be placed in front of the regular lenses. Some lenses gradually darken with bright light and lighten in darkness. These are known as photochromic lenses. Sunglass lenses are made from either glass or plastic. Plastic lenses are typically made from acrylic, polycarbonate, or CR-39. Glass lenses have the best optical clarity and scratch resistance, but are heavier than plastic lenses. They can also shatter or break on impact. Plastic lenses are lighter than glass lenses, but are more prone to scratching. They do however, offer more resistance to shattering than glass. Polycarbonate lenses are the lightest, and are also almost shatterproof, making them good for impact protection. CR-39 lenses are the most common plastic lenses, due to their low weight, high scratch resistance, low transparency for ultraviolet and infrared radiation, and other advantageous properties. For sunglasses that also include vision correction, see also corrective lens. ## Frames Frames are generally made from plastic, nylon, a metal or metal alloy. Nylon frames are usually used in sports because they are light weight and flexible. They are able to bend slightly and return to their original shape instead of breaking when pressure is applied to them. This flex can also help the glasses grip better on the wearer's face. Metal frames are usually more rigid than nylon frames thus they can be more easily damaged when participating in sporty activities, but this is not to say that they cannot be used for such activities. Because metal frames are more rigid, some models have spring loaded hinges to help them grip the wearer's face better. The end of the ear pieces and the bridge over the nose can be textured or have a rubber or plastic material to hold better. The end of the ear pieces are usually curved so that they wrap around the ear; however, some models have straight ear pieces. Oakley, for example, has straight ear pieces on all their glasses. Frames can be made to hold the lenses in several different ways. There are three common styles: full frame, half frame, and frameless. Full frame glasses have the frame go all around the lenses. Half frames go around only half the lens, typically the frames attach to the top of the lenses and on the side near the top. Frameless glasses have no frame around the lenses and the ear stems are attached directly to the lenses. There are two styles of frameless glasses: those that have a piece of frame material connecting the two lenses together, and those that are a single lens with ear stems on each side. Some sports-oriented sunglasses have interchangeable lens options. Lenses can be easily removed and swapped with a different lens, usually a different colored lens. The purpose of this is to allow the wearer to easily change lenses when light conditions or activities change. The reason for this is because the cost of a set of lenses is less than the cost of a separate pair of glasses and carrying extra lenses is less bulky than carrying multiple pairs of glasses. It also allows easy replacement of a set of lenses if they are damaged. The most common type of sunglasses with interchangeable lenses have a single lens or shield that covers both eyes. Styles that use two lenses also exist, but are less common. ## Nose Bridge Nose bridges allow support between the lens and the face. Nose bridges also prevent pressure marks caused by the weight of the lens or frame on the cheeks. People with large noses may need a low nose bridge on their sunglasses. People with medium noses may need a low or medium nose bridge. People with small noses may need sunglasses with high nose bridges to allow clearance. # Fashion ## Oversized sunglasses Oversize sunglasses are often used for humorous purposes, and look like a pair of sunglasses that is extremely large for the face. They usually come in bright colors with colored lenses and can be purchased cheaply. Over recent years however, moderately oversized sunglasses have become a fashion trend. There are many variations, such as the 'Onassis', discussed below, and Dior white sunglasses. ## Onassis glasses Onassis glasses or "Jackie O's" are very large sunglasses worn by women. This style of sunglasses is said to kind mimic the kind most famously worn by Jacqueline Kennedy Onassis. While originally worn by Onassis in the 1960's, the glasses eventually became popular with younger American girls around the year 2003. Big sunglasses have maintained their popularity through 2007. They have also expanded their demographic reach to adult women throughout the world. Modern day celebrities use these to hide from paparazzi. ## Mirrorshades Mirrorshades are sunglasses with a mirrored coating on the surface. Their popularity with police officers in the United States has earned them the nickname "cop shades". The two most popular styles for these are dual lenses set in metal frames (which are often confused with Aviators), and "Wraparound" (a single, smooth, semi-circular lense that covers both eyes and much of the same area of the face covered by protective goggles, combined with a minimal plastic frame and single piece of plastic serving as a nosepick). Wraparound sunglasses are also quite popular in the world of extreme sports. ## Aviators Aviators are sunglasses with an oversized teardrop-shaped lens and thin metal frames. This design first appeared in 1936 by Ray Ban for issue to U.S. military aviators. Their popularity with pilots, military and law enforcement personnel in the United States has never wavered. As a fashion statement, models of aviator sunglasses are often made in mirrored, colored, degregated, and wrap-around styles. In addition to pilots, Aviator-style sunglasses gained popularity with young people in the late 1960's and continued to be very popular through the 70's and early 80's. Aviators again became popular in the first decade of the 2000's, along with renewed interest in retro-fashion. ## Wayfarers First introduced by Ray-Ban, the Wayfarer design popularized since the 1950s by Hollywood celebrities such as James Dean is thought to be the bestselling sunglasses design to date[citation needed]. ## Teashades 'Teashades' (sometimes also called '"John Lennon glasses" or "Ozzy Glasses", after Ozzy Osbourne') were a type of Psychedelic art wire-rim sunglasses that were often worn, usually for purely aesthetic reasons, by members of the 60's drug counterculture, as well as by opponents of segregation. Rockstars such as Mick Jagger, John Lennon, Ozzy Osbourne, and Janis Joplin all wore teashades. The original teashade design was made up of medium-sized, perfectly round lenses, supported by pads on the bridge of the nose and a thin wire frame. When teashades became popular in the late 1960's, they were often elaborated; lenses were elaborately colored, mirrored, and degregated, and often of excessively large size, and the wire earpieces were sometimes exaggerated. A uniquely-colored or darkened glass lens was usually preferred. The term has now fallen into disuse, although references can still be found in literature of the time. Teashades are briefly referenced during a police training seminar in Hunter S. Thompson's Fear and Loathing in Las Vegas. ## Glacier Glasses Sunglasses with round lenses and leather blinders that protect the eyes by blocking the sun's rays around the edges of the lenses. Because they provide extra protection from bright sun and light reflected by snow and ice, they are often used when traveling across glaciers or snowfields. # History ## Precursors It is said that the Roman emperor Nero Rushawa liked to watch gladiator fights with emeralds. These, however, appear to have worked rather like mirrors.[10] Flat panes of Smoky quartz which offered no corrective powers but did protect the eyes from glare were used in China in the 12th century or possibly earlier. Contemporary documents describe the use of such crystals by judges in Chinese courts to conceal their facial expressions while questioning witnesses.[11] James Ayscough began experimenting with tinted lenses in spectacles in the mid-18th century. These were not "sunglasses" as such; Ayscough believed blue- or green-tinted glass could correct for specific vision impairments. Protection from the sun's rays was not a concern of his. ## Modern developments In the early 1900s, the use of sunglasses started to become more widespread, especially among the pioneering stars of silent movies. But early movie stars did not wear sunglasses as much to avoid being recognized than to protect their eyes from the harshly bright lighting of some early film studios, often taking their sunglasses off only when stepping in front of the camera to shoot a scene. Inexpensive mass-produced sunglasses were introduced to America by Sam Foster in 1929. Foster found a ready market on the beaches of Atlantic City, New Jersey, where he began selling sunglasses under the name Foster Grant from a Woolworth on the Boardwalk. Sunglasses first became polarized in 1936, when Edwin H. Land began experimenting with making lenses with his patented Polaroid filter. In 2004, Oakley developed Thump, sunglasses with built-in digital audio player. This design has been copied by a number of smaller companies. # Other names for sunglasses There are also various words referring to eyepieces with darkened lenses: - Glares is a term popular in India if the glass is dark. If it is light then Coolers - Sun spectacles is a term used by some opticians. - Spekkies is a term used predominantly in southern Australia. - Sun specs (also sunspecs) is the shortened form of the above term. - Sunglasses is a term in common usage in Britain and North America, and it is also used when preceded by "pair of". - Sun-shades can also refer to the sun-shading eyepiece-type, although the term is not exclusive to these. Also in use is the derivative abbreviation, shades. - Dark glasses (also preceded by pair of) - generic term in common usage. - Sunnies is Australian and New Zealand Slang - Specs is a common name for sunglasses in North America. - Smoked spectacles usually refers to the darkened eyepieces worn by blind people. - Solar Shields Usually refers to the models of sunglasses with large lenses. - Stunna shades - Shades - Hater blockers - Locs (also maddoggers) is a term for very dark lensed sunglasses. - Cheaters	https://www.wikidoc.org/index.php/Sunglasses
495a98a1ccdb271874f1380e5cb3f4c9911c9269	wikidoc	Super Atom	Super Atom Super atom is another term used for describing a Bose–Einstein condensate, whereby a group of atoms are super-cooled to only several billionths (0.000000001) of a Kelvin above Absolute Zero. The end result is an atom "blob" or super atom, so called because many of the individual super-cooled atoms merge together into one collective unit and begin to behave less like particles and more like waves. The maximum number of super-cooled atoms that may possibly merge together into one stable super atom is a topic of current research interest. # Notes - ↑ Jump up to: 1.0 1.1 BEC - What is it and where did the idea come from? - ↑ BEC: Temperature and Absolute Zero - ↑ Jump up to: 3.0 3.1 NOVA \| Absolute Zero \| Ultracold Atoms \| PBS - ↑ For example, see .	Super Atom Template:Mergeto Super atom is another term used for describing a Bose–Einstein condensate,[1] whereby a group of atoms are super-cooled to only several billionths (0.000000001) of a Kelvin above Absolute Zero.[2] The end result is an atom "blob"[1] or super atom, so called because many of the individual super-cooled atoms merge together into one collective unit[3] and begin to behave less like particles and more like waves.[3] The maximum number of super-cooled atoms that may possibly merge together into one stable super atom is a topic of current research interest.[4] # Notes - ↑ Jump up to: 1.0 1.1 BEC - What is it and where did the idea come from? - ↑ BEC: Temperature and Absolute Zero - ↑ Jump up to: 3.0 3.1 NOVA \| Absolute Zero \| Ultracold Atoms \| PBS - ↑ For example, see http://arxiv.org/PS_cache/cond-mat/pdf/0104/0104231v3.pdf .	https://www.wikidoc.org/index.php/Super_Atom
dcd191dfc3007e258c3066801abd37f2f7e0007e	wikidoc	Superfluid	Superfluid Superfluidity is a phase of matter or description of heat capacity in which unusual effects are observed when liquids, typically of helium-4 or helium-3, overcome friction by surface interaction when at a stage, known as the "lambda point" for helium-4, at which the liquid's viscosity becomes zero. Also known as a major facet in the study of quantum hydrodynamics, it was discovered by Pyotr Kapitsa, John F. Allen, and Don Misener in 1937 and has been described through phenomenological and microscopic theories. # Background Although the phenomenologies of the superfluid states of helium-4 and helium-3 are very similar, the microscopic details of the transitions are very different. Helium-4 atoms are bosons, and their superfluidity can be understood in terms of the Bose statistics that they obey. Specifically, the superfluidity of helium-4 can be regarded as a consequence of Bose-Einstein condensation in an interacting system. On the other hand, helium-3 atoms are fermions, and the superfluid transition in this system is described by a generalization of the BCS theory of superconductivity. In it, Cooper pairing takes place between atoms rather than electrons, and the attractive interaction between them is mediated by spin fluctuations rather than phonons. See fermion condensate. A unified description of superconductivity and superfluidity is possible in terms of gauge symmetry breaking. Superfluids, such as supercooled helium-4, exhibit many unusual properties. A superfluid acts as if it were a mixture of a normal component, with all the properties associated with normal fluid, and a superfluid component. The superfluid component has zero viscosity, zero entropy, and infinite thermal conductivity. (It is thus impossible to set up a temperature gradient in a superfluid, much as it is impossible to set up a voltage difference in a superconductor.) One of the most spectacular results of these properties is known as the thermomechanical or "fountain effect". If a capillary tube is placed into a bath of superfluid helium and then heated, even by shining a light on it, the superfluid helium will flow up through the tube and out the top as a result of the Clausius-Clapeyron relation. A second unusual effect is that superfluid helium can form a layer, a single atom thick, up the sides of any container in which it is placed. A more fundamental property than the disappearance of viscosity becomes visible if superfluid is placed in a rotating container. Instead of rotating uniformly with the container, the rotating state consists of quantized vortices. That is, when the container is rotated at speed below the first critical velocity (related to the quantum numbers for the element in question) the liquid remains perfectly stationary. Once the first critical velocity is reached, the superfluid will very quickly begin spinning at the critical speed. The speed is quantized - i.e. it can only spin at certain speeds. # Applications Recently in the field of chemistry, superfluid helium-4 has been successfully used in spectroscopic techniques, as a quantum solvent. Referred to as Superfluid Helium Droplet Spectroscopy (SHeDS), it is of great interest in studies of gas molecules, as a single molecule solvated in a superfluid medium allows a molecule to have effective rotational freedom - allowing it to behave exactly as it would in the "gas" phase. Superfluids are also used in high-precision devices, such as gyroscopes, which allow the measurement of some theoretically predicted gravitational effects (for an example see the Gravity Probe B article). Recently, superfluids have been used to trap light and slow its speed. In an experiment, performed by Lene Hau, light was passed through a superfluid and found to be slowed to 17 metres per second from its normal speed of 299,792,458 metres per second in vacuum. This does not change the absolute value of c, nor is it completely new: any medium other than vacuum, such as water or glass, also slows down the propagation of light in a certain fraction. The Infrared Astronomical Satellite (IRAS), launched in January 1983 to gather infrared data was cooled by 720 litres of superfluid helium, maintaining a temperature of 1.6K (-271.4 °C). # Recent discoveries Physicists have recently been able to create a Fermionic condensate from pairs of ultra-cold fermionic atoms. Under certain conditions, fermion pairs form diatomic molecules and undergo Bose–Einstein condensation. At the other limit, the fermions (most notably superconducting electrons) form Cooper pairs which also exhibit superfluidity. This recent work with ultra-cold atomic gases has allowed scientists to study the region in between these two extremes, known as the BEC-BCS crossover. Additionally, supersolids might have also been discovered, in 2004, by physicists at Penn State University. When helium-4 is cooled, below about 200 mK under high pressures, a fraction (~1%) of the solid appears to become superfluid .	Superfluid Superfluidity is a phase of matter or description of heat capacity in which unusual effects are observed when liquids, typically of helium-4 or helium-3, overcome friction by surface interaction when at a stage, known as the "lambda point" for helium-4, at which the liquid's viscosity becomes zero. Also known as a major facet in the study of quantum hydrodynamics, it was discovered by Pyotr Kapitsa, John F. Allen, and Don Misener in 1937 and has been described through phenomenological and microscopic theories. # Background Although the phenomenologies of the superfluid states of helium-4 and helium-3 are very similar, the microscopic details of the transitions are very different. Helium-4 atoms are bosons, and their superfluidity can be understood in terms of the Bose statistics that they obey. Specifically, the superfluidity of helium-4 can be regarded as a consequence of Bose-Einstein condensation in an interacting system. On the other hand, helium-3 atoms are fermions, and the superfluid transition in this system is described by a generalization of the BCS theory of superconductivity. In it, Cooper pairing takes place between atoms rather than electrons, and the attractive interaction between them is mediated by spin fluctuations rather than phonons. See fermion condensate. A unified description of superconductivity and superfluidity is possible in terms of gauge symmetry breaking. Superfluids, such as supercooled helium-4, exhibit many unusual properties. A superfluid acts as if it were a mixture of a normal component, with all the properties associated with normal fluid, and a superfluid component. The superfluid component has zero viscosity, zero entropy, and infinite thermal conductivity. (It is thus impossible to set up a temperature gradient in a superfluid, much as it is impossible to set up a voltage difference in a superconductor.) One of the most spectacular results of these properties is known as the thermomechanical or "fountain effect". If a capillary tube is placed into a bath of superfluid helium and then heated, even by shining a light on it, the superfluid helium will flow up through the tube and out the top as a result of the Clausius-Clapeyron relation. A second unusual effect is that superfluid helium can form a layer, a single atom thick, up the sides of any container in which it is placed. A more fundamental property than the disappearance of viscosity becomes visible if superfluid is placed in a rotating container. Instead of rotating uniformly with the container, the rotating state consists of quantized vortices. That is, when the container is rotated at speed below the first critical velocity (related to the quantum numbers for the element in question) the liquid remains perfectly stationary. Once the first critical velocity is reached, the superfluid will very quickly begin spinning at the critical speed. The speed is quantized - i.e. it can only spin at certain speeds. # Applications Recently in the field of chemistry, superfluid helium-4 has been successfully used in spectroscopic techniques, as a quantum solvent. Referred to as Superfluid Helium Droplet Spectroscopy (SHeDS), it is of great interest in studies of gas molecules, as a single molecule solvated in a superfluid medium allows a molecule to have effective rotational freedom - allowing it to behave exactly as it would in the "gas" phase. Superfluids are also used in high-precision devices, such as gyroscopes, which allow the measurement of some theoretically predicted gravitational effects (for an example see the Gravity Probe B article). Recently, superfluids have been used to trap light and slow its speed. In an experiment, performed by Lene Hau, light was passed through a superfluid and found to be slowed to 17 metres per second from its normal speed of 299,792,458 metres per second in vacuum.[1] This does not change the absolute value of c, nor is it completely new: any medium other than vacuum, such as water or glass, also slows down the propagation of light in a certain fraction. The Infrared Astronomical Satellite (IRAS), launched in January 1983 to gather infrared data was cooled by 720 litres of superfluid helium, maintaining a temperature of 1.6K (-271.4 °C). # Recent discoveries Physicists have recently been able to create a Fermionic condensate from pairs of ultra-cold fermionic atoms. Under certain conditions, fermion pairs form diatomic molecules and undergo Bose–Einstein condensation. At the other limit, the fermions (most notably superconducting electrons) form Cooper pairs which also exhibit superfluidity. This recent work with ultra-cold atomic gases has allowed scientists to study the region in between these two extremes, known as the BEC-BCS crossover. Additionally, supersolids might have also been discovered, in 2004, by physicists at Penn State University. When helium-4 is cooled, below about 200 mK under high pressures, a fraction (~1%) of the solid appears to become superfluid [1].	https://www.wikidoc.org/index.php/Superfluid
43f108da669a37d2c8f31596da6b518e6c0a2922	wikidoc	Superhelix	Superhelix A superhelix is a molecular structure in which a helix is itself coiled into a helix. This is significant to both proteins and genetic material, such as overwound circular DNA. The earliest significant reference in molecular biology is from 1971, by F.B. Fuller: About the writhing number, mathematician W.F. Pohl says: Contrary to intuition a topological property, the linking number, arises from the geometric properties twist and writhe according to the following relationship: where Lk is the linking number, W is the writhe and T is the twist of the coil. The linking number refers to the number of times that one strand wraps around the other. In DNA this property does not change and can only be modified by specialized enzymes called topoisomerases.	Superhelix A superhelix is a molecular structure in which a helix is itself coiled into a helix. This is significant to both proteins and genetic material, such as overwound circular DNA. The earliest significant reference in molecular biology is from 1971, by F.B. Fuller: About the writhing number, mathematician W.F. Pohl says: Contrary to intuition a topological property, the linking number, arises from the geometric properties twist and writhe according to the following relationship: where Lk is the linking number, W is the writhe and T is the twist of the coil. The linking number refers to the number of times that one strand wraps around the other. In DNA this property does not change and can only be modified by specialized enzymes called topoisomerases.	https://www.wikidoc.org/index.php/Superhelix
e7c0e2e0f8878c15dec029c3da0023bda8ba454b	wikidoc	Superoxide	Superoxide # Overview Superoxide is the anion O2−. It is important as the product of the one-electron reduction of dioxygen, which occurs widely in nature. With one unpaired electron, the superoxide ion is a free radical, and, like dioxygen, it is paramagnetic. # Synthesis, basic reactions, and structure Superoxides are compounds in which the oxidation number of oxygen is -1/2. The O-O bond distance in O2− is 1.33 Å, vs. 1.21 Å in O2 and 1.49 Å in O22−. The salts CsO2, RbO2, KO2, and NaO2 are prepared by the direct reaction of O2 with the respective alkali metal. The overall trend corresponds to a reduction in the bond order from 2 (O2), to 1.5 (O2−), to 1 (O22−). The alkali salts of O2− are orange-yellow in color and quite stable, provided they are kept dry. Upon dissolution of these salts in water, however, the dissolved O2− undergoes disproportionation (dismutation) extremely rapidly: In this process O2− acts as a strong Brønsted base, initially forming HO2. The pKa of its conjugate acid, hydrogen superoxide (HO2, also known as "hydroperoxyl" or "perhydroxy radical"), is 4.88 so that at neutral pH 7 the vast majority of superoxide is in the anionic form, O2−. Salts also decompose in the solid state, but this process requires heating: This reaction is the basis of the use of potassium superoxide as an oxygen source in chemical oxygen generators, such as those used on the space shuttle and on submarines. # Biology and superoxide Superoxide is biologically quite toxic and is deployed by the immune system to kill invading microorganisms. In phagocytes, superoxide is produced in large quantities by the enzyme NADPH oxidase for use in oxygen-dependent killing mechanisms of invading pathogens. Mutations in the gene coding for the NADPH oxidase cause an immunodeficiency syndrome called chronic granulomatous disease, characterized by extreme susceptibility to infection. Superoxide is also deleteriously produced as a byproduct of mitochondrial respiration (most notably by Complex I and Complex III), as well as several other enzymes, for example xanthine oxidase. The biological toxicity of superoxide is due to its capacity to inactivate iron-sulfur cluster containing enzymes (which are critical in a wide variety of metabolic pathways), thereby liberating free iron in the cell, which can undergo Fenton chemistry and generate the highly reactive hydroxyl radical. In its HO2 form, superoxide can also initiate lipid peroxidation of polyunsaturated fatty acids. It also reacts with carbonyl compounds and halogenated carbons to create toxic peroxy radicals. Superoxide can also react with nitric oxide (NO) to form ONOO−. As such, superoxide is one of the main causes of oxidative stress. Because superoxide is toxic, nearly all organisms living in the presence of oxygen contain isoforms of the superoxide scavenging enzyme, superoxide dismutase, or SOD. SOD is an extremely efficient enzyme; it catalyzes the neutralization of superoxide nearly as fast as the two can diffuse together spontaneously in solution. Genetic inactivation ("knockout") of SOD produces deleterious phenotypes in organisms ranging from bacteria to mice. The latter species dies around 21 days after birth if the mitochondrial variant of SOD (Mn-SOD) is inactivated, and suffers from multiple pathologies, including reduced lifespan, liver cancer, muscle atrophy, cataracts and female infertility when the cytoplasmic (Cu,Zn-SOD) variant is inactivated.	Superoxide # Overview Superoxide is the anion O2−. It is important as the product of the one-electron reduction of dioxygen, which occurs widely in nature.[1] With one unpaired electron, the superoxide ion is a free radical, and, like dioxygen, it is paramagnetic. # Synthesis, basic reactions, and structure Superoxides are compounds in which the oxidation number of oxygen is -1/2. The O-O bond distance in O2− is 1.33 Å, vs. 1.21 Å in O2 and 1.49 Å in O22−. The salts CsO2, RbO2, KO2, and NaO2 are prepared by the direct reaction of O2 with the respective alkali metal.[2] The overall trend corresponds to a reduction in the bond order from 2 (O2), to 1.5 (O2−), to 1 (O22−). The alkali salts of O2− are orange-yellow in color and quite stable, provided they are kept dry. Upon dissolution of these salts in water, however, the dissolved O2− undergoes disproportionation (dismutation) extremely rapidly: In this process O2− acts as a strong Brønsted base, initially forming HO2. The pKa of its conjugate acid, hydrogen superoxide (HO2, also known as "hydroperoxyl" or "perhydroxy radical"), is 4.88 so that at neutral pH 7 the vast majority of superoxide is in the anionic form, O2−. Salts also decompose in the solid state, but this process requires heating: This reaction is the basis of the use of potassium superoxide as an oxygen source in chemical oxygen generators, such as those used on the space shuttle and on submarines. # Biology and superoxide Superoxide is biologically quite toxic and is deployed by the immune system to kill invading microorganisms. In phagocytes, superoxide is produced in large quantities by the enzyme NADPH oxidase for use in oxygen-dependent killing mechanisms of invading pathogens. Mutations in the gene coding for the NADPH oxidase cause an immunodeficiency syndrome called chronic granulomatous disease, characterized by extreme susceptibility to infection. Superoxide is also deleteriously produced as a byproduct of mitochondrial respiration (most notably by Complex I and Complex III), as well as several other enzymes, for example xanthine oxidase. The biological toxicity of superoxide is due to its capacity to inactivate iron-sulfur cluster containing enzymes (which are critical in a wide variety of metabolic pathways), thereby liberating free iron in the cell, which can undergo Fenton chemistry and generate the highly reactive hydroxyl radical. In its HO2 form, superoxide can also initiate lipid peroxidation of polyunsaturated fatty acids. It also reacts with carbonyl compounds and halogenated carbons to create toxic peroxy radicals. Superoxide can also react with nitric oxide (NO) to form ONOO−. As such, superoxide is one of the main causes of oxidative stress. Because superoxide is toxic, nearly all organisms living in the presence of oxygen contain isoforms of the superoxide scavenging enzyme, superoxide dismutase, or SOD. SOD is an extremely efficient enzyme; it catalyzes the neutralization of superoxide nearly as fast as the two can diffuse together spontaneously in solution. Genetic inactivation ("knockout") of SOD produces deleterious phenotypes in organisms ranging from bacteria to mice. The latter species dies around 21 days after birth if the mitochondrial variant of SOD (Mn-SOD) is inactivated, and suffers from multiple pathologies, including reduced lifespan, liver cancer, muscle atrophy, cataracts and female infertility when the cytoplasmic (Cu,Zn-SOD) variant is inactivated.	https://www.wikidoc.org/index.php/Superoxide
2fd5fb9378619fafe2d1957a870b05822f9d63d3	wikidoc	Supersolid	Supersolid A supersolid is a spatially ordered material (that is, a solid or crystal) with superfluid properties. When specific fluids, such as helium-4, are cooled below a characteristic temperature, they undergo a superfluid transition and enter a state of zero viscosity. That is, they can flow without friction. This transition is thought to be associated with a Bose-Einstein condensation. In the case of helium-4, it has been conjectured since 1970 that it might be possible to create a supersolid. Several experiments looking for this state over the years failed to see it. However, in 2004 physicists Moses Chan and Eun-Seong Kim at Pennsylvania State University observed phenomena that were interpreted as supersolid behavior (that is, the molecules of superfluid that exhibit a weak internecine interaction can be condensated by lowering the temperature and allowing these weak forces to dominate - the internecine forces of whole ensemble would overcome the force of surface attraction which is the force between two different substances). If such an interpretation is correct, it would signify the discovery of a new quantum phase of matter. In most theories of this state, it is supposed that vacancies, empty sites normally occupied by particles in an ideal crystal, exist even at the absolute zero of temperature. These vacancies are caused by zero-point energy, which also causes them to be mobile—they move from site to site as waves. Vacancies are bosons and so, if such clouds of vacancies can exist at very low temperature then, a Bose-Einstein condensation of vacancies could occur at a few tenths of a kelvin in temperature. A coherent flow of vacancies is equivalent to a “superflow” (frictionless flow) of particles in the opposite direction. Despite the presence of the gas of vacancies, the ordered structure of a crystal is maintained, although with less than one particle on each lattice site on average. The experiment of Kim and Chan looked for superflow by means of a “torsional oscillator.” Picture a record turntable that is attached tightly to a springy spindle in the center. Instead of rotating at constant speed, the turntable is started off by a small twist clockwise and then let go. The spring causes it to spin back counterclockwise for a small angle, then clockwise, and then counterclockwise, and so on, a bit analogous to a swinging pendulum. Now glue a thin hollow donut centered on the turntable with solid helium-4 inside. The rate of oscillation of the turntable and donut depend on the amount of solid moving with it. If there is frictionless superfluid inside, then the mass moving with the donut is less and the twisting motion will occur at a faster rate. In this way one can measure the amount of superfluid existing at various temperatures. Kim and Chan found that up to about 2% of the material in the donut was superfluid. Similar experiments in other laboratories have confirmed these results.Template:Facts A mysterious feature, not in agreement with the old theories, is that the transition continues to occur at high pressures. Prior to 2007, many theorists performed calculations indicating that vacancies cannot exist at zero temperature in solid helium-4. While not all theorists are in perfect agreement in this, it seems more doubtful that what the experiments are seeing is the supersolid state. Indeed further experimentation, including that by Kim and Chan, also throws some doubt on the existence of a true supersolid. One experiment finds that, as one repeatedly warms and then slowly cools the sample the effect disappears. What such “annealing” does is to remove flaws in the crystal structure. Further, most samples of helium-4 have a small amount of the other helium isotope, helium-3, mixed in. When some of this is removed, the superfluid transition occurs at a lower temperature. These experimental results lead on to the possibility that the superflow is involved with actual fluid moving along imperfections in the crystal rather than a property of the perfect crystal. Experimental and theoretical work continues in hopes of finally settling the exciting question of the existence of a supersolid.	Supersolid A supersolid is a spatially ordered material (that is, a solid or crystal) with superfluid properties. When specific fluids, such as helium-4, are cooled below a characteristic temperature, they undergo a superfluid transition and enter a state of zero viscosity. That is, they can flow without friction. This transition is thought to be associated with a Bose-Einstein condensation. In the case of helium-4, it has been conjectured since 1970 that it might be possible to create a supersolid[1]. Several experiments looking for this state over the years failed to see it. However, in 2004 physicists Moses Chan and Eun-Seong Kim at Pennsylvania State University observed phenomena that were interpreted as supersolid behavior (that is, the molecules of superfluid that exhibit a weak internecine interaction can be condensated by lowering the temperature and allowing these weak forces to dominate - the internecine forces of whole ensemble would overcome the force of surface attraction which is the force between two different substances). If such an interpretation is correct, it would signify the discovery of a new quantum phase of matter. In most theories of this state, it is supposed that vacancies, empty sites normally occupied by particles in an ideal crystal, exist even at the absolute zero of temperature. These vacancies are caused by zero-point energy, which also causes them to be mobile—they move from site to site as waves. Vacancies are bosons and so, if such clouds of vacancies can exist at very low temperature then, a Bose-Einstein condensation of vacancies could occur at a few tenths of a kelvin in temperature. A coherent flow of vacancies is equivalent to a “superflow” (frictionless flow) of particles in the opposite direction. Despite the presence of the gas of vacancies, the ordered structure of a crystal is maintained, although with less than one particle on each lattice site on average. The experiment of Kim and Chan looked for superflow by means of a “torsional oscillator.” Picture a record turntable that is attached tightly to a springy spindle in the center. Instead of rotating at constant speed, the turntable is started off by a small twist clockwise and then let go. The spring causes it to spin back counterclockwise for a small angle, then clockwise, and then counterclockwise, and so on, a bit analogous to a swinging pendulum. Now glue a thin hollow donut centered on the turntable with solid helium-4 inside. The rate of oscillation of the turntable and donut depend on the amount of solid moving with it. If there is frictionless superfluid inside, then the mass moving with the donut is less and the twisting motion will occur at a faster rate. In this way one can measure the amount of superfluid existing at various temperatures. Kim and Chan found that up to about 2% of the material in the donut was superfluid. Similar experiments in other laboratories have confirmed these results.Template:Facts A mysterious feature, not in agreement with the old theories, is that the transition continues to occur at high pressures. Prior to 2007, many theorists performed calculations indicating that vacancies cannot exist at zero temperature in solid helium-4. While not all theorists are in perfect agreement in this, it seems more doubtful that what the experiments are seeing is the supersolid state. Indeed further experimentation, including that by Kim and Chan, also throws some doubt on the existence of a true supersolid. One experiment finds that, as one repeatedly warms and then slowly cools the sample the effect disappears. What such “annealing” does is to remove flaws in the crystal structure. Further, most samples of helium-4 have a small amount of the other helium isotope, helium-3, mixed in. When some of this is removed, the superfluid transition occurs at a lower temperature. These experimental results lead on to the possibility that the superflow is involved with actual fluid moving along imperfections in the crystal rather than a property of the perfect crystal. Experimental and theoretical work continues in hopes of finally settling the exciting question of the existence of a supersolid.	https://www.wikidoc.org/index.php/Supersolid
c835d1c5478431125a89357144be15b1e5e79199	wikidoc	Supination	Supination # Overview Supination is the rotation of either the forearm or foot. Supination in the forearm occurs when the palm faces anteriorly, or faces up (when the arms are unbent and at the sides). Supination in the foot occurs when a person appears "bow-legged" with their weight supported primarily on the anterior of their feet. The hand is supine (facing anteriorly) in the anatomical position. This action is performed by the Biceps brachii and the Supinator muscle. Supination is the opposite of pronation. # History Originally, supination of the forearm was attributed as a function of the brachioradialis muscle. However, the original idea of the biceps acting as a supinator was something hypothesised by Leonardo da Vinci, in a series of annotated drawings made between 1505 and 1510 (referred to as his Milanese period); in which the principle of the biceps as a supinator, as well as its role as a flexor to the elbow was devised. However, this function remained undiscovered by the medical community as Da Vinci was not regarded as a teacher of anatomy, nor were his results publicly released. It was not until 1713, that this movement was re-discovered by William Cheselden, and subsequently recorded for the medical community, being rewritten several times by different authors wishing to present information to different audiences. Nevertheless, the most notable recent expansion upon Cheselden's recordings was achieved by Guillaume Duchenne in 1867 in a journal named Physiology of Motion, something which to this day is one of the major references on supination action of the biceps brachii.	Supination # Overview Supination is the rotation of either the forearm or foot. Supination in the forearm occurs when the palm faces anteriorly, or faces up (when the arms are unbent and at the sides). Supination in the foot occurs when a person appears "bow-legged" with their weight supported primarily on the anterior of their feet[1]. The hand is supine (facing anteriorly) in the anatomical position. This action is performed by the Biceps brachii and the Supinator muscle. Supination is the opposite of pronation. # History Originally, supination of the forearm was attributed as a function of the brachioradialis muscle. However, the original idea of the biceps acting as a supinator was something hypothesised by Leonardo da Vinci, in a series of annotated drawings made between 1505 and 1510 (referred to as his Milanese period); in which the principle of the biceps as a supinator, as well as its role as a flexor to the elbow was devised. However, this function remained undiscovered by the medical community as Da Vinci was not regarded as a teacher of anatomy, nor were his results publicly released. It was not until 1713, that this movement was re-discovered by William Cheselden, and subsequently recorded for the medical community, being rewritten several times by different authors wishing to present information to different audiences. Nevertheless, the most notable recent expansion upon Cheselden's recordings was achieved by Guillaume Duchenne in 1867 in a journal named Physiology of Motion, something which to this day is one of the major references on supination action of the biceps brachii.	https://www.wikidoc.org/index.php/Supinate
9d7331d04eab51a7b1516be17cc6b72a661d7126	wikidoc	Suvorexant	Suvorexant # 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 Suvorexant is an orexin receptor antagonist that is FDA approved for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. Common adverse reactions include somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Indications - Suvorexant is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. ## Dosage ### Dosing Information - Use the lowest dose effective for the patient. - The recommended dose for suvorexant is 10 mg, taken no more than once per night and within 30 minutes of going to bed, with at least 7 hours remaining before the planned time of awakening. If the 10 mg dose is well-tolerated but not effective, the dose can be increased. The maximum recommended dose of suvorexant is 20 mg once daily. ### Special Populations - Exposure to suvorexant is increased in obese compared to non-obese patients, and in women compared to men. Particularly in obese women, the increased risk of exposure-related adverse effects should be considered before increasing the dose. ### Use with CNS Depressants - When suvorexant is combined with other CNS depressant drugs, dosage adjustment of suvorexant and/or the other drug(s) may be necessary because of potentially additive effects. ### Use with CYP3A Inhibitors - The recommended dose of suvorexant is 5 mg when used with moderate CYP3A inhibitors and the dose generally should not exceed 10 mg in these patients. Suvorexant is not recommended for use with strong CYP3A inhibitors. ### Food Effect - Time to effect of suvorexant may be delayed if taken with or soon after a meal. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Suvorexant in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Suvorexant 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 Suvorexant in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Suvorexant in pediatric patients. # Contraindications - Suvorexant is contraindicated in patients with narcolepsy. # Warnings ### CNS Depressant Effects and Daytime Impairment - Suvorexant is a central nervous system (CNS) depressant that can impair daytime wakefulness even when used as prescribed. Prescribers should monitor for somnolence and CNS depressant effects, but impairment can occur in the absence of symptoms, and may not be reliably detected by ordinary clinical exam (i.e., less than formal testing of daytime wakefulness and/or psychomotor performance). CNS depressant effects may persist in some patients for up to several days after discontinuing suvorexant. - Suvorexant can impair driving skills and may increase the risk of falling asleep while driving. Discontinue or decrease the dose in patients who drive if daytime somnolence develops. In a study of healthy adults, driving ability was impaired in some individuals taking 20 mg suvorexant. Although pharmacodynamic tolerance or adaptation to some adverse depressant effects of suvorexant may develop with daily use, patients using the 20 mg dose of suvorexant should be cautioned against next-day driving and other activities requiring full mental alertness. Patients taking lower doses of suvorexant should also be cautioned about the potential for driving impairment because there is individual variation in sensitivity to suvorexant. - Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Patients should be advised not to consume alcohol in combination with suvorexant because of additive effects. Dosage adjustments of suvorexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of suvorexant with other drugs to treat insomnia is not recommended. - The risk of next-day impairment, including impaired driving, is increased if suvorexant is taken with less than a full night of sleep remaining, if a higher than the recommended dose is taken, if co-administered with other CNS depressants, or if co-administered with other drugs that increase blood levels of suvorexant. Patients should be cautioned against driving and other activities requiring complete mental alertness if suvorexant is taken in these circumstances. ### Need to Evaluate for Co-morbid Diagnoses - Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, treatment of insomnia should be initiated only after 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 cognitive or behavioral abnormalities may be the result of an unrecognized underlying psychiatric or physical disorder, and can emerge during the course of treatment with hypnotic drugs such as suvorexant. ### Abnormal Thinking and Behavioral Changes - A variety of cognitive and behavioral changes (e.g., amnesia, anxiety, hallucinations and other neuro-psychiatric symptoms) have been reported to occur in association with the use of hypnotics such as suvorexant. Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after taking a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with the use of hypnotics. These events can occur in hypnotic-naïve as well as in hypnotic-experienced persons. The use of alcohol and other CNS depressants may increase the risk of such behaviors. Discontinuation of suvorexant should be strongly considered for patients who report any complex sleep behavior. ### Worsening of Depression/Suicidal Ideation - In clinical studies, a dose-dependent increase in suicidal ideation was observed in patients taking suvorexant as assessed by questionnaire. Immediately evaluate patients with suicidal ideation or any new behavioral sign or symptom. - In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides) have been reported. 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 lowest number of tablets that is feasible should be prescribed for the patient at any one time. - The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. ### Patients with Compromised Respiratory Function - Effect of suvorexant on respiratory function should be considered if prescribed to patients with compromised respiratory function. Suvorexant has not been studied in patients with severe obstructive sleep apnea (OSA) or severe chronic obstructive pulmonary disease (COPD). ### Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, Cataplexy-like Symptoms - Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions by the patient, can occur with the use of suvorexant. Prescribers should explain the nature of these events to patients when prescribing suvorexant. - Symptoms similar to mild cataplexy can occur, with risk increasing with the dose of suvorexant. Such symptoms can include periods of leg weakness lasting from seconds to a few minutes, can occur both at night and during the day, and may not be associated with an identified triggering event (e.g., laughter or surprise). # 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 clinical practice. - In 3-month controlled efficacy trials (Study 1 and Study 2), 1263 patients were exposed to suvorexant including 493 patients who received suvorexant 15 mg or 20 mg (see TABLE 1). - In a long-term study, additional patients (n=521) were treated with suvorexant at higher than recommended doses, including a total of 160 patients who received suvorexant for at least one year. The pooled safety data described below (see TABLE 2) reflect the adverse reaction profile during the first 3 months of treatment. ### Adverse Reactions Resulting in Discontinuation of Treatment - The incidence of discontinuation due to adverse reactions for patients treated with 15 mg or 20 mg of suvorexant was 3% compared to 5% for placebo. No individual adverse reaction led to discontinuation at an incidence ≥1%. ### Most Common Adverse Reactions - In clinical trials of patients with insomnia treated with suvorexant 15 mg or 20 mg, the most common adverse reaction (reported in 5% or more of patients treated with suvorexant and at least twice the placebo rate) was somnolence (suvorexant 7%; placebo 3%). - Table 2 shows the percentage of patients with adverse reactions during the first three months of treatment, based on the pooled data from 3-month controlled efficacy trials (Study 1 and Study 2). - At doses of 15 or 20 mg, the incidence of somnolence was higher in females (8%) than in males (3%). Of the adverse reactions reported in Table 2, the following occurred in women at an incidence of at least twice that in men: headache, abnormal dreams, dry mouth, cough, and upper respiratory tract infection. - The adverse reaction profile in elderly patients was generally consistent with non-elderly patients. The adverse reactions reported during long-term treatment up to 1 year were generally consistent with those observed during the first 3 months of treatment. ### Dose Relationship for Adverse Reactions - There is evidence of a dose relationship for many of the adverse reactions associated with suvorexant use, particularly for certain CNS adverse reactions. - In a placebo-controlled crossover study (Study 3), non-elderly adult patients were treated for up to one month with suvorexant at doses of 10 mg, 20 mg, 40 mg (2 times the maximum recommended dose) or 80 mg (4 times the maximum recommended dose). In patients treated with suvorexant 10 mg (n=62), although no adverse reactions were reported at an incidence of ≥2%, the types of adverse reactions observed were similar to those observed in patients treated with suvorexant 20 mg. suvorexant was associated with a dose-related increase in somnolence: 2% at the 10 mg dose, 5% at the 20 mg dose, 12% at the 40 mg dose, and 11% at the 80 mg dose, compared to <1% for placebo. suvorexant was also associated with a dose-related increase in serum cholesterol: 1 mg/dL at the 10 mg dose, 2 mg/dL at the 20 mg dose, 3 mg/dL at the 40 mg dose, and 6 mg/dL at the 80 mg dose after 4 weeks of treatment, compared to a 4 mg/dL decrease for placebo. ## Postmarketing Experience - There is limited information regarding postmarketing experience. # Drug Interactions ### CNS-Active Agents - When suvorexant was co-administered with alcohol, additive psychomotor impairment was demonstrated. There was no alteration in the pharmacokinetics of suvorexant . ### Effects of Other Drugs on Suvorexant - Metabolism by CYP3A is the major elimination pathway for suvorexant. - CYP3A Inhibitors - Concomitant use of suvorexant with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan) is not recommended. - The recommended dose of suvorexant is 5 mg in subjects receiving moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil). The dose can be increased to 10 mg in these patients if necessary for efficacy. - CYP3A Inducers - Suvorexant exposure can be substantially decreased when co-administered with strong CYP3A inducers (e.g., rifampin, carbamazepine and phenytoin). The efficacy of suvorexant may be reduced. ### Effects of Suvorexant on Other Drugs - Digoxin - Concomitant administration of suvorexant with digoxin slightly increased digoxin levels due to inhibition of intestinal P-gp. Digoxin concentrations should be monitored when co-administering suvorexant with digoxin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies in pregnant women. Suvorexant should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of suvorexant to pregnant rats throughout organogenesis in two separate studies at oral doses of 30, 150, and 1000 mg/kg or 30, 80, and 325 mg/kg resulted in a decrease in fetal body weight at doses greater than 80 mg/kg. Plasma exposures (AUC) at the no-effect dose were approximately 25 times that in humans at the maximum recommended human dose (MRHD) of 20 mg/day. - Administration of suvorexant to pregnant rabbits throughout organogenesis in two separate studies at oral doses of 40, 100, and 300 mg/kg or 50, 150, and 325 mg/kg resulted in no apparent adverse effects on embryo-fetal development. Excessive toxicity resulted in premature sacrifice of pregnant animals at 325 mg/kg. The highest maternal plasma exposures (AUC) for which there are fetal data were up to approximately 40 times that in humans at the MRHD. - Administration of suvorexant (oral doses of 30, 80, and 200 mg/kg) to pregnant rats throughout gestation and lactation resulted in decreased body weight in offspring at the highest dose tested. Plasma AUCs at the no-effect dose were approximately 25 times that in humans at the MRHD. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Suvorexant in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Suvorexant during labor and delivery. ### Nursing Mothers - Suvorexant and a hydroxyl-suvorexant metabolite were excreted in rat milk at levels higher (9 and 1.5 times, respectively) than that in maternal plasma. It is not known whether this drug is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when suvorexant is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of the total number of patients treated with suvorexant (n=1784) in controlled clinical safety and efficacy studies, 829 patients were 65 years and over, and 159 patients were 75 years and over. No clinically meaningful differences in safety or effectiveness were observed between these patients and younger patients at the recommended doses. ### Gender There is no FDA guidance on the use of Suvorexant with respect to specific gender populations. ### Race There is no FDA guidance on the use of Suvorexant with respect to specific racial populations. ### Renal Impairment - No dose adjustment is required in patients with renal impairment. ### Hepatic Impairment - No dose adjustment is required in patients with mild and moderate hepatic impairment. Suvorexant has not been studied in patients with severe hepatic impairment and is not recommended for these patients. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Suvorexant in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Suvorexant in patients who are immunocompromised. ### Patients with Compromised Respiratory Function - Effects of suvorexant on respiratory function should be considered if prescribed to patients with compromised respiratory function. - Obstructive Sleep Apnea - The respiratory depressant effect of suvorexant was evaluated after one night and after four consecutive nights of treatment in a randomized, placebo-controlled, 2-period crossover study in patients (n=26) with mild to moderate obstructive sleep apnea. Following once-daily doses of 40 mg, the mean Apnea/Hypopnea Index treatment difference (suvorexant – placebo) on Day 4 was 2.7 (90% CI: 0.22 to 5.09), but there was wide inter- and intra-individual variability such that clinically meaningful respiratory effects of suvorexant in obstructive sleep apnea cannot be excluded. Suvorexant has not been studied in patients with severe obstructive sleep apnea. - Chronic Obstructive Pulmonary Disease - The respiratory depressant effect of suvorexant was evaluated after one night and after four consecutive nights of treatment in a randomized, placebo-controlled, 2-period crossover study in patients (n=25) with mild to moderate chronic obstructive pulmonary disease (COPD). Suvorexant (40 mg in non-elderly, 30 mg in elderly) had no respiratory depressant effects in patients with mild to moderate COPD, as measured by oxygen saturation. There was wide inter- and intra-individual variability such that clinically meaningful respiratory effects of suvorexant in COPD cannot be excluded. Suvorexant has not been studied in patients with severe COPD. # Administration and Monitoring ### Administration - Oral. ### Monitoring - Prescribers should monitor for somnolence and CNS depressant effects. - Digoxin concentrations should be monitored when co-administering suvorexant with digoxin. - Vital signs should be monitored with general supportive measures in overdosage. # IV Compatibility - There is limited information regarding IV Compatibility. # Overdosage - There is limited premarketing clinical experience with an overdosage of suvorexant. In clinical pharmacology studies, healthy subjects who were administered morning doses of up to 240 mg of suvorexant showed dose-dependent increases in the frequency and duration of somnolence. - General symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. As in all cases of drug overdose, vital signs should be monitored and general supportive measures employed. The value of dialysis in the treatment of overdosage has not been determined. As suvorexant is highly protein-bound, hemodialysis is not expected to contribute to elimination of suvorexant. - As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. Consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage. # Pharmacology ## Mechanism of Action - The mechanism by which suvorexant exerts its therapeutic effect in insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive. - Antagonism of orexin receptors may also underlie potential adverse effects such as signs of narcolepsy/cataplexy. Genetic mutations in the orexin system in animals result in hereditary narcolepsy; loss of orexin neurons has been reported in humans with narcolepsy. ## Structure - BELSOMRA tablets contain suvorexant, a highly selective antagonist for orexin receptors OX1R and OX2R. - Suvorexant is described chemically as: - methanone - Its empirical formula is C23H23ClN6O2 and the molecular weight is 450.92. Its structural formula is: Suvorexant is a white to off-white powder that is insoluble in water. - Each film coated tablet contains 5 mg, 10 mg, 15 mg, or 20 mg of suvorexant and the following inactive ingredients: polyvinylpyrrolidone/vinyl acetate copolymer (copovidone), microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. - In addition, the film coating contains the following inactive ingredients: lactose monohydrate, hypromellose, titanium dioxide, and triacetin. The film coating for the 5 mg tablets also contains iron oxide yellow and iron oxide black, and the film coating for the 10 mg tablets also contains iron oxide yellow and FD&C Blue #1/Brilliant Blue FCF Aluminum Lake. ## Pharmacodynamics - The effects of suvorexant on the QTc interval were evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover study in healthy subjects (n=53). The upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc interval was below 10 ms based on analysis of suvorexant doses up to 240 mg, 12 times the maximum recommended dose. suvorexant thus does not prolong the QTc interval to any clinically relevant extent. ## Pharmacokinetics - Suvorexant exposure increases in a less than strictly dose-proportional manner over the range of 10-80 mg because of decreased absorption at higher doses. Suvorexant pharmacokinetics are similar in healthy subjects and patients with insomnia. - Suvorexant peak concentrations occur at a median Tmax of 2 hours (range 30 minutes to 6 hours) under fasted conditions. The mean absolute bioavailability of 10 mg is 82%. - Ingestion of suvorexant with a high-fat meal resulted in no meaningful change in AUC or Cmax but a delay in Tmax of approximately 1.5 hours. Suvorexant may be taken with or without food; however for faster sleep onset, suvorexant should not be administered with or soon after a meal. - The mean volume of distribution of suvorexant is approximately 49 liters. Suvorexant is extensively bound (>99%) to human plasma proteins and does not preferentially distribute into red blood cells. Suvorexant binds to both human serum albumin and α1-acid glycoprotein. - Suvorexant is mainly eliminated by metabolism, primarily by CYP3A with a minor contribution from CYP2C19. The major circulating entities are suvorexant and a hydroxy-suvorexant metabolite. This metabolite is not expected to be pharmacologically active. - The primary route of elimination is through the feces, with approximately 66% of radiolabeled dose recovered in the feces compared to 23% in the urine. The systemic pharmacokinetics of suvorexant are linear with an accumulation of approximately 1- to 2-fold with once-daily dosing. Steady-state is achieved by 3 days. The mean t1/2 is approximately 12 hours (95% CI: 12 to 13). - Gender, age, body mass index (BMI), and race were included as factors assessed in the population pharmacokinetic model to evaluate suvorexant pharmacokinetics in healthy subjects and to predict exposures in the patient population. Age and race are not predicted to have any clinically meaningful changes on suvorexant pharmacokinetics; therefore, no dose adjustment is warranted based upon these factors. - Suvorexant exposure is higher in females than in males. In females, the AUC and Cmax are increased by 17% and 9%, respectively, following administration of suvorexant 40 mg. The average concentration of suvorexant 9 hours after dosing is 5% higher for females across the dose range studied (10-40 mg). Dose adjustment of suvorexant is generally not needed based on gender only. - Apparent oral clearance of suvorexant is inversely related to body mass index. In obese patients, the AUC and Cmax are increased by 31% and 17%, respectively. The average concentration of suvorexant approximately 9 hours after a 20 mg dose is 15% higher in obese patients (BMI > 30 kg/m2) relative to those with a normal BMI (BMI ≤ 25 kg/m2). - In obese females, the AUC and Cmax are increased by 46% and 25%, respectively, compared to non-obese females. The higher exposure to suvorexant in obese females should be considered before increasing dose. - The effects of renal and hepatic impairment on the pharmacokinetics of suvorexant were evaluated in specific pharmacokinetic studies. - Suvorexant exposure after a single dose was similar in patients with moderate hepatic insufficiency (Child-Pugh category 7 to 9) and healthy matched control subjects; however, the suvorexant apparent terminal half-life was increased from approximately 15 hours (range 10 - 22 hours) in healthy subjects to approximately 19 hours (range 11 - 49 hours) in patients with moderate hepatic insufficiency. - Suvorexant exposure (expressed as total and unbound concentrations) was similar between patients with severe renal impairment (urinary creatinine clearance ≤30 mL/min/1.73m2) and healthy matched control subjects. No dose adjustment is required in patients with renal impairment. - An additive effect on psychomotor performance was observed when a single dose of 40 mg of suvorexant was co-administered with a single dose of 0.7 g/kg alcohol. Suvorexant did not affect alcohol concentrations and alcohol did not affect suvorexant concentration. - An interaction study with a single dose of 40 mg suvorexant and paroxetine 20 mg at steady-state levels in healthy subjects did not demonstrate a clinically significant pharmacokinetic or pharmacodynamic interaction. - The effects of other drugs on the pharmacokinetics of suvorexant are presented in Figure 1 as change relative to suvorexant administered alone (test/reference). Strong (e.g., ketoconazole or itraconazole) and moderate (e.g., diltiazem) CYP3A inhibitors significantly increased suvorexant exposure. Strong CYP3A inducers (e.g., rifampin) substantially decreased suvorexant exposure. In vitro metabolism studies demonstrate that suvorexant has the potential to inhibit CYP3A and intestinal P-gp; however, suvorexant is unlikely to cause clinically significant inhibition of human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. In addition, no clinically meaningful inhibition of OATP1B1, BCRP and OCT2 transporters is anticipated. Chronic administration of suvorexant is unlikely to induce the metabolism of drugs metabolized by major CYP isoforms. Specific in vivo effects on the pharmacokinetics of midazolam, warfarin, digoxin and oral contraceptives are presented in Figure 2 as a change relative to the interacting drug administered alone (test/reference). ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - In a 26-week study in Tg.rasH2 mice, there was no evidence of suvorexant-induced neoplasms at oral doses of 25, 50, 200, and 650 mg/kg/day. - In a 2-year study in rats (oral suvorexant doses of 80, 160, and 325 mg/kg/day), increases in thyroid (follicular cell adenoma and combined adenoma/carcinoma in high-dose females; follicular cell adenoma in mid- and high-dose males) and liver (hepatocellular adenoma in high-dose males) neoplasms were observed. These findings were consistent with increased TSH and hepatic enzyme induction, respectively, which are mechanisms believed to be rodent-specific. Plasma exposures (AUC) at doses not associated with drug-induced neoplasms in rats were approximately 7 times that in humans at the maximum recommended human dose (MRHD) of 20 mg. - Suvorexant was negative in in vitro (bacterial reverse mutation and chromosomal aberration) and in vivo (mouse and rat micronucleus) assays. - In two separate studies, male and female rats were treated with suvorexant prior to and during mating and continuing in females to gestation day 7. Increases in peri-implantation loss and resorptions, resulting in a decrease in live fetuses, were observed at the highest doses tested (1200 or 325 mg/kg) when treated males and females were mated with untreated animals. At the no-effect dose for adverse effects on fertility in males and females, plasma AUCs were approximately 20 times that in humans at the MRHD. ### Animal Toxicology and/or Pharmacology - In dogs, daily oral administration of suvorexant (5, 30 mg/kg) for 4-7 days resulted in behavior characteristic of cataplexy (e.g., transient limb buckling, prone posture) when presented with food enrichment, a stimulus demonstrated to induce cataplexy in dogs with hereditary narcolepsy. - In the 2-year carcinogenicity study in rats, an increased incidence of retinal atrophy was observed at all doses. Plasma AUCs at the lowest dose tested were approximately 7 times that in humans at the MRHD. - In subsequent studies of suvorexant in albino and pigmented rats, retinal atrophy was delayed in onset and, after approximately one year of dosing, was of lower incidence and severity in pigmented rats. # Clinical Studies - Suvorexant was evaluated in three clinical trials in patients with insomnia characterized by difficulties with sleep onset and sleep maintenance. - Two similarly designed, 3-month, randomized, double-blind, placebo-controlled, parallel-group studies were conducted (Study 1 and Study 2). In both studies, non-elderly (age 18-64) and elderly (age ≥ 65) patients were randomized separately. For the studies together, non-elderly adults (mean age 46 years; 465 females, 275 males) were treated with suvorexant 20 mg (n=291) or placebo (n=449). Elderly patients (mean age 71 years, 346 females, 174 males) were treated with suvorexant 15 mg (n=202) or placebo (n=318). - In Study 1 and Study 2, suvorexant 15 mg or 20 mg was superior to placebo for sleep latency as assessed both objectively by polysomnography (Table 3) and subjectively by patient-estimated sleep latency (Table 4). Suvorexant 15 mg or 20 mg was also superior to placebo for sleep maintenance, as assessed both objectively by polysomnography (Table 5) and subjectively by patient-estimated total sleep time (Table 6). The effects of suvorexant at night 1 (objective) and week 1 (subjective) were generally consistent with later time points. The efficacy of suvorexant was similar between women and men and, based on limited data, between Caucasians and non-Caucasians. Twenty seven percent of patients treated with suvorexant 15 mg or 20 mg in Study 1 and Study 2 were non-Caucasians. The majority (69%) of the non-Caucasian patients was Asian. - In the 1-month crossover study (Study 3), non-elderly adults (age 18-64 years, mean age 44 years) were treated with placebo (n=249) and suvorexant at a dose of 10 mg (n=62), 20 mg (n=61), or up to 80 mg. Suvorexant 10 mg and 20 mg were superior to placebo for sleep latency and sleep maintenance, as assessed objectively by polysomnography. - Suvorexant was also evaluated at doses of 30 mg and 40 mg in the 3-month placebo-controlled trials (Study 1 and Study 2). The higher doses were found to have similar efficacy to lower doses, but significantly more adverse reactions were reported at the higher doses. ## Special Safety Studies ### Effects on Driving - Two randomized, double-blind, placebo- and active-controlled, four-period crossover studies evaluated the effects of nighttime administration of suvorexant on next-morning driving performance 9 hours after dosing in 24 healthy elderly subjects (≥65 years old, mean age 69 years; 14 men, 10 women) who received 15 mg and 30 mg suvorexant, and 28 non-elderly subjects (mean age 46 years; 13 men, 15 women) who received 20 mg and 40 mg suvorexant. Testing was conducted after one night and after 8 consecutive nights of treatment with suvorexant at these doses. - The primary outcome measure was change in Standard Deviation of Lane Position (SDLP), a measure of driving performance, assessed using a symmetry analysis. The analysis showed clinically meaningful impaired driving performance in some subjects. After one night of dosing, this effect was observed in non-elderly subjects after either a 20 mg or 40 mg dose of suvorexant. A statistically significant effect was not observed in elderly subjects after a 15 mg or 30 mg dose of suvorexant. Across these two studies, five subjects (4 non-elderly women on suvorexant; 1 elderly woman on placebo) prematurely stopped their driving tests due to somnolence. Patients using the 20 mg dose of suvorexant should be cautioned against next-day driving and other activities requiring full mental alertness. Patients taking lower doses of suvorexant should also be cautioned about the potential for driving impairment because there is individual variation in sensitivity to suvorexant. ### Effects on Next-day Memory and Balance in Elderly and Non-elderly - Four placebo-controlled trials evaluated the effects of nighttime administration of suvorexant on next-day memory and balance using word learning tests and body sway tests, respectively. Three trials showed no significant effects on memory or balance compared to placebo. In a fourth trial in healthy non-elderly subjects, there was a significant decrease in word recall after the words were presented to subjects in the morning following a single dose of 40 mg suvorexant, and there was a significant increase on body sway area in the morning following a single dose of 20 mg or 40 mg suvorexant. ### Middle of the Night Safety in Elderly Subjects - A double-blind, randomized, placebo-controlled trial evaluated the effect of a single dose of suvorexant on balance, memory and psychomotor performance in healthy elderly subjects (n=12) after being awakened during the night. Nighttime dosing of suvorexant 30 mg resulted in impairment of balance (measured by body sway area) at 90 minutes as compared to placebo. Memory was not impaired, as assessed by an immediate and delayed word recall test at 4 hours post-dose. ### Rebound Effects - In 3-month controlled safety and efficacy trials (Study 1, Study 2), rebound insomnia was assessed following discontinuation of suvorexant relative to placebo and baseline in non-elderly adult patients receiving suvorexant 40 mg or 20 mg and in elderly patients receiving suvorexant 30 mg or 15 mg. No clear effects were observed on measures of sleep onset or maintenance. ### Withdrawal Effects - In 3-month controlled safety and efficacy trials (Study 1, Study 2), withdrawal effects were assessed following discontinuation in non-elderly adult patients who received suvorexant 40 mg or 20 mg and elderly patients who received suvorexant 30 mg or 15 mg. The analysis showed no clear evidence of withdrawal in the overall study population based on assessment of patient responses to the Tyrer Withdrawal Symptom Questionnaire or assessment of withdrawal-related adverse events following the discontinuation of suvorexant. ### Respiratory Safety - A randomized, placebo-controlled, double-blind, crossover trial in healthy non-elderly subjects (n=12) evaluated the respiratory depressant effect of suvorexant (40 mg and 150 mg) after one night of treatment. At the doses studied, suvorexant had no respiratory depressant effect as measured by oxygen saturation. # How Supplied - No. 3062 — suvorexant tablets, 5 mg, are yellow, round, film-coated tablets, with "5" on one side and plain on the other side. They are supplied as follows: NDC 0006-0005-30 unit-of-use blisters of 30 - No. 3063 — suvorexant tablets, 10 mg, are green, round, film-coated tablets, with "33" on one side and plain on the other side. They are supplied as follows: NDC 0006-0033-30 unit-of-use blisters of 30 - No. 3981 — suvorexant tablets, 15 mg, are white, oval, film-coated tablets with the Merck logo on one side and "325" on the other side. They are supplied as follows: NDC 0006-0325-30 unit-of-use blisters of 30 - No. 3982 — suvorexant tablets, 20 mg, are white, round, film-coated tablets with the Merck logo and "335" on one side and plain on the other side. They are supplied as follows: NDC 0006-0335-30 unit-of-use blisters of 30 ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F), . Store in the original package until use to protect from light and moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). - Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment and with each prescription refill. Review the suvorexant Medication Guide with every patient prior to initiation of treatment. ### CNS Depressant Effects and Next-Day Impairment - Tell patients that suvorexant has the potential to cause next-day impairment, and that this risk is increased with higher doses or if dosing instructions are not carefully followed. Patients using the 20 mg dose should be cautioned against next-day driving and other activities requiring full mental alertness as this dose is associated with a higher risk of impaired driving. Patients taking lower doses should also be cautioned about the potential for driving impairment because there is individual variation in sensitivity to suvorexant. - Patients should not drive or engage in other activities requiring full alertness within 8 hours of dosing of suvorexant. ### Sleep-driving and Other Complex Behaviors - Instruct patients to inform their families that suvorexant has been associated with getting out of bed while not being fully awake, and tell patients and their families to call their healthcare providers if this occurs. - Hypnotics, like suvorexant, have been associated with "sleep-driving" and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients and their families to call their healthcare providers if they develop any of these symptoms. ### Suicide - Tell patients to report any worsening of depression or suicidal thoughts immediately. ### Alcohol and Other Drugs - Ask patients about alcohol consumption, prescription medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use suvorexant if they drank alcohol that evening or before bed. ### Tolerance, Abuse, and Dependence - Tell patients not to increase the dose of suvorexant on their own, and to inform you if they believe the drug "does not work." ### Administration Instructions - Advise patients to take suvorexant only when preparing for or getting into bed and only if they can stay in bed for a full night before being active again. Advise patients to report all of their prescription and nonprescription medicines, vitamins and herbal supplements to the prescriber. # Precautions with Alcohol - Alcohol-Suvorexant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - BELSOMRA® # Look-Alike Drug Names - There is limited information regarding Look-Alike Drug Names. # Drug Shortage Status # Price	Suvorexant Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Turky Alkathery, 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 Suvorexant is an orexin receptor antagonist that is FDA approved for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. Common adverse reactions include somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Indications - Suvorexant is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. ## Dosage ### Dosing Information - Use the lowest dose effective for the patient. - The recommended dose for suvorexant is 10 mg, taken no more than once per night and within 30 minutes of going to bed, with at least 7 hours remaining before the planned time of awakening. If the 10 mg dose is well-tolerated but not effective, the dose can be increased. The maximum recommended dose of suvorexant is 20 mg once daily. ### Special Populations - Exposure to suvorexant is increased in obese compared to non-obese patients, and in women compared to men. Particularly in obese women, the increased risk of exposure-related adverse effects should be considered before increasing the dose. ### Use with CNS Depressants - When suvorexant is combined with other CNS depressant drugs, dosage adjustment of suvorexant and/or the other drug(s) may be necessary because of potentially additive effects. ### Use with CYP3A Inhibitors - The recommended dose of suvorexant is 5 mg when used with moderate CYP3A inhibitors and the dose generally should not exceed 10 mg in these patients. Suvorexant is not recommended for use with strong CYP3A inhibitors. ### Food Effect - Time to effect of suvorexant may be delayed if taken with or soon after a meal. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Suvorexant in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Suvorexant 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 Suvorexant in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Suvorexant in pediatric patients. # Contraindications - Suvorexant is contraindicated in patients with narcolepsy. # Warnings ### CNS Depressant Effects and Daytime Impairment - Suvorexant is a central nervous system (CNS) depressant that can impair daytime wakefulness even when used as prescribed. Prescribers should monitor for somnolence and CNS depressant effects, but impairment can occur in the absence of symptoms, and may not be reliably detected by ordinary clinical exam (i.e., less than formal testing of daytime wakefulness and/or psychomotor performance). CNS depressant effects may persist in some patients for up to several days after discontinuing suvorexant. - Suvorexant can impair driving skills and may increase the risk of falling asleep while driving. Discontinue or decrease the dose in patients who drive if daytime somnolence develops. In a study of healthy adults, driving ability was impaired in some individuals taking 20 mg suvorexant. Although pharmacodynamic tolerance or adaptation to some adverse depressant effects of suvorexant may develop with daily use, patients using the 20 mg dose of suvorexant should be cautioned against next-day driving and other activities requiring full mental alertness. Patients taking lower doses of suvorexant should also be cautioned about the potential for driving impairment because there is individual variation in sensitivity to suvorexant. - Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Patients should be advised not to consume alcohol in combination with suvorexant because of additive effects. Dosage adjustments of suvorexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of suvorexant with other drugs to treat insomnia is not recommended. - The risk of next-day impairment, including impaired driving, is increased if suvorexant is taken with less than a full night of sleep remaining, if a higher than the recommended dose is taken, if co-administered with other CNS depressants, or if co-administered with other drugs that increase blood levels of suvorexant. Patients should be cautioned against driving and other activities requiring complete mental alertness if suvorexant is taken in these circumstances. ### Need to Evaluate for Co-morbid Diagnoses - Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, treatment of insomnia should be initiated only after 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 cognitive or behavioral abnormalities may be the result of an unrecognized underlying psychiatric or physical disorder, and can emerge during the course of treatment with hypnotic drugs such as suvorexant. ### Abnormal Thinking and Behavioral Changes - A variety of cognitive and behavioral changes (e.g., amnesia, anxiety, hallucinations and other neuro-psychiatric symptoms) have been reported to occur in association with the use of hypnotics such as suvorexant. Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after taking a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with the use of hypnotics. These events can occur in hypnotic-naïve as well as in hypnotic-experienced persons. The use of alcohol and other CNS depressants may increase the risk of such behaviors. Discontinuation of suvorexant should be strongly considered for patients who report any complex sleep behavior. ### Worsening of Depression/Suicidal Ideation - In clinical studies, a dose-dependent increase in suicidal ideation was observed in patients taking suvorexant as assessed by questionnaire. Immediately evaluate patients with suicidal ideation or any new behavioral sign or symptom. - In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides) have been reported. 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 lowest number of tablets that is feasible should be prescribed for the patient at any one time. - The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. ### Patients with Compromised Respiratory Function - Effect of suvorexant on respiratory function should be considered if prescribed to patients with compromised respiratory function. Suvorexant has not been studied in patients with severe obstructive sleep apnea (OSA) or severe chronic obstructive pulmonary disease (COPD). ### Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, Cataplexy-like Symptoms - Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions by the patient, can occur with the use of suvorexant. Prescribers should explain the nature of these events to patients when prescribing suvorexant. - Symptoms similar to mild cataplexy can occur, with risk increasing with the dose of suvorexant. Such symptoms can include periods of leg weakness lasting from seconds to a few minutes, can occur both at night and during the day, and may not be associated with an identified triggering event (e.g., laughter or surprise). # 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 clinical practice. - In 3-month controlled efficacy trials (Study 1 and Study 2), 1263 patients were exposed to suvorexant including 493 patients who received suvorexant 15 mg or 20 mg (see TABLE 1). - In a long-term study, additional patients (n=521) were treated with suvorexant at higher than recommended doses, including a total of 160 patients who received suvorexant for at least one year. The pooled safety data described below (see TABLE 2) reflect the adverse reaction profile during the first 3 months of treatment. ### Adverse Reactions Resulting in Discontinuation of Treatment - The incidence of discontinuation due to adverse reactions for patients treated with 15 mg or 20 mg of suvorexant was 3% compared to 5% for placebo. No individual adverse reaction led to discontinuation at an incidence ≥1%. ### Most Common Adverse Reactions - In clinical trials of patients with insomnia treated with suvorexant 15 mg or 20 mg, the most common adverse reaction (reported in 5% or more of patients treated with suvorexant and at least twice the placebo rate) was somnolence (suvorexant 7%; placebo 3%). - Table 2 shows the percentage of patients with adverse reactions during the first three months of treatment, based on the pooled data from 3-month controlled efficacy trials (Study 1 and Study 2). - At doses of 15 or 20 mg, the incidence of somnolence was higher in females (8%) than in males (3%). Of the adverse reactions reported in Table 2, the following occurred in women at an incidence of at least twice that in men: headache, abnormal dreams, dry mouth, cough, and upper respiratory tract infection. - The adverse reaction profile in elderly patients was generally consistent with non-elderly patients. The adverse reactions reported during long-term treatment up to 1 year were generally consistent with those observed during the first 3 months of treatment. ### Dose Relationship for Adverse Reactions - There is evidence of a dose relationship for many of the adverse reactions associated with suvorexant use, particularly for certain CNS adverse reactions. - In a placebo-controlled crossover study (Study 3), non-elderly adult patients were treated for up to one month with suvorexant at doses of 10 mg, 20 mg, 40 mg (2 times the maximum recommended dose) or 80 mg (4 times the maximum recommended dose). In patients treated with suvorexant 10 mg (n=62), although no adverse reactions were reported at an incidence of ≥2%, the types of adverse reactions observed were similar to those observed in patients treated with suvorexant 20 mg. suvorexant was associated with a dose-related increase in somnolence: 2% at the 10 mg dose, 5% at the 20 mg dose, 12% at the 40 mg dose, and 11% at the 80 mg dose, compared to <1% for placebo. suvorexant was also associated with a dose-related increase in serum cholesterol: 1 mg/dL at the 10 mg dose, 2 mg/dL at the 20 mg dose, 3 mg/dL at the 40 mg dose, and 6 mg/dL at the 80 mg dose after 4 weeks of treatment, compared to a 4 mg/dL decrease for placebo. ## Postmarketing Experience - There is limited information regarding postmarketing experience. # Drug Interactions ### CNS-Active Agents - When suvorexant was co-administered with alcohol, additive psychomotor impairment was demonstrated. There was no alteration in the pharmacokinetics of suvorexant . ### Effects of Other Drugs on Suvorexant - Metabolism by CYP3A is the major elimination pathway for suvorexant. - CYP3A Inhibitors - Concomitant use of suvorexant with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan) is not recommended. - The recommended dose of suvorexant is 5 mg in subjects receiving moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil). The dose can be increased to 10 mg in these patients if necessary for efficacy. - CYP3A Inducers - Suvorexant exposure can be substantially decreased when co-administered with strong CYP3A inducers (e.g., rifampin, carbamazepine and phenytoin). The efficacy of suvorexant may be reduced. ### Effects of Suvorexant on Other Drugs - Digoxin - Concomitant administration of suvorexant with digoxin slightly increased digoxin levels due to inhibition of intestinal P-gp. Digoxin concentrations should be monitored when co-administering suvorexant with digoxin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies in pregnant women. Suvorexant should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of suvorexant to pregnant rats throughout organogenesis in two separate studies at oral doses of 30, 150, and 1000 mg/kg or 30, 80, and 325 mg/kg resulted in a decrease in fetal body weight at doses greater than 80 mg/kg. Plasma exposures (AUC) at the no-effect dose were approximately 25 times that in humans at the maximum recommended human dose (MRHD) of 20 mg/day. - Administration of suvorexant to pregnant rabbits throughout organogenesis in two separate studies at oral doses of 40, 100, and 300 mg/kg or 50, 150, and 325 mg/kg resulted in no apparent adverse effects on embryo-fetal development. Excessive toxicity resulted in premature sacrifice of pregnant animals at 325 mg/kg. The highest maternal plasma exposures (AUC) for which there are fetal data were up to approximately 40 times that in humans at the MRHD. - Administration of suvorexant (oral doses of 30, 80, and 200 mg/kg) to pregnant rats throughout gestation and lactation resulted in decreased body weight in offspring at the highest dose tested. Plasma AUCs at the no-effect dose were approximately 25 times that in humans at the MRHD. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Suvorexant in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Suvorexant during labor and delivery. ### Nursing Mothers - Suvorexant and a hydroxyl-suvorexant metabolite were excreted in rat milk at levels higher (9 and 1.5 times, respectively) than that in maternal plasma. It is not known whether this drug is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when suvorexant is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of the total number of patients treated with suvorexant (n=1784) in controlled clinical safety and efficacy studies, 829 patients were 65 years and over, and 159 patients were 75 years and over. No clinically meaningful differences in safety or effectiveness were observed between these patients and younger patients at the recommended doses. ### Gender There is no FDA guidance on the use of Suvorexant with respect to specific gender populations. ### Race There is no FDA guidance on the use of Suvorexant with respect to specific racial populations. ### Renal Impairment - No dose adjustment is required in patients with renal impairment. ### Hepatic Impairment - No dose adjustment is required in patients with mild and moderate hepatic impairment. Suvorexant has not been studied in patients with severe hepatic impairment and is not recommended for these patients. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Suvorexant in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Suvorexant in patients who are immunocompromised. ### Patients with Compromised Respiratory Function - Effects of suvorexant on respiratory function should be considered if prescribed to patients with compromised respiratory function. - Obstructive Sleep Apnea - The respiratory depressant effect of suvorexant was evaluated after one night and after four consecutive nights of treatment in a randomized, placebo-controlled, 2-period crossover study in patients (n=26) with mild to moderate obstructive sleep apnea. Following once-daily doses of 40 mg, the mean Apnea/Hypopnea Index treatment difference (suvorexant – placebo) on Day 4 was 2.7 (90% CI: 0.22 to 5.09), but there was wide inter- and intra-individual variability such that clinically meaningful respiratory effects of suvorexant in obstructive sleep apnea cannot be excluded. Suvorexant has not been studied in patients with severe obstructive sleep apnea. - Chronic Obstructive Pulmonary Disease - The respiratory depressant effect of suvorexant was evaluated after one night and after four consecutive nights of treatment in a randomized, placebo-controlled, 2-period crossover study in patients (n=25) with mild to moderate chronic obstructive pulmonary disease (COPD). Suvorexant (40 mg in non-elderly, 30 mg in elderly) had no respiratory depressant effects in patients with mild to moderate COPD, as measured by oxygen saturation. There was wide inter- and intra-individual variability such that clinically meaningful respiratory effects of suvorexant in COPD cannot be excluded. Suvorexant has not been studied in patients with severe COPD. # Administration and Monitoring ### Administration - Oral. ### Monitoring - Prescribers should monitor for somnolence and CNS depressant effects. - Digoxin concentrations should be monitored when co-administering suvorexant with digoxin. - Vital signs should be monitored with general supportive measures in overdosage. # IV Compatibility - There is limited information regarding IV Compatibility. # Overdosage - There is limited premarketing clinical experience with an overdosage of suvorexant. In clinical pharmacology studies, healthy subjects who were administered morning doses of up to 240 mg of suvorexant showed dose-dependent increases in the frequency and duration of somnolence. - General symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. As in all cases of drug overdose, vital signs should be monitored and general supportive measures employed. The value of dialysis in the treatment of overdosage has not been determined. As suvorexant is highly protein-bound, hemodialysis is not expected to contribute to elimination of suvorexant. - As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. Consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage. # Pharmacology ## Mechanism of Action - The mechanism by which suvorexant exerts its therapeutic effect in insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive. - Antagonism of orexin receptors may also underlie potential adverse effects such as signs of narcolepsy/cataplexy. Genetic mutations in the orexin system in animals result in hereditary narcolepsy; loss of orexin neurons has been reported in humans with narcolepsy. ## Structure - BELSOMRA tablets contain suvorexant, a highly selective antagonist for orexin receptors OX1R and OX2R. - Suvorexant is described chemically as: - [(7R)-4-(5-chloro-2-benzoxazolyl) hexahydro-7-methyl-1H-1,4-diazepin-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone - Its empirical formula is C23H23ClN6O2 and the molecular weight is 450.92. Its structural formula is: Suvorexant is a white to off-white powder that is insoluble in water. - Each film coated tablet contains 5 mg, 10 mg, 15 mg, or 20 mg of suvorexant and the following inactive ingredients: polyvinylpyrrolidone/vinyl acetate copolymer (copovidone), microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. - In addition, the film coating contains the following inactive ingredients: lactose monohydrate, hypromellose, titanium dioxide, and triacetin. The film coating for the 5 mg tablets also contains iron oxide yellow and iron oxide black, and the film coating for the 10 mg tablets also contains iron oxide yellow and FD&C Blue #1/Brilliant Blue FCF Aluminum Lake. ## Pharmacodynamics - The effects of suvorexant on the QTc interval were evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover study in healthy subjects (n=53). The upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc interval was below 10 ms based on analysis of suvorexant doses up to 240 mg, 12 times the maximum recommended dose. suvorexant thus does not prolong the QTc interval to any clinically relevant extent. ## Pharmacokinetics - Suvorexant exposure increases in a less than strictly dose-proportional manner over the range of 10-80 mg because of decreased absorption at higher doses. Suvorexant pharmacokinetics are similar in healthy subjects and patients with insomnia. - Suvorexant peak concentrations occur at a median Tmax of 2 hours (range 30 minutes to 6 hours) under fasted conditions. The mean absolute bioavailability of 10 mg is 82%. - Ingestion of suvorexant with a high-fat meal resulted in no meaningful change in AUC or Cmax but a delay in Tmax of approximately 1.5 hours. Suvorexant may be taken with or without food; however for faster sleep onset, suvorexant should not be administered with or soon after a meal. - The mean volume of distribution of suvorexant is approximately 49 liters. Suvorexant is extensively bound (>99%) to human plasma proteins and does not preferentially distribute into red blood cells. Suvorexant binds to both human serum albumin and α1-acid glycoprotein. - Suvorexant is mainly eliminated by metabolism, primarily by CYP3A with a minor contribution from CYP2C19. The major circulating entities are suvorexant and a hydroxy-suvorexant metabolite. This metabolite is not expected to be pharmacologically active. - The primary route of elimination is through the feces, with approximately 66% of radiolabeled dose recovered in the feces compared to 23% in the urine. The systemic pharmacokinetics of suvorexant are linear with an accumulation of approximately 1- to 2-fold with once-daily dosing. Steady-state is achieved by 3 days. The mean t1/2 is approximately 12 hours (95% CI: 12 to 13). - Gender, age, body mass index (BMI), and race were included as factors assessed in the population pharmacokinetic model to evaluate suvorexant pharmacokinetics in healthy subjects and to predict exposures in the patient population. Age and race are not predicted to have any clinically meaningful changes on suvorexant pharmacokinetics; therefore, no dose adjustment is warranted based upon these factors. - Suvorexant exposure is higher in females than in males. In females, the AUC and Cmax are increased by 17% and 9%, respectively, following administration of suvorexant 40 mg. The average concentration of suvorexant 9 hours after dosing is 5% higher for females across the dose range studied (10-40 mg). Dose adjustment of suvorexant is generally not needed based on gender only. - Apparent oral clearance of suvorexant is inversely related to body mass index. In obese patients, the AUC and Cmax are increased by 31% and 17%, respectively. The average concentration of suvorexant approximately 9 hours after a 20 mg dose is 15% higher in obese patients (BMI > 30 kg/m2) relative to those with a normal BMI (BMI ≤ 25 kg/m2). - In obese females, the AUC and Cmax are increased by 46% and 25%, respectively, compared to non-obese females. The higher exposure to suvorexant in obese females should be considered before increasing dose. - The effects of renal and hepatic impairment on the pharmacokinetics of suvorexant were evaluated in specific pharmacokinetic studies. - Suvorexant exposure after a single dose was similar in patients with moderate hepatic insufficiency (Child-Pugh category 7 to 9) and healthy matched control subjects; however, the suvorexant apparent terminal half-life was increased from approximately 15 hours (range 10 - 22 hours) in healthy subjects to approximately 19 hours (range 11 - 49 hours) in patients with moderate hepatic insufficiency. - Suvorexant exposure (expressed as total and unbound concentrations) was similar between patients with severe renal impairment (urinary creatinine clearance ≤30 mL/min/1.73m2) and healthy matched control subjects. No dose adjustment is required in patients with renal impairment. - An additive effect on psychomotor performance was observed when a single dose of 40 mg of suvorexant was co-administered with a single dose of 0.7 g/kg alcohol. Suvorexant did not affect alcohol concentrations and alcohol did not affect suvorexant concentration. - An interaction study with a single dose of 40 mg suvorexant and paroxetine 20 mg at steady-state levels in healthy subjects did not demonstrate a clinically significant pharmacokinetic or pharmacodynamic interaction. - The effects of other drugs on the pharmacokinetics of suvorexant are presented in Figure 1 as change relative to suvorexant administered alone (test/reference). Strong (e.g., ketoconazole or itraconazole) and moderate (e.g., diltiazem) CYP3A inhibitors significantly increased suvorexant exposure. Strong CYP3A inducers (e.g., rifampin) substantially decreased suvorexant exposure. In vitro metabolism studies demonstrate that suvorexant has the potential to inhibit CYP3A and intestinal P-gp; however, suvorexant is unlikely to cause clinically significant inhibition of human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. In addition, no clinically meaningful inhibition of OATP1B1, BCRP and OCT2 transporters is anticipated. Chronic administration of suvorexant is unlikely to induce the metabolism of drugs metabolized by major CYP isoforms. Specific in vivo effects on the pharmacokinetics of midazolam, warfarin, digoxin and oral contraceptives are presented in Figure 2 as a change relative to the interacting drug administered alone (test/reference). ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - In a 26-week study in Tg.rasH2 mice, there was no evidence of suvorexant-induced neoplasms at oral doses of 25, 50, 200, and 650 mg/kg/day. - In a 2-year study in rats (oral suvorexant doses of 80, 160, and 325 mg/kg/day), increases in thyroid (follicular cell adenoma and combined adenoma/carcinoma in high-dose females; follicular cell adenoma in mid- and high-dose males) and liver (hepatocellular adenoma in high-dose males) neoplasms were observed. These findings were consistent with increased TSH and hepatic enzyme induction, respectively, which are mechanisms believed to be rodent-specific. Plasma exposures (AUC) at doses not associated with drug-induced neoplasms in rats were approximately 7 times that in humans at the maximum recommended human dose (MRHD) of 20 mg. - Suvorexant was negative in in vitro (bacterial reverse mutation and chromosomal aberration) and in vivo (mouse and rat micronucleus) assays. - In two separate studies, male and female rats were treated with suvorexant prior to and during mating and continuing in females to gestation day 7. Increases in peri-implantation loss and resorptions, resulting in a decrease in live fetuses, were observed at the highest doses tested (1200 or 325 mg/kg) when treated males and females were mated with untreated animals. At the no-effect dose for adverse effects on fertility in males and females, plasma AUCs were approximately 20 times that in humans at the MRHD. ### Animal Toxicology and/or Pharmacology - In dogs, daily oral administration of suvorexant (5, 30 mg/kg) for 4-7 days resulted in behavior characteristic of cataplexy (e.g., transient limb buckling, prone posture) when presented with food enrichment, a stimulus demonstrated to induce cataplexy in dogs with hereditary narcolepsy. - In the 2-year carcinogenicity study in rats, an increased incidence of retinal atrophy was observed at all doses. Plasma AUCs at the lowest dose tested were approximately 7 times that in humans at the MRHD. - In subsequent studies of suvorexant in albino and pigmented rats, retinal atrophy was delayed in onset and, after approximately one year of dosing, was of lower incidence and severity in pigmented rats. # Clinical Studies - Suvorexant was evaluated in three clinical trials in patients with insomnia characterized by difficulties with sleep onset and sleep maintenance. - Two similarly designed, 3-month, randomized, double-blind, placebo-controlled, parallel-group studies were conducted (Study 1 and Study 2). In both studies, non-elderly (age 18-64) and elderly (age ≥ 65) patients were randomized separately. For the studies together, non-elderly adults (mean age 46 years; 465 females, 275 males) were treated with suvorexant 20 mg (n=291) or placebo (n=449). Elderly patients (mean age 71 years, 346 females, 174 males) were treated with suvorexant 15 mg (n=202) or placebo (n=318). - In Study 1 and Study 2, suvorexant 15 mg or 20 mg was superior to placebo for sleep latency as assessed both objectively by polysomnography (Table 3) and subjectively by patient-estimated sleep latency (Table 4). Suvorexant 15 mg or 20 mg was also superior to placebo for sleep maintenance, as assessed both objectively by polysomnography (Table 5) and subjectively by patient-estimated total sleep time (Table 6). The effects of suvorexant at night 1 (objective) and week 1 (subjective) were generally consistent with later time points. The efficacy of suvorexant was similar between women and men and, based on limited data, between Caucasians and non-Caucasians. Twenty seven percent of patients treated with suvorexant 15 mg or 20 mg in Study 1 and Study 2 were non-Caucasians. The majority (69%) of the non-Caucasian patients was Asian. - In the 1-month crossover study (Study 3), non-elderly adults (age 18-64 years, mean age 44 years) were treated with placebo (n=249) and suvorexant at a dose of 10 mg (n=62), 20 mg (n=61), or up to 80 mg. Suvorexant 10 mg and 20 mg were superior to placebo for sleep latency and sleep maintenance, as assessed objectively by polysomnography. - Suvorexant was also evaluated at doses of 30 mg and 40 mg in the 3-month placebo-controlled trials (Study 1 and Study 2). The higher doses were found to have similar efficacy to lower doses, but significantly more adverse reactions were reported at the higher doses. ## Special Safety Studies ### Effects on Driving - Two randomized, double-blind, placebo- and active-controlled, four-period crossover studies evaluated the effects of nighttime administration of suvorexant on next-morning driving performance 9 hours after dosing in 24 healthy elderly subjects (≥65 years old, mean age 69 years; 14 men, 10 women) who received 15 mg and 30 mg suvorexant, and 28 non-elderly subjects (mean age 46 years; 13 men, 15 women) who received 20 mg and 40 mg suvorexant. Testing was conducted after one night and after 8 consecutive nights of treatment with suvorexant at these doses. - The primary outcome measure was change in Standard Deviation of Lane Position (SDLP), a measure of driving performance, assessed using a symmetry analysis. The analysis showed clinically meaningful impaired driving performance in some subjects. After one night of dosing, this effect was observed in non-elderly subjects after either a 20 mg or 40 mg dose of suvorexant. A statistically significant effect was not observed in elderly subjects after a 15 mg or 30 mg dose of suvorexant. Across these two studies, five subjects (4 non-elderly women on suvorexant; 1 elderly woman on placebo) prematurely stopped their driving tests due to somnolence. Patients using the 20 mg dose of suvorexant should be cautioned against next-day driving and other activities requiring full mental alertness. Patients taking lower doses of suvorexant should also be cautioned about the potential for driving impairment because there is individual variation in sensitivity to suvorexant. ### Effects on Next-day Memory and Balance in Elderly and Non-elderly - Four placebo-controlled trials evaluated the effects of nighttime administration of suvorexant on next-day memory and balance using word learning tests and body sway tests, respectively. Three trials showed no significant effects on memory or balance compared to placebo. In a fourth trial in healthy non-elderly subjects, there was a significant decrease in word recall after the words were presented to subjects in the morning following a single dose of 40 mg suvorexant, and there was a significant increase on body sway area in the morning following a single dose of 20 mg or 40 mg suvorexant. ### Middle of the Night Safety in Elderly Subjects - A double-blind, randomized, placebo-controlled trial evaluated the effect of a single dose of suvorexant on balance, memory and psychomotor performance in healthy elderly subjects (n=12) after being awakened during the night. Nighttime dosing of suvorexant 30 mg resulted in impairment of balance (measured by body sway area) at 90 minutes as compared to placebo. Memory was not impaired, as assessed by an immediate and delayed word recall test at 4 hours post-dose. ### Rebound Effects - In 3-month controlled safety and efficacy trials (Study 1, Study 2), rebound insomnia was assessed following discontinuation of suvorexant relative to placebo and baseline in non-elderly adult patients receiving suvorexant 40 mg or 20 mg and in elderly patients receiving suvorexant 30 mg or 15 mg. No clear effects were observed on measures of sleep onset or maintenance. ### Withdrawal Effects - In 3-month controlled safety and efficacy trials (Study 1, Study 2), withdrawal effects were assessed following discontinuation in non-elderly adult patients who received suvorexant 40 mg or 20 mg and elderly patients who received suvorexant 30 mg or 15 mg. The analysis showed no clear evidence of withdrawal in the overall study population based on assessment of patient responses to the Tyrer Withdrawal Symptom Questionnaire or assessment of withdrawal-related adverse events following the discontinuation of suvorexant. ### Respiratory Safety - A randomized, placebo-controlled, double-blind, crossover trial in healthy non-elderly subjects (n=12) evaluated the respiratory depressant effect of suvorexant (40 mg and 150 mg) after one night of treatment. At the doses studied, suvorexant had no respiratory depressant effect as measured by oxygen saturation. # How Supplied - No. 3062 — suvorexant tablets, 5 mg, are yellow, round, film-coated tablets, with "5" on one side and plain on the other side. They are supplied as follows: NDC 0006-0005-30 unit-of-use blisters of 30 - No. 3063 — suvorexant tablets, 10 mg, are green, round, film-coated tablets, with "33" on one side and plain on the other side. They are supplied as follows: NDC 0006-0033-30 unit-of-use blisters of 30 - No. 3981 — suvorexant tablets, 15 mg, are white, oval, film-coated tablets with the Merck logo on one side and "325" on the other side. They are supplied as follows: NDC 0006-0325-30 unit-of-use blisters of 30 - No. 3982 — suvorexant tablets, 20 mg, are white, round, film-coated tablets with the Merck logo and "335" on one side and plain on the other side. They are supplied as follows: NDC 0006-0335-30 unit-of-use blisters of 30 ## Storage - Store at 20°C to 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]. Store in the original package until use to protect from light and moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). - Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment and with each prescription refill. Review the suvorexant Medication Guide with every patient prior to initiation of treatment. ### CNS Depressant Effects and Next-Day Impairment - Tell patients that suvorexant has the potential to cause next-day impairment, and that this risk is increased with higher doses or if dosing instructions are not carefully followed. Patients using the 20 mg dose should be cautioned against next-day driving and other activities requiring full mental alertness as this dose is associated with a higher risk of impaired driving. Patients taking lower doses should also be cautioned about the potential for driving impairment because there is individual variation in sensitivity to suvorexant. - Patients should not drive or engage in other activities requiring full alertness within 8 hours of dosing of suvorexant. ### Sleep-driving and Other Complex Behaviors - Instruct patients to inform their families that suvorexant has been associated with getting out of bed while not being fully awake, and tell patients and their families to call their healthcare providers if this occurs. - Hypnotics, like suvorexant, have been associated with "sleep-driving" and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients and their families to call their healthcare providers if they develop any of these symptoms. ### Suicide - Tell patients to report any worsening of depression or suicidal thoughts immediately. ### Alcohol and Other Drugs - Ask patients about alcohol consumption, prescription medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use suvorexant if they drank alcohol that evening or before bed. ### Tolerance, Abuse, and Dependence - Tell patients not to increase the dose of suvorexant on their own, and to inform you if they believe the drug "does not work." ### Administration Instructions - Advise patients to take suvorexant only when preparing for or getting into bed and only if they can stay in bed for a full night before being active again. Advise patients to report all of their prescription and nonprescription medicines, vitamins and herbal supplements to the prescriber. # Precautions with Alcohol - Alcohol-Suvorexant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - BELSOMRA®[1] # Look-Alike Drug Names - There is limited information regarding Look-Alike Drug Names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Suvorexant
7da916f7f567db1c594e2ea49630c5cc8b92e48a	wikidoc	Sweat test	Sweat test # Overview The Sweat test measures the concentration of chloride and sodium that is excreted in sweat. It is used to diagnose cystic fibrosis (CF). # Method Sweating is induced by pilocarpine iontophoresis. At the test site, an electrode is placed over gauze containing pilocarpine and electrolyte solution that will not interfere with the sodium and chloride measurement. A second electrode (without pilocarpine) will be placed at another site and a mild electrical current will draw the pilocarpine into the skin where it stimulates the sweat glands. The test site is carefully cleaned and dried, then a piece of preweighed filter paper is placed over the test site and covered with paraffin to prevent evaporation. Specialized collection devices may also be used. Sweat is collected for 30 minutes. The filter paper is retrieved and weighed to determine the weight of sweat collected. Several laboratory methods are then used to determine the sodium and chloride concentrations. # Results ## Reference ranges If the concentration of chloride is >60 mEq/L, the test is positive; 40-60 mEq/L is borderline; <40 mEq/L is negative. The reference range for sodium is <70-90 mEq/L. The minimum sample weight varies with the collection method. ## Interpretation Two reliable positive results on two separate days is diagnostic for CF. Because of the existence of milder variants, borderline or even near-borderline negative results may be used to diagnose CF. Clinical presentation, family history and patient age must be considered to interpret the results. Highly discordant sodium and chloride values may indicate technical errors. ## Sources of Error Technical errors, insufficient sample, evaporation, contamination, dehydration, mineralocorticoid hormone therapy, and skin rash on the tested area may produce incorrect results. False positive test results may be caused by malnutrition, adrenal insufficiency, glycogen storage diseases, hypothyroidism, hypoparathyroidism, nephrogenic diabetes insipidus, G6PD deficiency or ectodermal dysplasia (source: )	Sweat test Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The Sweat test measures the concentration of chloride and sodium that is excreted in sweat. It is used to diagnose cystic fibrosis (CF). # Method Sweating is induced by pilocarpine iontophoresis. At the test site, an electrode is placed over gauze containing pilocarpine and electrolyte solution that will not interfere with the sodium and chloride measurement. A second electrode (without pilocarpine) will be placed at another site and a mild electrical current will draw the pilocarpine into the skin where it stimulates the sweat glands. The test site is carefully cleaned and dried, then a piece of preweighed filter paper is placed over the test site and covered with paraffin to prevent evaporation. Specialized collection devices may also be used. Sweat is collected for 30 minutes. The filter paper is retrieved and weighed to determine the weight of sweat collected. Several laboratory methods are then used to determine the sodium and chloride concentrations. # Results ## Reference ranges If the concentration of chloride is >60 mEq/L, the test is positive; 40-60 mEq/L is borderline; <40 mEq/L is negative. The reference range for sodium is <70-90 mEq/L. The minimum sample weight varies with the collection method. ## Interpretation Two reliable positive results on two separate days is diagnostic for CF. Because of the existence of milder variants, borderline or even near-borderline negative results may be used to diagnose CF. Clinical presentation, family history and patient age must be considered to interpret the results. Highly discordant sodium and chloride values may indicate technical errors. ## Sources of Error Technical errors, insufficient sample, evaporation, contamination, dehydration, mineralocorticoid hormone therapy, and skin rash on the tested area may produce incorrect results. False positive test results may be caused by malnutrition, adrenal insufficiency, glycogen storage diseases, hypothyroidism, hypoparathyroidism, nephrogenic diabetes insipidus, G6PD deficiency or ectodermal dysplasia (source: http://www.eMRCP.com) # External links - Cystic Fibrosis Foundation Sweat Test Information Page nn:Sveittetest	https://www.wikidoc.org/index.php/Sweat_chloride_test
c7152a3cf659a24cd8b2d5f657e556395f2197bf	wikidoc	Sweet Flag	Sweet Flag Calamus or Common Sweet Flag (Acorus calamus) is a plant from the Acoraceae family, Acorus genues. It is a tall perennial wetland monocot with scented leaves and rhizomes which have been used medicinally, for its odor, and as a psychotropic drug. It is known by a variety of names, including cinnamon sedge, flagroot, gladdon, myrtle flag, myrtle grass, myrtle sedge, sweet cane, sweet myrtle, sweet root, sweet rush, and sweet sedge. Probably indigenous to India, Acorus calamus is now found across Europe, in southern Russia, northern Asia Minor, southern Siberia, China, Japan, Burma, Sri Lanka, and northern USA. # Botanical information The morphological distinction between the Acorus species is made by the number of prominent leaf veins. Acorus calamus has a single prominent midvein and then on both sides slightly raised secondary veins (with a diameter less than half the midvein) and many, fine tertiary veins. This makes it clearly distinct from Acorus americanus. The leaves are between 0.7 and 1.7 cm wide, with average of 1 cm. The sympodial leaf of Acorus calamus is somewhat shorter than the vegetative leaves. The margin is curly-edged or undulate. The spadix, at the time of expansion, can reach a length between 4.9 and 8.9 cm (longer than A. americanus). The flowers are longer too, between 3 and 4 mm. Acorus calamus is infertile and shows an abortive ovary with a shriveled appearance. # Chemistry Both triploid and tetraploid calamus contain asarone, but diploid does not contain any. # Regulations Calamus and products derived from calamus (such as its oil) were banned in 1968 as food additives and medicines by the United States Food and Drug Administration. # Usage Calamus has been an item of trade in many cultures for thousands of years. Calamus has been used medicinally for a wide variety of ailments. In antiquity in the Orient and Egypt, the rhizome was thought to be a powerful aphrodisiac. In Europe Acorus calamus was often added to wine, and the root is also one of the possible ingredients of absinthe. Among the northern Native Americans, it is used both medicinally and as a stimulant; in addition, the root is thought to have been used as an entheogen among the northern Native Americans. In high doses, it is hallucinogenic. # Cultural symbolism The calamus has long been a symbol of male love. The name is associated with a Greek myth: Kalamos, a son of the river-god Maeander, who loved Karpos, the son of Zephyrus and Chloris. When Karpos drowned, Kalamos was transformed into a reed, whose rustling in the wind was interpreted as a sigh of lamentation. The plant was a favorite of Henry David Thoreau (who called it sweet flag), and also of Walt Whitman, who added a section called The Calamus Poems, celebrating the love of men, to the third edition of Leaves of Grass (1860). In the poems the calamus is used as a symbol of love, lust, and affection. It has been suggested that the symbology derives from the visual resemblance of the spadix to the erect human penis. The name Sweet Flag refers to its sweet scent (it has been used as a strewing herb) and the wavy edges of the leaves which are supposed to resemble a fluttering flag. In Japan, the plant is a symbol of the samurai's bravery because of its sharp sword-like leaves. Even now many families with young boys enjoy "Sweet Flag Bath (shōbu yu)" in the Boy's Festival (Tango no Sekku) on May 5. # Etymology of the word Calamus Cognates of the Latin word Calamus are found in both Greek (kalamos, meaning "reed") and Sanskrit (kalama, meaning "reed" and "pen" as well as a sort of rice) — strong evidence that the word is older than all three languages and exists in their parent language, Proto-Indo European. The Arabic word qalam (meaning "pen") is likely to have been borrowed from one of these languages in antiquity, or directly from Indo-European itself. From the Latin root "calamus", a number of modern English words arise: - calamari, meaning "squid", via the Latin calamarium, "ink horn" or "pen case", as reeds were then used as writing implements; - calumet, another name for the Native American peace pipe, which was often made from a hollow reed; - shawm, a medieval oboe-like instrument (whose sound is produced by a vibrating reed mouthpiece); - chalumeau register, the lower notes of a clarinet's range (another reed instrument).	Sweet Flag Calamus or Common Sweet Flag (Acorus calamus) is a plant from the Acoraceae family, Acorus genues. It is a tall perennial wetland monocot with scented leaves and rhizomes which have been used medicinally, for its odor, and as a psychotropic drug. It is known by a variety of names, including cinnamon sedge, flagroot, gladdon, myrtle flag, myrtle grass, myrtle sedge, sweet cane, sweet myrtle, sweet root, sweet rush, and sweet sedge. Probably indigenous to India, Acorus calamus is now found across Europe, in southern Russia, northern Asia Minor, southern Siberia, China, Japan, Burma, Sri Lanka, and northern USA. # Botanical information The morphological distinction between the Acorus species is made by the number of prominent leaf veins. Acorus calamus has a single prominent midvein and then on both sides slightly raised secondary veins (with a diameter less than half the midvein) and many, fine tertiary veins. This makes it clearly distinct from Acorus americanus. The leaves are between 0.7 and 1.7 cm wide, with average of 1 cm. The sympodial leaf of Acorus calamus is somewhat shorter than the vegetative leaves. The margin is curly-edged or undulate. The spadix, at the time of expansion, can reach a length between 4.9 and 8.9 cm (longer than A. americanus). The flowers are longer too, between 3 and 4 mm. Acorus calamus is infertile and shows an abortive ovary with a shriveled appearance. # Chemistry Both triploid and tetraploid calamus contain asarone, but diploid does not contain any. # Regulations Calamus and products derived from calamus (such as its oil) were banned in 1968 as food additives and medicines by the United States Food and Drug Administration. # Usage Calamus has been an item of trade in many cultures for thousands of years. Calamus has been used medicinally for a wide variety of ailments. In antiquity in the Orient and Egypt, the rhizome was thought to be a powerful aphrodisiac. In Europe Acorus calamus was often added to wine, and the root is also one of the possible ingredients of absinthe. Among the northern Native Americans, it is used both medicinally and as a stimulant; in addition, the root is thought to have been used as an entheogen among the northern Native Americans. In high doses, it is hallucinogenic. # Cultural symbolism The calamus has long been a symbol of male love. The name is associated with a Greek myth: Kalamos, a son of the river-god Maeander, who loved Karpos, the son of Zephyrus and Chloris. When Karpos drowned, Kalamos was transformed into a reed, whose rustling in the wind was interpreted as a sigh of lamentation. The plant was a favorite of Henry David Thoreau (who called it sweet flag), and also of Walt Whitman, who added a section called The Calamus Poems, celebrating the love of men, to the third edition of Leaves of Grass (1860). In the poems the calamus is used as a symbol of love, lust, and affection. It has been suggested that the symbology derives from the visual resemblance of the spadix to the erect human penis. The name Sweet Flag refers to its sweet scent (it has been used as a strewing herb) and the wavy edges of the leaves which are supposed to resemble a fluttering flag. In Japan, the plant is a symbol of the samurai's bravery because of its sharp sword-like leaves. Even now many families with young boys enjoy "Sweet Flag Bath (shōbu yu)" in the Boy's Festival (Tango no Sekku) on May 5. # Etymology of the word Calamus Cognates of the Latin word Calamus are found in both Greek (kalamos, meaning "reed") and Sanskrit (kalama, meaning "reed" and "pen" as well as a sort of rice) — strong evidence that the word is older than all three languages and exists in their parent language, Proto-Indo European. The Arabic word qalam (meaning "pen") is likely to have been borrowed from one of these languages in antiquity, or directly from Indo-European itself. From the Latin root "calamus", a number of modern English words arise: - calamari, meaning "squid", via the Latin calamarium, "ink horn" or "pen case", as reeds were then used as writing implements; - calumet, another name for the Native American peace pipe, which was often made from a hollow reed; - shawm, a medieval oboe-like instrument (whose sound is produced by a vibrating reed mouthpiece); - chalumeau register, the lower notes of a clarinet's range (another reed instrument). # External links - Family Araceae in L. Watson and M.J. Dallwitz (1992 onwards). The families of flowering plants: descriptions, illustrations, identification, information retrieval. http://delta-intkey.com - FDA street drug alternative warning letter - Acorus calamus at Plants for a Future - Calamus Acorus Calamus Online Herb Guide be-x-old:Аер ang:Bēowyrt be:Аер bg:Блатен аир ca:Càlam (botànica) cs:Puškvorec obecný de:Kalmus (Art) et:Harilik kalmus fy:Kalmuswoartel ko:창포 lt:Balinis ajeras hu:Orvosi kálmos ml:വയമ്പ്‌ nl:Kalmoes sq:Kashtëfryza fi:Rohtokalmojuuri sv:Kalmus ur:داج قلموس	https://www.wikidoc.org/index.php/Sweet_Flag
2eabc19d33cc7102ad8f47815adf5087d55f6f80	wikidoc	Swiss-Prot	Swiss-Prot # Overview Swiss-Prot is a manually curated biological database of protein sequences. Swiss-Prot was created in 1986 by Amos Bairoch during his PhD and developed by the Swiss Institute of Bioinformatics and the European Bioinformatics Institute. Swiss-Prot strives to provide reliable protein sequences associated with a high level of annotation (such as the description of the function of a protein, its domains structure, post-translational modifications, variants, etc.), a minimal level of redundancy and high level of integration with other databases. In 2002, the UniProt consortium was created: it is a collaboration between the Swiss Institute of Bioinformatics, the European Bioinfomatics Institute and the Protein Information Resource (PIR), funded by the National Institutes of Health. Swiss-Prot and its automatically curated supplement TrEMBL, have joined with the Protein Information Resource protein database to produce the UniProt Knowledgebase, the world's most comprehensive catalogue of information on proteins. As of 3 April 2007, UniProtKB/Swiss-Prot release 52.2 contains 263,525 entries. As of 3 April 2007, the UniProtKB/TrEMBL release 35.2 contains 4,232,122 entries. The UniProt consortium produced 3 database components, each optimised for different uses. The UniProt Knowledgebase (UniProtKB (Swiss-Prot + TrEMBL)), the UniProt Non-redundant Reference (UniRef) databases, which combine closely related sequences into a single record to speed similarity searches and the UniProt Archive (UniParc), which is a comprehensive repository of protein sequences, reflecting the history of all protein sequences.	Swiss-Prot # Overview Swiss-Prot is a manually curated biological database of protein sequences. Swiss-Prot was created in 1986 by Amos Bairoch during his PhD and developed by the Swiss Institute of Bioinformatics and the European Bioinformatics Institute.[1] Swiss-Prot strives to provide reliable protein sequences associated with a high level of annotation (such as the description of the function of a protein, its domains structure, post-translational modifications, variants, etc.), a minimal level of redundancy and high level of integration with other databases. In 2002, the UniProt consortium was created: it is a collaboration between the Swiss Institute of Bioinformatics, the European Bioinfomatics Institute and the Protein Information Resource (PIR), funded by the National Institutes of Health. Swiss-Prot and its automatically curated supplement TrEMBL, have joined with the Protein Information Resource protein database to produce the UniProt Knowledgebase, the world's most comprehensive catalogue of information on proteins.[2] As of 3 April 2007, UniProtKB/Swiss-Prot release 52.2 contains 263,525 entries. As of 3 April 2007, the UniProtKB/TrEMBL release 35.2 contains 4,232,122 entries. The UniProt consortium produced 3 database components, each optimised for different uses. The UniProt Knowledgebase (UniProtKB (Swiss-Prot + TrEMBL)), the UniProt Non-redundant Reference (UniRef) databases, which combine closely related sequences into a single record to speed similarity searches and the UniProt Archive (UniParc), which is a comprehensive repository of protein sequences, reflecting the history of all protein sequences.	https://www.wikidoc.org/index.php/Swiss-Prot
b63c4aa2f3f7530d01a6fb9a9bf8969d3a99cc64	wikidoc	Synapsin 2	Synapsin 2 Synapsin II is the collective name for synapsin IIa and synapsin IIb, two nearly identical phosphoproteins in the synapsin family that in humans are encoded by the SYN2 gene. Synapsins associate as endogenous substrates to the surface of synaptic vesicles and act as key modulators in neurotransmitter release across the presynaptic membrane of axonal neurons in the nervous system. # Gene Alternative splicing of the SYN2 gene results in two transcripts. The TIMP4 gene is located within an intron of this gene and is transcribed in the opposite direction. # Protein Synapsin II is a member of the synapsin family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family encodes a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic nerve terminal. Synapsin II the collective name for two proteins, synapsin IIa and synapsin IIb, with synapsin IIa being the larger of the two isoforms. Their apparent molecular weights are 74,000 and 55,000 Da, per SDS gel electrophoresis. Synapsin II along with synapsin I comprise approximately 9% of the proteins in highly purified samples of synaptic vesicles. # Structure Synapsin II shares common domains within its amino acid sequence with other phosphoproteins in the synapsin family. Sharing the same N-terminal, synapsin II diverges from synapsin I in its C-terminal domains. It is much shorter than synapsin I and is missing most of the elongated domains seen in synapsin I. Roughly 70% of the amino acid residues are common between the two synapsins, which share common phosphorylation sites in the overlapping regions based on the homologous domains. Domain A of this neural protein contains phosphorylation sites for cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase I, and domain B has two mitogen-activated protein kinase phosphorylation sites. At its B domain, between amino acids 43 and 121, synapsin II binds to a protein component in the cytosolic surface membrane of synaptic vesicles, organelles in neurons which carry neurotransmitters. # Function Synapsin II regulates synaptic function of neurons in the central and peripheral nervous system. Synapsin IIa is the only synapsin isoform of the six synapsin isoforms (synapsin I-III each with isoforms A and B), which has been shown to significantly reverse synaptic depression and have a restorative effect on the density of synaptic vesicles within synapsinless neurons. Because of its restorative effect, synapsin IIa is believed to play a fundamental role in synaptic vesicle mobilization and reserve pool regulation in presynaptic nerve terminals. Lack of synapsins altogether in neurons, leads to behavioral alterations as well as epileptic-type seizures. The lack affects nervous signal transduction across excitatory and inhibitory synapses of neurons differently and is believed to be synapse-specific. Initial signal transduction appears to be unaffected by the lack of synapsins, but repeated stimulation of cultured synapsinless hippocampal neurons subsequently showed depressed responses at the excitatory synapse. At the inhibitory synapse, base signal transduction is reduced in neurons lacking pre-existing synapsins, but the reduced level of transduction is less affected by progressive stimulation. However, the restoration of synapsin IIa to neurons without pre-existing synapsins, can partially recover presumably lost signal transduction and slow the depression of synaptic response with progressive stimulation. Its isoform synapsin IIb may have a similar but weaker effect. Through fluorescence and staining, it has been demonstrated that synapsin IIa increases the number and density of glutamatergic synaptic vesicles in the nerve terminal of neural axons. The recovery of nervous signal transduction is attributed to the increase in density of synaptic vesicles, which carry neurotransmitters to the synaptic cleft, and the amount of synaptic vesicles in the reserve pool in the presence of synapsin IIa. In turn, this is thought to increase the number of vesicles available for mobilization from the reserve pool to the ready-release pool. The reserve pool is the pool of synaptic vesicles which reside in the nerve terminal away from the presynaptic membrane of the axon, but are not in the ready to release or ready-release pool. Those vesicles in the ready-release pool reside very close to the presynaptic membrane and are primed to release neurotransmitters for nervous signal transduction. # Interactions The synapsin II protein has been shown to interact with SYN1. # Clinical significance Mutations in the SYN2 gene may be associated with abnormal presynaptic function and schizophrenia.	Synapsin 2 Synapsin II is the collective name for synapsin IIa and synapsin IIb, two nearly identical phosphoproteins in the synapsin family that in humans are encoded by the SYN2 gene.[1][2] Synapsins associate as endogenous substrates to the surface of synaptic vesicles and act as key modulators in neurotransmitter release across the presynaptic membrane of axonal neurons in the nervous system. # Gene Alternative splicing of the SYN2 gene results in two transcripts. The TIMP4 gene is located within an intron of this gene and is transcribed in the opposite direction.[2] # Protein Synapsin II is a member of the synapsin family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family encodes a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic nerve terminal.[2] Synapsin II the collective name for two proteins, synapsin IIa and synapsin IIb, with synapsin IIa being the larger of the two isoforms. Their apparent molecular weights are 74,000 and 55,000 Da, per SDS gel electrophoresis.[3] Synapsin II along with synapsin I comprise approximately 9% of the proteins in highly purified samples of synaptic vesicles. # Structure Synapsin II shares common domains within its amino acid sequence with other phosphoproteins in the synapsin family.[4] Sharing the same N-terminal, synapsin II diverges from synapsin I in its C-terminal domains. It is much shorter than synapsin I and is missing most of the elongated domains seen in synapsin I. Roughly 70% of the amino acid residues are common between the two synapsins,[3] which share common phosphorylation sites in the overlapping regions based on the homologous domains. Domain A of this neural protein contains phosphorylation sites for cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase I, and domain B has two mitogen-activated protein kinase phosphorylation sites. At its B domain, between amino acids 43 and 121, synapsin II binds to a protein component in the cytosolic surface membrane of synaptic vesicles, organelles in neurons which carry neurotransmitters.[3] # Function Synapsin II regulates synaptic function of neurons in the central and peripheral nervous system.[5] Synapsin IIa is the only synapsin isoform of the six synapsin isoforms (synapsin I-III each with isoforms A and B), which has been shown to significantly reverse synaptic depression and have a restorative effect on the density of synaptic vesicles within synapsinless neurons. Because of its restorative effect, synapsin IIa is believed to play a fundamental role in synaptic vesicle mobilization and reserve pool regulation in presynaptic nerve terminals.[6] Lack of synapsins altogether in neurons, leads to behavioral alterations as well as epileptic-type seizures. The lack affects nervous signal transduction across excitatory and inhibitory synapses of neurons differently and is believed to be synapse-specific. Initial signal transduction appears to be unaffected by the lack of synapsins, but repeated stimulation of cultured synapsinless hippocampal neurons subsequently showed depressed responses at the excitatory synapse. At the inhibitory synapse, base signal transduction is reduced in neurons lacking pre-existing synapsins, but the reduced level of transduction is less affected by progressive stimulation.[7] However, the restoration of synapsin IIa to neurons without pre-existing synapsins, can partially recover presumably lost signal transduction and slow the depression of synaptic response with progressive stimulation. Its isoform synapsin IIb may have a similar but weaker effect. Through fluorescence and staining, it has been demonstrated that synapsin IIa increases the number and density of glutamatergic synaptic vesicles in the nerve terminal of neural axons. The recovery of nervous signal transduction is attributed to the increase in density of synaptic vesicles, which carry neurotransmitters to the synaptic cleft, and the amount of synaptic vesicles in the reserve pool in the presence of synapsin IIa.[6] In turn, this is thought to increase the number of vesicles available for mobilization from the reserve pool to the ready-release pool. The reserve pool is the pool of synaptic vesicles which reside in the nerve terminal away from the presynaptic membrane of the axon, but are not in the ready to release or ready-release pool. Those vesicles in the ready-release pool reside very close to the presynaptic membrane and are primed to release neurotransmitters for nervous signal transduction. # Interactions The synapsin II protein has been shown to interact with SYN1.[8] # Clinical significance Mutations in the SYN2 gene may be associated with abnormal presynaptic function and schizophrenia.[2]	https://www.wikidoc.org/index.php/Synapsin_2
982341c79dcfc3e8f7bbee6d756139fbc21afbe4	wikidoc	Synapsin I	Synapsin I Synapsin I, is the collective name for Synapsin Ia and Synapsin Ib, two nearly identical phosphoproteins that in humans are encoded by the SYN1 gene. In its phosphorylated form, Synapsin I may also be referred to as phosphosynaspin I. Synapsin I is the first of the proteins in the synapsin family of phosphoproteins in the synaptic vesicles present in the central and peripheral nervous systems. Synapsin Ia and Ib are close in length and almost the same in make up, however, Synapsin Ib stops short of the last segment of the C-terminal in the amino acid sequence found in Synapsin Ia. # Protein The synapsin I protein is a member of the synapsin family that are neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. The phosphoprotein plays a role in regulation of axonogenesis and synaptogenesis. The protein serves as a substrate for several different protein kinases and phosphorylation may function in the regulation of this protein in the nerve terminal. Synapsin I is found in two isoforms of the protein, Synapsin Ia and Synapsin Ib, with Synapsin Ib being a slightly shorter version of the protein. Both Synapsin I proteins are highly basic with a pI in the range of 10.3 and 10.2, respectively. Both isoforms are phosphorylated at identical locations within their protein sequences at the same three serine residues. Synapsin I phosphoproteins make up approximately 6% of the total protein in synaptic vesicles. Among bovine, rat, and human it has been shown to be 95% homologous, with the central 'C' domain evolutionarily conserved. This phosphoprotein is loosely associated with the vesicular membrance and is easily dissociated by treatment with a salt, versus a detergent being required for its removal from the membrane. # Structure Synapsin I proteins are made up of a globular portion at the N-terminal and an elongated C-terminal domain, rendering them largely elongated. Synapsin Ib has the same protein domains as synapsin Ia, however synapsin Ib lacks the last C-terminal segment, making it slightly shorter in its elongated domain. 706 amino acids comprise synapsin Ia, and starting from the N-terminal, the same first 670 amino acids comprise synapsin Ib. Rich in the amino acids proline and glycine, the compositional and structural natures of this protein are somewhat similar to collagen. This aided in the early determination of its structure using collagenase, which was later confirmed by amino acid sequencing and modern techniques. Cleavage of synapsin I by collagenase fragments the elongated C-terminal and leaves the globular N-terminal domain intact. Amino acid sequencing has shown that synapsin I has common N-terminals across both isoforms and shares the same N-terminal as synapsin II. Synapsin I isoforms differ from synapsin II isoforms in their C-terminal domains as well. Further research has been done on the interactions of synapsin I, synapsin II, and synapsin III with each other to create heterodimers of the proteins in COS cells. # Function Synapsin I is present in the nerve terminal of axons, specifically in the membranes of synaptic vesicles based on immunocytochemistry. This phosphoprotein is as an endogenous substrate bound to the vesicular membrane. It is phosphorylated by four known classes of protein kinases including those activated by cAMP, calcium/calmodulin, mitogen, and cyclin. Both isoforms have the same six phosphorylation sites: The N-terminal globular domain contains three sites: the cAMP-dependent protein kinase-mediated phosphorylation site near the end in domain A, and two sites further in, in domain B, mediated by mitogen-activated protein kinase (MAP kinase). The tail portion of the protein, the C-terminal end, bears three phosphorylation sites: two sites at which calcium/calmodulin dependent protein kinase II acts, and a third site at which MAP kinase and cyclin-dependent protein kinase (CDK) acts. Specificity for calcium/calmodulin dependent protein kinase binding to Synapsin I is very high in comparison to other substrate proteins. Cyclic AMP-dependent protein kinase is unique in its mechanism of activation. The protein kinase is composed of two regulatory (R) subunits and two catalytic (C) subunits, creating a tetrameric holoenzyme. Cyclic AMP binds to the regulatory subunits of cAMP-dependent protein kinase and causes the dissociation of its regulatory subunits from the catalytic subunits, generating the active form of the kinase. This active form of the protein kinase catalyses the phosphorylation of Synapsin I. The phosphorylated form of Synapsin I is referred to as phosphosynapsin I. Depolarization of the presynaptic membrane induces a calcium ion influx into the axonal nerve terminal of neurons, and increases the intracellular concentration of calcium ions. Synapsin I was shown to be phosphorylated by this calcium influx. The calcium ion, Ca2+, binds to calmodulin to form a calcium/calmodulin complex which then activates the calcium/calmodulin-dependent protein kinase, in turn triggering phosphorylation. Calcium/calmodulin-dependent phosphorylation of synapsin I causes dissociation of synapsin I from the vesicular membrane. In the nerve terminal ending, there are two pools of synaptic vesicles, the reserve pool and the ready-release pool. The reserve pool refers to the synaptic vesicles that are not ready to release neurotransmitters and the ready-release pool refers to the vesicles which are primed to release their neurotransmitters across the presynaptic cytoplasmic membrane and into the synaptic cleft. The removal of Synapsin I from synaptic vesicles is thought to mobilize synaptic vesicles from the reserve pool to the release-ready pool, thereby modulating neurotransmitter release. Since it is only present in the vesicles in the reserve pool, the non-phosphorylated form of Synapsin I is considered to be an inhibitory regulator of neurotransmission. # Interactions The synapsin I protein has been shown to interact with NOS1AP and SYN2. # Clinical significance Mutations in the SYN1 gene may be associated with X-linked disorders with primary neuronal degeneration such as Rett syndrome. # Discovery The first member of the synapsin family, synapsin I was initially observed in 1973, as a neuronal membrane protein that was phosphorylated by membrane bound cAMP-dependent protein kinase. Synapsin I was detected by radioactive P-32 incorporated into the unknown protein through phosphorylation, using a then newly developed technique: a combination of SDS gel electrophoresis and autoradiography. This groundbreaking technique allowed the advancement of the analysis of phosphorylated proteins, and introduced the identification of specific proteins. This was accomplished by the measuring the radioactivity through autoradiography of the individual protein bands phosphorylated by radioactive ATP, which is radio-labelled with P-32 at the gamma phosphate. In 1977, at the same laboratory at Yale University, this first neuronal phosphoprotein was purified and initially characterized by Tetsufumi Ueda and Nobel Prize winner Paul Greengard. Originally named Protein I, it was found as an endogenous substrate for cAMP-dependent protein kinase in the synaptic membrane of the rat brain and was the first collagenous protein to be described in the nervous system.	Synapsin I Synapsin I, is the collective name for Synapsin Ia and Synapsin Ib, two nearly identical phosphoproteins that in humans are encoded by the SYN1 gene.[1][2] In its phosphorylated form, Synapsin I may also be referred to as phosphosynaspin I. Synapsin I is the first of the proteins in the synapsin family of phosphoproteins in the synaptic vesicles present in the central and peripheral nervous systems. Synapsin Ia and Ib are close in length and almost the same in make up, however, Synapsin Ib stops short of the last segment of the C-terminal in the amino acid sequence found in Synapsin Ia. # Protein The synapsin I protein is a member of the synapsin family that are neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. The phosphoprotein plays a role in regulation of axonogenesis and synaptogenesis. The protein serves as a substrate for several different protein kinases and phosphorylation may function in the regulation of this protein in the nerve terminal.[2] Synapsin I is found in two isoforms of the protein, Synapsin Ia and Synapsin Ib, with Synapsin Ib being a slightly shorter version of the protein. Both Synapsin I proteins are highly basic with a pI in the range of 10.3 and 10.2, respectively. Both isoforms are phosphorylated at identical locations within their protein sequences at the same three serine residues. Synapsin I phosphoproteins make up approximately 6% of the total protein in synaptic vesicles.[3] Among bovine, rat, and human it has been shown to be 95% homologous, with the central 'C' domain evolutionarily conserved. This phosphoprotein is loosely associated with the vesicular membrance and is easily dissociated by treatment with a salt, versus a detergent being required for its removal from the membrane. # Structure Synapsin I proteins are made up of a globular portion at the N-terminal and an elongated C-terminal domain, rendering them largely elongated. Synapsin Ib has the same protein domains as synapsin Ia, however synapsin Ib lacks the last C-terminal segment, making it slightly shorter in its elongated domain. 706 amino acids comprise synapsin Ia, and starting from the N-terminal, the same first 670 amino acids comprise synapsin Ib. Rich in the amino acids proline and glycine, the compositional and structural natures of this protein are somewhat similar to collagen. This aided in the early determination of its structure using collagenase, which was later confirmed by amino acid sequencing and modern techniques. Cleavage of synapsin I by collagenase fragments the elongated C-terminal and leaves the globular N-terminal domain intact.[4] Amino acid sequencing has shown that synapsin I has common N-terminals across both isoforms and shares the same N-terminal as synapsin II. Synapsin I isoforms differ from synapsin II isoforms in their C-terminal domains as well.[5] Further research has been done on the interactions of synapsin I, synapsin II, and synapsin III with each other to create heterodimers of the proteins in COS cells.[6] # Function Synapsin I is present in the nerve terminal of axons, specifically in the membranes of synaptic vesicles based on immunocytochemistry.[7] This phosphoprotein is as an endogenous substrate bound to the vesicular membrane. It is phosphorylated by four known classes of protein kinases including those activated by cAMP,[8][9] calcium/calmodulin,[10] mitogen, and cyclin. Both isoforms have the same six phosphorylation sites: The N-terminal globular domain contains three sites: the cAMP-dependent protein kinase-mediated phosphorylation site near the end in domain A, and two sites further in, in domain B, mediated by mitogen-activated protein kinase (MAP kinase). The tail portion of the protein, the C-terminal end, bears three phosphorylation sites: two sites at which calcium/calmodulin dependent protein kinase II acts, and a third site at which MAP kinase and cyclin-dependent protein kinase (CDK) acts. Specificity for calcium/calmodulin dependent protein kinase binding to Synapsin I is very high in comparison to other substrate proteins.[11] Cyclic AMP-dependent protein kinase is unique in its mechanism of activation. The protein kinase is composed of two regulatory (R) subunits and two catalytic (C) subunits, creating a tetrameric holoenzyme. Cyclic AMP binds to the regulatory subunits of cAMP-dependent protein kinase and causes the dissociation of its regulatory subunits from the catalytic subunits, generating the active form of the kinase. This active form of the protein kinase catalyses the phosphorylation of Synapsin I. The phosphorylated form of Synapsin I is referred to as phosphosynapsin I. Depolarization of the presynaptic membrane induces a calcium ion influx into the axonal nerve terminal of neurons, and increases the intracellular concentration of calcium ions. Synapsin I was shown to be phosphorylated by this calcium influx.[12] The calcium ion, Ca2+, binds to calmodulin to form a calcium/calmodulin complex which then activates the calcium/calmodulin-dependent protein kinase, in turn triggering phosphorylation.[10] Calcium/calmodulin-dependent phosphorylation of synapsin I causes dissociation of synapsin I from the vesicular membrane. In the nerve terminal ending, there are two pools of synaptic vesicles, the reserve pool and the ready-release pool. The reserve pool refers to the synaptic vesicles that are not ready to release neurotransmitters and the ready-release pool refers to the vesicles which are primed to release their neurotransmitters across the presynaptic cytoplasmic membrane and into the synaptic cleft. The removal of Synapsin I from synaptic vesicles is thought to mobilize synaptic vesicles from the reserve pool to the release-ready pool, thereby modulating neurotransmitter release. Since it is only present in the vesicles in the reserve pool, the non-phosphorylated form of Synapsin I is considered to be an inhibitory regulator of neurotransmission. # Interactions The synapsin I protein has been shown to interact with NOS1AP[13] and SYN2.[6] # Clinical significance Mutations in the SYN1 gene may be associated with X-linked disorders with primary neuronal degeneration such as Rett syndrome.[2] # Discovery The first member of the synapsin family, synapsin I was initially observed in 1973, as a neuronal membrane protein that was phosphorylated by membrane bound cAMP-dependent protein kinase. Synapsin I was detected by radioactive P-32 incorporated into the unknown protein through phosphorylation, using a then newly developed technique: a combination of SDS gel electrophoresis and autoradiography.[7] This groundbreaking technique allowed the advancement of the analysis of phosphorylated proteins, and introduced the identification of specific proteins. This was accomplished by the measuring the radioactivity through autoradiography of the individual protein bands phosphorylated by radioactive ATP, which is radio-labelled with P-32 at the gamma phosphate. In 1977, at the same laboratory at Yale University, this first neuronal phosphoprotein was purified and initially characterized by Tetsufumi Ueda and Nobel Prize winner Paul Greengard. Originally named Protein I, it was found as an endogenous substrate for cAMP-dependent protein kinase in the synaptic membrane of the rat brain and was the first collagenous protein to be described in the nervous system.[9]	https://www.wikidoc.org/index.php/Synapsin_I
7cb2548f9aa558ebacc9b9666fd6a7bbd52eb794	wikidoc	Syncytin-1	Syncytin-1 Syncytin-1 also known as enverin is a protein found in humans and other primates that is encoded by the ERVW-1 gene (endogenous retrovirus group W envelope member 1). Syncytin-1 is a cell-cell fusion protein whose function is best characterized in placental development. The placenta in turn aids in embryo attachment to the uterus and establishment of a nutrient supply. The gene encoding this protein is an endogenous retroviral element that is the remnant of an ancient retroviral infection integrated into the primate germ line. In the case of syncytin-1 (which is found in humans, apes, and Old World but not New World monkeys), this integration likely occurred more than 25 million years ago. Syncytin-1 is one of two known syncytin proteins expressed in catarrhini primates (the other being syncytin-2) and one of many syncytins captured and domesticated on multiple occasions over evolutionary time in diverse mammalian species. This is analogous to the incorporation of certain bacterial species into eukaryotic cells during the course of evolution that eventually developed into mitochondria. ERVW-1 is located within ERVWE1, a full length provirus on chromosome 7 at locus 7q21.2 flanked by long terminal repeats (LTRs) and is preceded by ERVW1 gag (Group AntiGen) and pol (POLmerase) within the provirus, both of which contain nonsense mutations rendering them non-coding. Syncytin-1 is also implicated in a number of neurological pathologies, most notably, multiple sclerosis, as an immunogen. # Placental development Syncytin-1 mediated trophoblast fusion is essential for normal placental development. The placenta is composed on two cell layers: cytotrophoblast and syncytiotrophoblast layer. Cytotrophoblasts are continually dividing, non-differentiated cells and syncytiotrophoblasts are fully differentiated, non dividing, fused cells. Syncytin-1 expression on the surface of cytotrophoblasts and syncytiotrophoblasts mediate fusion. The syncytiotrophoblast layer is the necessary interface between the developing embryo and the maternal blood supply, allowing nutrient and waste exchange and blocking maternal immune cell invasion, preventing immune rejection of the foetus. Syncytiotrophoblasts are forced into senescence by fusion. Therefore, cytotrophoblast proliferation is necessary for growth and maintenance of the syncytiotrophoblast layer. Syncytin-1 expression in cytotrophoblasts promotes G1/S transition and proliferation thereby ensuring continual replenishment of the cytotrophoblast pool. The name syncytin derives from its involvement in the formation of syncytium, the multinucleated syncytiotrophoblast protoplasm. There is another endogenous retroviral envelope protein expressed in the placenta from a different ERV family: syncytin-2 (of HERV-FRD). # Receptor The syncytin-1 receptor is the Na-dependent amino acid transporter 2 (ASCT2 or SLC1A5). This receptor places syncytin-1 in a large viral interference group called retroviral mammalian type D receptor (RDR) interference group. Syncytin-1 has been shown to interfere with viral infection in-vitro by RDR interference group member spleen necrosis virus. Syncytin-1 can also recognize ASCT1 or SLC1A4, but this receptor is not a receptor for the RDR interference group. Mutation studies of syncytin-1 and of ASCT2 have provided insight into potential receptor binding domains and determinants. A putative receptor binding domain was identified in syncytin-1 at residues 117-144. The amino acid sequence at this region is well conserved amongst RDR interference group members. The motif SDGGGX2DX2R is present in all RDR interference group members within this conserved region and may play an important role in binding. Preliminary evidence with syncytin-1 and spleen necrosis virus indicate this motif contains the ASCT2 binding determinants. The largest ectodomain of ASCT1 and ASCT2, extracellular loop 2 (ECL2), contains at its C-terminus a 21 residue hypervariable region between human, mouse, and hamster receptors. This region was shown to confer specificity to receptor binding by most RDR interference group members. Both glycosylation pattern and amino acid sequence differences between human and rodent receptors are determinants in susceptibility to infection by RDR interference group members. Murine (mouse) ASCT1 expressing cells are only susceptible to syncytin-1 and another endogenous retroviral env protein (that of Baboon Endogenous Retrovrius) and human ASCT1 has only been shown to bind syncytin-1. Further research is needed to elucidate ASCT and RDR binding determinants. # Structure Syncytin-1 shares many structural elements with class I retroviral glycoproteins (such as, Murine Leukemia Virus gp, Ebolavirus gp, and HIV gp120, gp41). It is composed of a surface subunit (SU) and transmembrane subunit (TM), separated by a furin cleavage site. The two subunits form a heterodimer and are likely linked by a disulfide bond between two conserved cysteine rich motifs: CXXC in SU and CX6CC in TM. This heterodimer likely forms a homotrimer at the cell surface. Syncytin-1 TM contains the fusion peptide, and two heptad repeats separated by a chain reversal region common to class I retroviral glycoproteins. Syncytin-1 is a single pass membrane protein and has a relatively long cytoplasmic tail; however, truncation of the cytoplasmic tail to just 14 residues has been shown to increase fusogenic activity, indicating its C-terminus is likely involved in modulating fusion activity. # Clinical significance ## Pre-eclampsia Hypoxic conditions characteristic of Pre-eclampsia and IUGR are associated with abnormal expression of syncytin-1 in trophoblast cells and pre-eclamptic placental tissue has reduced levels of syncytin-1 expression. Abnormal syncytin-1 expression likely plays an important role in placental pathologies. ## Neurological pathologies ERVW-1 is a single locus within the HERV-W family encoding a fully functional env protein. mRNA and protein expression of the ERVW-1 locus in neural tissue is implicated in neurodegeneration and development of multiple sclerosis. Multiple sclerosis retrovirus like particle (MSRV) envelope protein shares high sequence similarity to ERVW-1 encoded syncytin-1 and has long been studied as an important factor in MS pathogenesis. The gene locus of MSRV env has not been determined. Preliminary evidence implicates aberrant expression of ERVW-1 in neuron and glial cells and HERV-W LTR mediated aberrant cellular protein expression in the pathogenesis of bipolar disorder and schizophrenia.	Syncytin-1 Syncytin-1 also known as enverin is a protein found in humans and other primates that is encoded by the ERVW-1 gene (endogenous retrovirus group W envelope member 1). Syncytin-1 is a cell-cell fusion protein whose function is best characterized in placental development.[1][2] The placenta in turn aids in embryo attachment to the uterus and establishment of a nutrient supply. The gene encoding this protein is an endogenous retroviral element that is the remnant of an ancient retroviral infection integrated into the primate germ line. In the case of syncytin-1 (which is found in humans, apes, and Old World but not New World monkeys), this integration likely occurred more than 25 million years ago.[3] Syncytin-1 is one of two known syncytin proteins expressed in catarrhini primates (the other being syncytin-2) and one of many syncytins captured and domesticated on multiple occasions over evolutionary time in diverse mammalian species.[4] This is analogous to the incorporation of certain bacterial species into eukaryotic cells during the course of evolution that eventually developed into mitochondria. ERVW-1 is located within ERVWE1,[5][6] a full length provirus on chromosome 7 at locus 7q21.2 flanked by long terminal repeats (LTRs) and is preceded by ERVW1 gag (Group AntiGen) and pol (POLmerase) within the provirus, both of which contain nonsense mutations rendering them non-coding.[7][8] Syncytin-1 is also implicated in a number of neurological pathologies, most notably, multiple sclerosis, as an immunogen. # Placental development Syncytin-1 mediated trophoblast fusion is essential for normal placental development. The placenta is composed on two cell layers: cytotrophoblast and syncytiotrophoblast layer. Cytotrophoblasts are continually dividing, non-differentiated cells and syncytiotrophoblasts are fully differentiated, non dividing, fused cells. Syncytin-1 expression on the surface of cytotrophoblasts and syncytiotrophoblasts mediate fusion. The syncytiotrophoblast layer is the necessary interface between the developing embryo and the maternal blood supply, allowing nutrient and waste exchange and blocking maternal immune cell invasion, preventing immune rejection of the foetus. Syncytiotrophoblasts are forced into senescence by fusion.[9] Therefore, cytotrophoblast proliferation is necessary for growth and maintenance of the syncytiotrophoblast layer. Syncytin-1 expression in cytotrophoblasts promotes G1/S transition and proliferation thereby ensuring continual replenishment of the cytotrophoblast pool.[10] The name syncytin derives from its involvement in the formation of syncytium, the multinucleated syncytiotrophoblast protoplasm. There is another endogenous retroviral envelope protein expressed in the placenta from a different ERV family: syncytin-2 (of HERV-FRD). # Receptor The syncytin-1 receptor is the Na-dependent amino acid transporter 2 (ASCT2 or SLC1A5).[11][12] This receptor places syncytin-1 in a large viral interference group called retroviral mammalian type D receptor (RDR) interference group.[13] Syncytin-1 has been shown to interfere with viral infection in-vitro by RDR interference group member spleen necrosis virus.[14] Syncytin-1 can also recognize ASCT1 or SLC1A4, but this receptor is not a receptor for the RDR interference group. Mutation studies of syncytin-1 and of ASCT2 have provided insight into potential receptor binding domains and determinants. A putative receptor binding domain was identified in syncytin-1 at residues 117-144.[15] The amino acid sequence at this region is well conserved amongst RDR interference group members. The motif SDGGGX2DX2R is present in all RDR interference group members within this conserved region and may play an important role in binding. Preliminary evidence with syncytin-1 and spleen necrosis virus indicate this motif contains the ASCT2 binding determinants.[15][16][17] The largest ectodomain of ASCT1 and ASCT2, extracellular loop 2 (ECL2), contains at its C-terminus a 21 residue hypervariable region between human, mouse, and hamster receptors. This region was shown to confer specificity to receptor binding by most RDR interference group members.[18] Both glycosylation pattern and amino acid sequence differences between human and rodent receptors are determinants in susceptibility to infection by RDR interference group members. Murine (mouse) ASCT1 expressing cells are only susceptible to syncytin-1 and another endogenous retroviral env protein (that of Baboon Endogenous Retrovrius) and human ASCT1 has only been shown to bind syncytin-1.[18] Further research is needed to elucidate ASCT and RDR binding determinants. # Structure Syncytin-1 shares many structural elements with class I retroviral glycoproteins (such as, Murine Leukemia Virus gp, Ebolavirus gp, and HIV gp120, gp41). It is composed of a surface subunit (SU) and transmembrane subunit (TM), separated by a furin cleavage site.[6] The two subunits form a heterodimer and are likely linked by a disulfide bond between two conserved cysteine rich motifs: CXXC in SU and CX6CC in TM.[6] This heterodimer likely forms a homotrimer at the cell surface. Syncytin-1 TM contains the fusion peptide, and two heptad repeats separated by a chain reversal region common to class I retroviral glycoproteins. Syncytin-1 is a single pass membrane protein and has a relatively long cytoplasmic tail; however, truncation of the cytoplasmic tail to just 14 residues has been shown to increase fusogenic activity, indicating its C-terminus is likely involved in modulating fusion activity.[19] # Clinical significance ## Pre-eclampsia Hypoxic conditions characteristic of Pre-eclampsia and IUGR are associated with abnormal expression of syncytin-1 in trophoblast cells[20] and pre-eclamptic placental tissue has reduced levels of syncytin-1 expression.[21] Abnormal syncytin-1 expression likely plays an important role in placental pathologies. ## Neurological pathologies ERVW-1 is a single locus within the HERV-W family encoding a fully functional env protein. mRNA and protein expression of the ERVW-1 locus in neural tissue is implicated in neurodegeneration and development of multiple sclerosis. Multiple sclerosis retrovirus like particle (MSRV) envelope protein shares high sequence similarity to ERVW-1 encoded syncytin-1 and has long been studied as an important factor in MS pathogenesis.[22] The gene locus of MSRV env has not been determined. Preliminary evidence implicates aberrant expression of ERVW-1 in neuron and glial cells and HERV-W LTR mediated aberrant cellular protein expression in the pathogenesis of bipolar disorder and schizophrenia.[15][23]	https://www.wikidoc.org/index.php/Syncytin-1
cd6419d8dbd0e3bb60f51e1d4be655edbf016e47	wikidoc	Syndecan-4	Syndecan-4 Syndecan-4 is a protein that in humans is encoded by the SDC4 gene. Syndecan-4 is one of the four vertebrate syndecans and has a molecular weight of ~20 kDa. Syndecans are the best-characterized plasma membrane proteoglycans. Their intracellular domain of membrane-spanning core protein interacts with actin cytoskeleton and signaling molecules in the cell cortex. Syndecans are normally found on the cell surface of fibroblasts and epithelial cells. Syndecans interact with fibronectin on the cell surface, cytoskeletal and signaling proteins inside the cell to modulate the function of integrin in cell-matrix adhesion. Also, syndecans bind to FGFs and bring them to the FGF receptor on the same cell. As a co-receptor or regulator, mutated certain proteoglycans could cause severe developmental defects, like disordered distribution or inactivation of signaling molecules. Syndecans have similar structural features: - Attach to heparan sulfate chains – interacting factors (e.g. Matrix molecules, growth factors, and enzymes) - Chondroitin sulfate chain - Transmembrane domain – self-association - C1 domain – actin-association cytoskeleton - Variable domain – syndecan-specific - C2 domain – attach to PDZ proteins Syndecans normally form homodimers or multimers. Their biological function includes cell growth regulation, differentiation, and adhesion. Syndecan-4 has more widespread distribution than other syndecans and it is the only syndecan that has been found consistently in focal adhesions. # Gene Syndecan-4 is also called ryudocan or amphiglycan. It is found on chromosome 20, while a pseudogene has been found on chromosome 22. Syndecan-4 is one of the four vertebrate syndecans and has a molecular weight of ~20 kDa. It has more widespread distribution than other syndecans, and it is the only syndecan that has been found consistently in focal adhesions. # Function Syndecan-4 is a transmembrane (type I) heparan sulfate proteoglycan that functions as a receptor in intracellular signaling. The protein is found as a homodimer and is a member of the syndecan proteoglycan family. Syndecan-4 interacts with extracellular matrix, anticoagulants, and growth-factors. It also regulates the actin cytoskeleton, cell adhesion, and cell migration. Syndecan-4 activates protein kinase C (PKC), an enzyme involved in signal transduction. The variable domain of syndecan-4 could be a site of self-association. The degree of oligomerization correlates with the activity of kinases, so the degree of clustering of syndecan-4 correlates to PKC activity. Syndecan-4 also binds to phosphatidylinositol (4,5)-bisphosphate (PIP2) through the variable domain and increases PKC activity ten-fold. Syndecan-4 is also a regulator of fibroblast growth factor-2 (FGF-2) signaling. Syndecan-4 binds to FGF and mediates interaction with the FGF receptor. Because the tight correlation between syndecan-4 and growth factors, the efficiency of angiogenic therapies have been thought to relate to syndecan-4. Growth factor signaling may be disrupted by changes in syndecan-4 expression. The cellular uptake, trafficking, and nuclear localization of FGF-2 could be increased by co-delivery of syndecan-4 proteoliposomes. These alterations should be considered in FGF-2-based therapies. Syndecan-4 is also associated with the healing process. Lack of Sdc4 gene causes delayed wound healing in mice. This delay may be due to compromised fibroblast motility. # Clinical significance ## Osteoarthritis Syndecan-4 is upregulated in osteoarthritis and inhibition of syndecan-4 reduces cartilage destruction in mouse models of OA. See Sindecán-4 at the Spanish Wikipedia	Syndecan-4 Syndecan-4 is a protein that in humans is encoded by the SDC4 gene.[1][2] Syndecan-4 is one of the four vertebrate syndecans and has a molecular weight of ~20 kDa. Syndecans are the best-characterized plasma membrane proteoglycans. Their intracellular domain of membrane-spanning core protein interacts with actin cytoskeleton and signaling molecules in the cell cortex. Syndecans are normally found on the cell surface of fibroblasts and epithelial cells. Syndecans interact with fibronectin on the cell surface, cytoskeletal and signaling proteins inside the cell to modulate the function of integrin in cell-matrix adhesion. Also, syndecans bind to FGFs and bring them to the FGF receptor on the same cell. As a co-receptor or regulator, mutated certain proteoglycans could cause severe developmental defects, like disordered distribution or inactivation of signaling molecules. Syndecans have similar structural features: - Attach to heparan sulfate chains – interacting factors (e.g. Matrix molecules, growth factors, and enzymes) - Chondroitin sulfate chain - Transmembrane domain – self-association - C1 domain – actin-association cytoskeleton - Variable domain – syndecan-specific - C2 domain – attach to PDZ proteins Syndecans normally form homodimers or multimers. Their biological function includes cell growth regulation, differentiation, and adhesion. Syndecan-4 has more widespread distribution than other syndecans and it is the only syndecan that has been found consistently in focal adhesions.[3] # Gene Syndecan-4 is also called ryudocan or amphiglycan. It is found on chromosome 20, while a pseudogene has been found on chromosome 22.[4] Syndecan-4 is one of the four vertebrate syndecans and has a molecular weight of ~20 kDa. It has more widespread distribution than other syndecans, and it is the only syndecan that has been found consistently in focal adhesions.[5] # Function Syndecan-4 is a transmembrane (type I) heparan sulfate proteoglycan that functions as a receptor in intracellular signaling. The protein is found as a homodimer and is a member of the syndecan proteoglycan family.[4] Syndecan-4 interacts with extracellular matrix, anticoagulants, and growth-factors. It also regulates the actin cytoskeleton, cell adhesion, and cell migration.[6] Syndecan-4 activates protein kinase C (PKC), an enzyme involved in signal transduction.[7] The variable domain of syndecan-4 could be a site of self-association. The degree of oligomerization correlates with the activity of kinases, so the degree of clustering of syndecan-4 correlates to PKC activity.[8] Syndecan-4 also binds to phosphatidylinositol (4,5)-bisphosphate (PIP2) through the variable domain and increases PKC activity ten-fold.[9] Syndecan-4 is also a regulator of fibroblast growth factor-2 (FGF-2) signaling. Syndecan-4 binds to FGF and mediates interaction with the FGF receptor.[10] Because the tight correlation between syndecan-4 and growth factors, the efficiency of angiogenic therapies have been thought to relate to syndecan-4. Growth factor signaling may be disrupted by changes in syndecan-4 expression.[11][12][13] The cellular uptake, trafficking, and nuclear localization of FGF-2 could be increased by co-delivery of syndecan-4 proteoliposomes. These alterations should be considered in FGF-2-based therapies.[14] Syndecan-4 is also associated with the healing process. Lack of Sdc4 gene causes delayed wound healing in mice. This delay may be due to compromised fibroblast motility.[15] # Clinical significance ## Osteoarthritis Syndecan-4 is upregulated in osteoarthritis and inhibition of syndecan-4 reduces cartilage destruction in mouse models of OA.[16] See Sindecán-4 at the Spanish Wikipedia	https://www.wikidoc.org/index.php/Syndecan-4
ce9bdf055c2176de6f4dc3c02db6b46441faf0ba	wikidoc	Syntaxin 3	Syntaxin 3 Syntaxin 3, also known as STX3, is a protein which in humans is encoded by the STX3 gene. # Function The protein encoded by this gene is a member of the syntaxin family of cellular receptors for transport vesicles which participate in exocytosis in neutrophils. STX3 has an important role in the growth of neurites and serves as a direct target for omega-6 arachidonic acid. Mutations in Syntaxin 3 cause Microvillus inclusion disease . # Interactions Syntaxin 3 has been shown to interact with SNAP-25, SNAP23 and SNAP29.	Syntaxin 3 Syntaxin 3, also known as STX3, is a protein[1] which in humans is encoded by the STX3 gene.[2][3] # Function The protein encoded by this gene is a member of the syntaxin family of cellular receptors for transport vesicles which participate in exocytosis in neutrophils.[2] STX3 has an important role in the growth of neurites and serves as a direct target for omega-6 arachidonic acid.[4] Mutations in Syntaxin 3 cause Microvillus inclusion disease .[5] # Interactions Syntaxin 3 has been shown to interact with SNAP-25,[6][7][8] SNAP23[7][8][9][10] and SNAP29.[8]	https://www.wikidoc.org/index.php/Syntaxin_3
824e22a1401ba57cd9caef6a2dafd05477fdf447	wikidoc	T-cadherin	T-cadherin T-cadherin also known as cadherin 13, H-cadherin (heart) (CDH13) is a unique member of cadherin superfamily because it lacks the transmembrane and cytoplasmic domains and is anchored to the cells membrane through the GPI anchor. Classical cadherins are necessary for cell–cell contacts, dynamic regulation of morphogenetic processes in embryos and tissue integrity in adult organism. Cadherins function as membrane receptors mediating outside-in signals, activating small GTPases and beta-catenin/Wnt pathway, and resulting in dynamic cytoskeleton reorganization and changes in the phenotype. T-cadherin is a GPI-anchored member of cadherin superfamily, which lacks a direct contact with cytoskeleton and therefore is not involved in cell–cell adhesion. It is involved in low density lipoproteins (LDL) hormone-like effects on Ca2+-mobilization and increased cell migration as well as phenotype changes. Exact signaling partners and adapter proteins for T-cadherin remain to be elucidated. # Mediation of intracellular signaling in vascular cells Though T-cadherin can mediate weak adhesion in aggregation assays in vitro, the lack of intracellular domain suggests that T-cadherin is not involved in stable cell-cell adhesion. In vivo T-cadherin was detected on the apical cell surface of the chick interstinal epithelium. In cultures of transfected MDCS cells, T-cadherin was also expressed apically, whereas N-cadherin located basolaterally corresponded to the zone of cell contacts. The apical cell surface distribution of T-cadherin was proposed to possibly endow T-cadherin with recognition functions. In confluent cultures of vascular cells, T-cadherin was distributed equally over the entire cell surface, in contrast to VE-cadherin, which was restricted to the cell junctions. In migrating vascular cells, T-cadherin was located at the leading edge as revealed by confocal microscopy. The distribution of T-cadherin on the cell membrane is restricted to lipid rafts where it co-localizes with signal-transducing molecules. These data strongly implicates T-cadherin in intracellular signaling rather than adhesion. Studying signaling effects of low density lipoproteins (LDL) in vascular smooth muscles (VSMCs), T-cadherin was isolated and identified as new LDL receptor using human aortic media and the ligand-blotting method. The properties of T-cadherin as an LDL receptor were markedly different from the presently known types of LDL receptors. LDL binding to T-cadherin leads to the activation of Erk 1/2 tyrosine kinase and the nuclear translocation of NF-kappaB. T-cadherin overexpression in ECs facilitates spontaneous cell migration, formation of stress fibers and change of the phenotype from quiescent to promigratory. T-cadherin expression results in LDL-induced migration of T-cadherin expressing cells compared to control. It is likely that T-cadherin regulates cell migration and phenotype via activation of small G-proteins with subsequent actin reorganization. RhoA/ROCK activation is necessary for cell contraction, stress fiber assembly and inhibition of spreading, while Rac is required for the formation of membrane protrusions and actin-rich lamellopodia at the leading edge of migrating cells. # Functions in the vasculature The function of T-cadherin in situ, in normal conditions, and in pathology is still largely unknown. T-cadherin is highly expressed in the heart, aortic wall, neurons of the brain cortex and spinal cord and also in the small blood vessels in spleen and other organs. Expression of T-cadherin is upregulated in atherosclerotic lesions and post-angioplasty restenosis —conditions associated with pathological angiogenesis. T-cadherin expression is upregulated in ECs, pericytes and VSMC of atherosclerotic lesions. T-cadherin expression in arterial wall after balloon angioplasty correlates with late stages of neointima formation and coincidentally with the peak in proliferation and differentiation of vascular cells. It is highly expressed in adventitial vasa vasorum of injured arteries suggesting the involvement of T-cadherin in the processes of angiogenesis after vessel injury. These data implicate T-cadherin to be involved in regulation of vascular functioning and remodeling; however, the exact role of T-cadherin in neointima formation and atherosclerosis development is poorly understood. LDL is not the only ligand for T-cadherin. High-molecular weight (HMW) complexes of adiponectin were suggested to be a specific ligand for T-cadherin. Adiponectin (adipocyte complement-related protein of 30 kDa) is a cytokine produced by adipose tissue and its deficiency is associated with metabolic syndrome, obesity, type II diabetes and atherosclerosis. Adiponectin binding to T-cadherin on vascular cells is associated with NF-kappa B activation. Two membrane adiponectin receptors with distant homology to seven-transmembrane spanning G-protein-coupled receptors, namely AdipoR1 and AdipoR2 were identified in several tissues, but the University of Tokyo announced it was launching an investigation into anonymously made claims of fabricated and falsified data on the identification of AdipoR1 and AdipoR2 in 2016. # Regulation of cell growth In vitro T-cadherin is implicated in regulation of cell growth, survival and proliferation. In cultured VSMC and primary astrocytes, the expression of T-cadherin depends on proliferation status with maximum at confluency suggesting its regulation of cell growth by contact inhibition. Known mitogens such as platelet-derived growth factor (PDGF)-BB, epidermal growth factor (EGF) or insulin-like growth factor (IGF) elicit a reversible dose- and time-dependent decrease in T-cadherin expression in cultured VSMCs. Expression of T-cadherin leads to complete inhibition of subcutaneous tumor growth in nude mice. Seeding T-cadherin expressing cells on plastic coated with recombinant aminoterminal fragments of T-cadherin resulted in suppression of cell growth and was found to be associated with increased expression of p21. In T-cadherin deficient C6 glioma cell lines, its overexpression results in growth suppression involving p21CIP1/WAF1 production and G2 arrest. T-cadherin loss in tumor cells is associated with tumor malignancy, invasiveness and metastasis. Thus, tumor progression in basal cell carcinoma, cutaneous squamous carcinoma, non-small cell lung carcinoma (NSCLC), ovarian cancer, pancreatic cancer, colorectal cancer correlates with downregulation of T-cadherin expression. In psoriasis vulgaris the hyperproliferation of keratinocytes also correlates with the downregulation of T-cadherin expression. The mechanism for T-cadherin suppression is associated with allelic loss or hypermethylation of the T-cadherin gene promoter region. Transfection of T-cadherin negative neuroblastoma TGW and NH-12 cells with T-cadherin results in their loss of mitogenic proliferative response to epidermal growth factor (EGF) growth stimulation. Re-expression of T-cadherin in human breast cancer cells (MDAMB435) in culture, which originally do not express T-cadherin, results in the change of the phenotype from invasive to normal epithelial-like morphology. Thus, it was hypothesized that T-cadherin functions as a tumor-suppressor factor; inactivation of T-cadherin is associated with tumor malignancy, invasiveness and metastasis. However, in other tumors T-cadherin expression could promote tumor growth and metastasis. In primary lung tumors the loss of T-cadherin was not attributed to the presence of metastasis in lymph nodes, and in osteosarcomas T-cadherin expression was correlated with metastasis. Furthermore, T-cadherin overexpression was found to be a common feature of human high grade astrocytomas and associated with malignant transformation of astrocytes. Hetezygosity for NF1 (neurofibromatosis 1) tumor suppressor resulting in reduced attachment and spreading and increased motility also coincides with upregulated T-cadherin expression. Data show that HUVEC cells overexpressing T-cadherin after adenovirus infection enter S-phase more rapidly and exhibit increased proliferation potential. T-cadherin expression increases in HUVEC under conditions of oxidative stress, and production of reactive oxygen species (ROS) contributes to T-cadherin elevated expression. T-cadherin overexpression in HUVEC leads to higher phosphorylation of Phosphatidylinositol 3-kinase (PIK3) – target of Akt, and mTOR – target p70S6K (survival pathway regulator), resulting in reduced levels of caspase activation and increased survival after exposure to oxidative stress. It was suggested that in vascular cells T-cadherin performs a protective role against stress-induced apoptosis. Tumor cells can regulate gene expression in growing vessels and the surrounding stroma during tumor neovascularization. T-cadherin expression was found to be altered in tumor vessels: in Lewis carcinoma lung metastasis the expression of T-cadherin was upregulated in blood vessels penetrating the tumor, while T-cadherin was not detected in the surrounding tumor tissue. In tumor neovascularization of hepatocellular carcinoma (HCC) T-cadherin is upregulated in intratumoral capillary endothelial cells, whereas in surrounding tumor tissue as well as in normal liver no T-cadherin could be detected. The increase in T-cadherin expression in endothelial cell in HCC was shown to correlate with tumors progression. Presumably, T-cadherin could play a navigating role in the growing tumor vessels, which in the absence of contact inhibition from the stromal cells, grow into the surrounding tumor tissue. # Guiding molecules in vascular and nervous systems T-cadherin was originally cloned from chick embryo brain, where it was implicated as a negative guiding cue for motor axon projectioning through the somitic sclerotome and presumably for migrating neural crest cells . As a substrate or in soluble form, T-cadherin inhibits neurite outgrowth by motor neurons in vitro supporting the assumption that T-cadherin acts as a negative guiding molecule in the developing nervous system. Considering that the maximal expression of T-cadherin has been observed in nervous and cardiovascular systems, it is likely that T-cadherin is involved in guiding the growing vessel as well. The mechanism of T-cadherin mediated negative guidance in nervous system involves homophilic interaction and contact inhibition; in vascular system it is supposed that T-cadherin expressing blood vessels would avoid T-cadherin expressing tissues. # Bibliography - Ranscht B, Dours-Zimmermann MT (1991). "T-cadherin, a novel cadherin cell adhesion molecule in the nervous system lacks the conserved cytoplasmic region". Neuron. 7 (3): 391–402. doi:10.1016/0896-6273(91)90291-7. PMID 1654948..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} - Angst BD, Marcozzi C, Magee AI (15 February 2001). "The cadherin superfamily: diversity in form and function". J. Cell Sci. 114 (Pt 4): 629–41. PMID 11171368. - Angst BD, Marcozzi C, Magee AI (15 February 2001). "The cadherin superfamily". J. Cell Sci. 114 (Pt 4): 625–6. PMID 11171365. - Takeuchi T, Ohtsuki Y (2001). "Recent progress in T-cadherin (CDH13, H-cadherin) research". Histol. Histopathol. 16 (4): 1287–93. PMID 11642747. # Further reading - Takeuchi T, Ohtsuki Y (2002). "Recent progress in T-cadherin (CDH13, H-cadherin) research". Histol. Histopathol. 16 (4): 1287–93. PMID 11642747. - Suzuki S, Sano K, Tanihara H (1991). "Diversity of the cadherin family: evidence for eight new cadherins in nervous tissue". Cell Regul. 2 (4): 261–70. doi:10.1091/mbc.2.4.261. PMC 361775. PMID 2059658. - Tanihara H, Sano K, Heimark RL, et al. (1995). "Cloning of five human cadherins clarifies characteristic features of cadherin extracellular domain and provides further evidence for two structurally different types of cadherin". Cell Adhes. Commun. 2 (1): 15–26. doi:10.3109/15419069409014199. PMID 7982033. - Lee SW (1996). "H-cadherin, a novel cadherin with growth inhibitory functions and diminished expression in human breast cancer". Nat. Med. 2 (7): 776–82. doi:10.1038/nm0796-776. PMID 8673923. - Tkachuk VA, Bochkov VN, Philippova MP, et al. (1998). "Identification of an atypical lipoprotein-binding protein from human aortic smooth muscle as T-cadherin". FEBS Lett. 421 (3): 208–12. doi:10.1016/S0014-5793(97)01562-7. PMID 9468307. - Kremmidiotis G, Baker E, Crawford J, et al. (1998). "Localization of human cadherin genes to chromosome regions exhibiting cancer-related loss of heterozygosity". Genomics. 49 (3): 467–71. doi:10.1006/geno.1998.5281. PMID 9615235. - Philippova MP, Bochkov VN, Stambolsky DV, et al. (1998). "T-cadherin and signal-transducing molecules co-localize in caveolin-rich membrane domains of vascular smooth muscle cells". FEBS Lett. 429 (2): 207–10. doi:10.1016/S0014-5793(98)00598-5. PMID 9650591. - Sato M, Mori Y, Sakurada A, et al. (1998). "The H-cadherin (CDH13) gene is inactivated in human lung cancer". Hum. Genet. 103 (1): 96–101. doi:10.1007/s004390050790. PMID 9737784. - Sato M, Mori Y, Sakurada A, et al. (1999). "A GT dinucleotide repeat polymorphism in intron 1 of the H-cadherin (CDH13) gene". J. Hum. Genet. 43 (4): 285–6. doi:10.1007/s100380050093. PMID 9852687. - Resink TJ, Kuzmenko YS, Kern F, et al. (2000). "LDL binds to surface-expressed human T-cadherin in transfected HEK293 cells and influences homophilic adhesive interactions". FEBS Lett. 463 (1–2): 29–34. doi:10.1016/S0014-5793(99)01594-X. PMID 10601632. - Takeuchi T, Misaki A, Liang SB, et al. (2000). "Expression of T-cadherin (CDH13, H-Cadherin) in human brain and its characteristics as a negative growth regulator of epidermal growth factor in neuroblastoma cells". J. Neurochem. 74 (4): 1489–97. doi:10.1046/j.1471-4159.2000.0741489.x. PMID 10737605. - Niermann T, Kern F, Erne P, Resink T (2000). "The glycosyl phosphatidylinositol anchor of human T-cadherin binds lipoproteins". Biochem. Biophys. Res. Commun. 276 (3): 1240–7. doi:10.1006/bbrc.2000.3465. PMID 11027617. - Ivanov D, Philippova M, Antropova J, et al. (2001). "Expression of cell adhesion molecule T-cadherin in the human vasculature". Histochem. Cell Biol. 115 (3): 231–42. doi:10.1007/s004180100252. PMID 11326751. - Zhou S, Matsuyoshi N, Liang SB, et al. (2002). "Expression of T-cadherin in Basal keratinocytes of skin". J. Invest. Dermatol. 118 (6): 1080–4. doi:10.1046/j.1523-1747.2002.01795.x. PMID 12060406. - Toyooka S, Toyooka KO, Harada K, et al. (2002). "Aberrant methylation of the CDH13 (H-cadherin) promoter region in colorectal cancers and adenomas". Cancer Res. 62 (12): 3382–6. PMID 12067979. - Takeuchi T, Liang SB, Matsuyoshi N, et al. (2002). "Loss of T-cadherin (CDH13, H-cadherin) expression in cutaneous squamous cell carcinoma". Lab. Invest. 82 (8): 1023–9. doi:10.1097/01.lab.0000025391.35798.f1. PMID 12177241. - Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. - Takeuchi T, Liang SB, Ohtsuki Y (2003). "Downregulation of expression of a novel cadherin molecule, T-cadherin, in basal cell carcinoma of the skin". Mol. Carcinog. 35 (4): 173–9. doi:10.1002/mc.10088. PMID 12489108. - Roman-Gomez J, Castillejo JA, Jimenez A, et al. (2003). "Cadherin-13, a mediator of calcium-dependent cell–cell adhesion, is silenced by methylation in chronic myeloid leukemia and correlates with pretreatment risk profile and cytogenetic response to interferon alfa". J. Clin. Oncol. 21 (8): 1472–9. doi:10.1200/JCO.2003.08.166. PMID 12697869.	T-cadherin T-cadherin also known as cadherin 13, H-cadherin (heart) (CDH13) is a unique member of cadherin superfamily because it lacks the transmembrane and cytoplasmic domains and is anchored to the cells membrane through the GPI anchor. Classical cadherins are necessary for cell–cell contacts, dynamic regulation of morphogenetic processes in embryos and tissue integrity in adult organism. Cadherins function as membrane receptors mediating outside-in signals, activating small GTPases and beta-catenin/Wnt pathway, and resulting in dynamic cytoskeleton reorganization and changes in the phenotype. T-cadherin is a GPI-anchored member of cadherin superfamily, which lacks a direct contact with cytoskeleton and therefore is not involved in cell–cell adhesion. It is involved in low density lipoproteins (LDL) hormone-like effects on Ca2+-mobilization and increased cell migration as well as phenotype changes. Exact signaling partners and adapter proteins for T-cadherin remain to be elucidated. # Mediation of intracellular signaling in vascular cells Though T-cadherin can mediate weak adhesion in aggregation assays in vitro, the lack of intracellular domain suggests that T-cadherin is not involved in stable cell-cell adhesion. In vivo T-cadherin was detected on the apical cell surface of the chick interstinal epithelium. In cultures of transfected MDCS cells, T-cadherin was also expressed apically, whereas N-cadherin located basolaterally corresponded to the zone of cell contacts. The apical cell surface distribution of T-cadherin was proposed to possibly endow T-cadherin with recognition functions. In confluent cultures of vascular cells, T-cadherin was distributed equally over the entire cell surface, in contrast to VE-cadherin, which was restricted to the cell junctions. In migrating vascular cells, T-cadherin was located at the leading edge as revealed by confocal microscopy. The distribution of T-cadherin on the cell membrane is restricted to lipid rafts where it co-localizes with signal-transducing molecules. These data strongly implicates T-cadherin in intracellular signaling rather than adhesion. Studying signaling effects of low density lipoproteins (LDL) in vascular smooth muscles (VSMCs), T-cadherin was isolated and identified as new LDL receptor using human aortic media and the ligand-blotting method. The properties of T-cadherin as an LDL receptor were markedly different from the presently known types of LDL receptors. LDL binding to T-cadherin leads to the activation of Erk 1/2 tyrosine kinase and the nuclear translocation of NF-kappaB. T-cadherin overexpression in ECs facilitates spontaneous cell migration, formation of stress fibers and change of the phenotype from quiescent to promigratory. T-cadherin expression results in LDL-induced migration of T-cadherin expressing cells compared to control. It is likely that T-cadherin regulates cell migration and phenotype via activation of small G-proteins with subsequent actin reorganization. RhoA/ROCK activation is necessary for cell contraction, stress fiber assembly and inhibition of spreading, while Rac is required for the formation of membrane protrusions and actin-rich lamellopodia at the leading edge of migrating cells. # Functions in the vasculature The function of T-cadherin in situ, in normal conditions, and in pathology is still largely unknown. T-cadherin is highly expressed in the heart, aortic wall, neurons of the brain cortex and spinal cord and also in the small blood vessels in spleen and other organs. Expression of T-cadherin is upregulated in atherosclerotic lesions and post-angioplasty restenosis —conditions associated with pathological angiogenesis. T-cadherin expression is upregulated in ECs, pericytes and VSMC of atherosclerotic lesions. T-cadherin expression in arterial wall after balloon angioplasty correlates with late stages of neointima formation and coincidentally with the peak in proliferation and differentiation of vascular cells. It is highly expressed in adventitial vasa vasorum of injured arteries suggesting the involvement of T-cadherin in the processes of angiogenesis after vessel injury. These data implicate T-cadherin to be involved in regulation of vascular functioning and remodeling; however, the exact role of T-cadherin in neointima formation and atherosclerosis development is poorly understood. LDL is not the only ligand for T-cadherin. High-molecular weight (HMW) complexes of adiponectin were suggested to be a specific ligand for T-cadherin. Adiponectin (adipocyte complement-related protein of 30 kDa) is a cytokine produced by adipose tissue and its deficiency is associated with metabolic syndrome, obesity, type II diabetes and atherosclerosis. Adiponectin binding to T-cadherin on vascular cells is associated with NF-kappa B activation. Two membrane adiponectin receptors with distant homology to seven-transmembrane spanning G-protein-coupled receptors, namely AdipoR1 and AdipoR2 were identified in several tissues, but the University of Tokyo announced it was launching an investigation into anonymously made claims of fabricated and falsified data on the identification of AdipoR1 and AdipoR2 in 2016.[1] # Regulation of cell growth In vitro T-cadherin is implicated in regulation of cell growth, survival and proliferation. In cultured VSMC and primary astrocytes, the expression of T-cadherin depends on proliferation status with maximum at confluency suggesting its regulation of cell growth by contact inhibition. Known mitogens such as platelet-derived growth factor (PDGF)-BB, epidermal growth factor (EGF) or insulin-like growth factor (IGF) elicit a reversible dose- and time-dependent decrease in T-cadherin expression in cultured VSMCs. Expression of T-cadherin leads to complete inhibition of subcutaneous tumor growth in nude mice. Seeding T-cadherin expressing cells on plastic coated with recombinant aminoterminal fragments of T-cadherin resulted in suppression of cell growth and was found to be associated with increased expression of p21. In T-cadherin deficient C6 glioma cell lines, its overexpression results in growth suppression involving p21CIP1/WAF1 production and G2 arrest. T-cadherin loss in tumor cells is associated with tumor malignancy, invasiveness and metastasis. Thus, tumor progression in basal cell carcinoma, cutaneous squamous carcinoma, non-small cell lung carcinoma (NSCLC), ovarian cancer, pancreatic cancer, colorectal cancer correlates with downregulation of T-cadherin expression. In psoriasis vulgaris the hyperproliferation of keratinocytes also correlates with the downregulation of T-cadherin expression. The mechanism for T-cadherin suppression is associated with allelic loss or hypermethylation of the T-cadherin gene promoter region. Transfection of T-cadherin negative neuroblastoma TGW and NH-12 cells with T-cadherin results in their loss of mitogenic proliferative response to epidermal growth factor (EGF) growth stimulation. Re-expression of T-cadherin in human breast cancer cells (MDAMB435) in culture, which originally do not express T-cadherin, results in the change of the phenotype from invasive to normal epithelial-like morphology. Thus, it was hypothesized that T-cadherin functions as a tumor-suppressor factor; inactivation of T-cadherin is associated with tumor malignancy, invasiveness and metastasis. However, in other tumors T-cadherin expression could promote tumor growth and metastasis. In primary lung tumors the loss of T-cadherin was not attributed to the presence of metastasis in lymph nodes, and in osteosarcomas T-cadherin expression was correlated with metastasis. Furthermore, T-cadherin overexpression was found to be a common feature of human high grade astrocytomas and associated with malignant transformation of astrocytes. Hetezygosity for NF1 (neurofibromatosis 1) tumor suppressor resulting in reduced attachment and spreading and increased motility also coincides with upregulated T-cadherin expression. Data show that HUVEC cells overexpressing T-cadherin after adenovirus infection enter S-phase more rapidly and exhibit increased proliferation potential. T-cadherin expression increases in HUVEC under conditions of oxidative stress, and production of reactive oxygen species (ROS) contributes to T-cadherin elevated expression. T-cadherin overexpression in HUVEC leads to higher phosphorylation of Phosphatidylinositol 3-kinase (PIK3) – target of Akt, and mTOR – target p70S6K (survival pathway regulator), resulting in reduced levels of caspase activation and increased survival after exposure to oxidative stress.[clarification needed] It was suggested that in vascular cells T-cadherin performs a protective role against stress-induced apoptosis. Tumor cells can regulate gene expression in growing vessels and the surrounding stroma during tumor neovascularization. T-cadherin expression was found to be altered in tumor vessels: in Lewis carcinoma lung metastasis the expression of T-cadherin was upregulated in blood vessels penetrating the tumor, while T-cadherin was not detected in the surrounding tumor tissue. In tumor neovascularization of hepatocellular carcinoma (HCC) T-cadherin is upregulated in intratumoral capillary endothelial cells, whereas in surrounding tumor tissue as well as in normal liver no T-cadherin could be detected. The increase in T-cadherin expression in endothelial cell in HCC was shown to correlate with tumors progression. Presumably, T-cadherin could play a navigating role in the growing tumor vessels, which in the absence of contact inhibition from the stromal cells, grow into the surrounding tumor tissue. # Guiding molecules in vascular and nervous systems T-cadherin was originally cloned from chick embryo brain, where it was implicated as a negative guiding cue for motor axon projectioning through the somitic sclerotome and presumably for migrating neural crest cells . As a substrate or in soluble form, T-cadherin inhibits neurite outgrowth by motor neurons in vitro supporting the assumption that T-cadherin acts as a negative guiding molecule in the developing nervous system. Considering that the maximal expression of T-cadherin has been observed in nervous and cardiovascular systems, it is likely that T-cadherin is involved in guiding the growing vessel as well. The mechanism of T-cadherin mediated negative guidance in nervous system involves homophilic interaction and contact inhibition; in vascular system it is supposed that T-cadherin expressing blood vessels would avoid T-cadherin expressing tissues. # Bibliography - Ranscht B, Dours-Zimmermann MT (1991). "T-cadherin, a novel cadherin cell adhesion molecule in the nervous system lacks the conserved cytoplasmic region". Neuron. 7 (3): 391–402. doi:10.1016/0896-6273(91)90291-7. PMID 1654948..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} - Angst BD, Marcozzi C, Magee AI (15 February 2001). "The cadherin superfamily: diversity in form and function". J. Cell Sci. 114 (Pt 4): 629–41. PMID 11171368. - Angst BD, Marcozzi C, Magee AI (15 February 2001). "The cadherin superfamily". J. Cell Sci. 114 (Pt 4): 625–6. PMID 11171365. - Takeuchi T, Ohtsuki Y (2001). "Recent progress in T-cadherin (CDH13, H-cadherin) research". Histol. Histopathol. 16 (4): 1287–93. PMID 11642747. # Further reading - Takeuchi T, Ohtsuki Y (2002). "Recent progress in T-cadherin (CDH13, H-cadherin) research". Histol. Histopathol. 16 (4): 1287–93. PMID 11642747. - Suzuki S, Sano K, Tanihara H (1991). "Diversity of the cadherin family: evidence for eight new cadherins in nervous tissue". Cell Regul. 2 (4): 261–70. doi:10.1091/mbc.2.4.261. PMC 361775. PMID 2059658. - Tanihara H, Sano K, Heimark RL, et al. (1995). "Cloning of five human cadherins clarifies characteristic features of cadherin extracellular domain and provides further evidence for two structurally different types of cadherin". Cell Adhes. Commun. 2 (1): 15–26. doi:10.3109/15419069409014199. PMID 7982033. - Lee SW (1996). "H-cadherin, a novel cadherin with growth inhibitory functions and diminished expression in human breast cancer". Nat. Med. 2 (7): 776–82. doi:10.1038/nm0796-776. PMID 8673923. - Tkachuk VA, Bochkov VN, Philippova MP, et al. (1998). "Identification of an atypical lipoprotein-binding protein from human aortic smooth muscle as T-cadherin". FEBS Lett. 421 (3): 208–12. doi:10.1016/S0014-5793(97)01562-7. PMID 9468307. - Kremmidiotis G, Baker E, Crawford J, et al. (1998). "Localization of human cadherin genes to chromosome regions exhibiting cancer-related loss of heterozygosity". Genomics. 49 (3): 467–71. doi:10.1006/geno.1998.5281. PMID 9615235. - Philippova MP, Bochkov VN, Stambolsky DV, et al. (1998). "T-cadherin and signal-transducing molecules co-localize in caveolin-rich membrane domains of vascular smooth muscle cells". FEBS Lett. 429 (2): 207–10. doi:10.1016/S0014-5793(98)00598-5. PMID 9650591. - Sato M, Mori Y, Sakurada A, et al. (1998). "The H-cadherin (CDH13) gene is inactivated in human lung cancer". Hum. Genet. 103 (1): 96–101. doi:10.1007/s004390050790. PMID 9737784. - Sato M, Mori Y, Sakurada A, et al. (1999). "A GT dinucleotide repeat polymorphism in intron 1 of the H-cadherin (CDH13) gene". J. Hum. Genet. 43 (4): 285–6. doi:10.1007/s100380050093. PMID 9852687. - Resink TJ, Kuzmenko YS, Kern F, et al. (2000). "LDL binds to surface-expressed human T-cadherin in transfected HEK293 cells and influences homophilic adhesive interactions". FEBS Lett. 463 (1–2): 29–34. doi:10.1016/S0014-5793(99)01594-X. PMID 10601632. - Takeuchi T, Misaki A, Liang SB, et al. (2000). "Expression of T-cadherin (CDH13, H-Cadherin) in human brain and its characteristics as a negative growth regulator of epidermal growth factor in neuroblastoma cells". J. Neurochem. 74 (4): 1489–97. doi:10.1046/j.1471-4159.2000.0741489.x. PMID 10737605. - Niermann T, Kern F, Erne P, Resink T (2000). "The glycosyl phosphatidylinositol anchor of human T-cadherin binds lipoproteins". Biochem. Biophys. Res. Commun. 276 (3): 1240–7. doi:10.1006/bbrc.2000.3465. PMID 11027617. - Ivanov D, Philippova M, Antropova J, et al. (2001). "Expression of cell adhesion molecule T-cadherin in the human vasculature". Histochem. Cell Biol. 115 (3): 231–42. doi:10.1007/s004180100252. PMID 11326751. - Zhou S, Matsuyoshi N, Liang SB, et al. (2002). "Expression of T-cadherin in Basal keratinocytes of skin". J. Invest. Dermatol. 118 (6): 1080–4. doi:10.1046/j.1523-1747.2002.01795.x. PMID 12060406. - Toyooka S, Toyooka KO, Harada K, et al. (2002). "Aberrant methylation of the CDH13 (H-cadherin) promoter region in colorectal cancers and adenomas". Cancer Res. 62 (12): 3382–6. PMID 12067979. - Takeuchi T, Liang SB, Matsuyoshi N, et al. (2002). "Loss of T-cadherin (CDH13, H-cadherin) expression in cutaneous squamous cell carcinoma". Lab. Invest. 82 (8): 1023–9. doi:10.1097/01.lab.0000025391.35798.f1. PMID 12177241. - Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. - Takeuchi T, Liang SB, Ohtsuki Y (2003). "Downregulation of expression of a novel cadherin molecule, T-cadherin, in basal cell carcinoma of the skin". Mol. Carcinog. 35 (4): 173–9. doi:10.1002/mc.10088. PMID 12489108. - Roman-Gomez J, Castillejo JA, Jimenez A, et al. (2003). "Cadherin-13, a mediator of calcium-dependent cell–cell adhesion, is silenced by methylation in chronic myeloid leukemia and correlates with pretreatment risk profile and cytogenetic response to interferon alfa". J. Clin. Oncol. 21 (8): 1472–9. doi:10.1200/JCO.2003.08.166. PMID 12697869.	https://www.wikidoc.org/index.php/T-cadherin
e844c717da07d333d7deaa900b4cb3ba37fe3be3	wikidoc	TGF beta 1	TGF beta 1 Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation, and apoptosis. In humans, TGF-β1 is encoded by the TGFB1 gene. # Function TGF-β is a multifunctional set of peptides that controls proliferation, differentiation, and other functions in many cell types. TGF-β acts synergistically with TGFA in inducing transformation. It also acts as a negative autocrine growth factor. Dysregulation of TGF-β activation and signaling may result in apoptosis. Many cells synthesize TGF-β and almost all of them have specific receptors for this peptide. TGF-β1, TGF-β2, and TGF-β3 all function through the same receptor signaling systems. TGF-β1 was first identified in human platelets as a protein with a molecular mass of 25 kilodaltons with a potential role in wound healing. It was later characterized as a large protein precursor (containing 390 amino acids) that was proteolytically processed to produce a mature peptide of 112 amino acids. TGF-β1 plays an important role in controlling the immune system, and shows different activities on different types of cell, or cells at different developmental stages. Most immune cells (or leukocytes) secrete TGF-β1. ## T cells Some T cells (e.g. regulatory T cells) release TGF-β1 to inhibit the actions of other T cells. Interleukin 1- and interleukin 2-dependent proliferation of activated T cells, and the activation of quiescent helper T cells and cytotoxic T cells is prevented by the activity of TGF-β1. Similarly, TGF-β1 can inhibit the secretion and activity of many other cytokines including interferon-γ, tumor necrosis factor-alpha (TNF-α) and various interleukins. It can also decrease the expression levels of cytokine receptors, such as the IL-2 receptor to down-regulate the activity of immune cells. However, TGF-β1 can also increase the expression of certain cytokines in T cells and promote their proliferation, particularly if the cells are immature. ## B cells TGF-β1 has similar effects on B cells that also vary according to the differentiation state of the cell. It inhibits proliferation and stimulates apoptosis of B cells, and plays a role in controlling the expression of antibody, transferrin and MHC class II proteins on immature and mature B cells. ## Myeloid cells The effects of TGF-β1 on macrophages and monocytes is predominantly suppressive; this cytokine can inhibit the proliferation of these cells and prevent their production of reactive oxygen (e.g. superoxide (O2−)) and nitrogen (e.g. nitric oxide (NO)) intermediates. However, as with other cell types, TGF-β1 can also have the opposite effect on cells of myeloid origin. For example, TGF-β1 acts as a chemoattractant, directing an immune response to some pathogens; macrophages and monocytes respond to low levels of TGF-β1 in a chemotactic manner. Furthermore, the expression of monocytic cytokines (including interleukin-1(IL-1)-alpha, IL-1-beta, and TNF-α), and phagocytic killing by macrophages can be increased by the action of TGF-β1. TGF-β1 reduces the efficacy of the MHC II in astrocytes and dendritic cells, which in turn decreases the activation of appropriate helper T cell populations. # Interactions TGF beta 1 has been shown to interact with: - Decorin, - EIF3I - LTBP1, - TGF beta receptor 1, and - YWHAE.	TGF beta 1 Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation, and apoptosis. In humans, TGF-β1 is encoded by the TGFB1 gene.[1][2] # Function TGF-β is a multifunctional set of peptides that controls proliferation, differentiation, and other functions in many cell types. TGF-β acts synergistically with TGFA in inducing transformation. It also acts as a negative autocrine growth factor. Dysregulation of TGF-β activation and signaling may result in apoptosis. Many cells synthesize TGF-β and almost all of them have specific receptors for this peptide. TGF-β1, TGF-β2, and TGF-β3 all function through the same receptor signaling systems.[3] TGF-β1 was first identified in human platelets as a protein with a molecular mass of 25 kilodaltons with a potential role in wound healing.[4] It was later characterized as a large protein precursor (containing 390 amino acids) that was proteolytically processed to produce a mature peptide of 112 amino acids.[5] TGF-β1 plays an important role in controlling the immune system, and shows different activities on different types of cell, or cells at different developmental stages. Most immune cells (or leukocytes) secrete TGF-β1.[6] ## T cells Some T cells (e.g. regulatory T cells) release TGF-β1 to inhibit the actions of other T cells. Interleukin 1- and interleukin 2-dependent proliferation of activated T cells,[7][8] and the activation of quiescent helper T cells and cytotoxic T cells is prevented by the activity of TGF-β1.[9][10] Similarly, TGF-β1 can inhibit the secretion and activity of many other cytokines including interferon-γ, tumor necrosis factor-alpha (TNF-α) and various interleukins. It can also decrease the expression levels of cytokine receptors, such as the IL-2 receptor to down-regulate the activity of immune cells. However, TGF-β1 can also increase the expression of certain cytokines in T cells and promote their proliferation, particularly if the cells are immature.[6] ## B cells TGF-β1 has similar effects on B cells that also vary according to the differentiation state of the cell. It inhibits proliferation and stimulates apoptosis of B cells,[11] and plays a role in controlling the expression of antibody, transferrin and MHC class II proteins on immature and mature B cells.[6][11] ## Myeloid cells The effects of TGF-β1 on macrophages and monocytes is predominantly suppressive; this cytokine can inhibit the proliferation of these cells and prevent their production of reactive oxygen (e.g. superoxide (O2−)) and nitrogen (e.g. nitric oxide (NO)) intermediates. However, as with other cell types, TGF-β1 can also have the opposite effect on cells of myeloid origin. For example, TGF-β1 acts as a chemoattractant, directing an immune response to some pathogens; macrophages and monocytes respond to low levels of TGF-β1 in a chemotactic manner. Furthermore, the expression of monocytic cytokines (including interleukin-1(IL-1)-alpha, IL-1-beta, and TNF-α),[10] and phagocytic killing by macrophages can be increased by the action of TGF-β1.[6] TGF-β1 reduces the efficacy of the MHC II in astrocytes and dendritic cells, which in turn decreases the activation of appropriate helper T cell populations.[12][13] # Interactions TGF beta 1 has been shown to interact with: - Decorin,[14][15][16] - EIF3I[17] - LTBP1,[18] - TGF beta receptor 1,[19][20] and - YWHAE.[21]	https://www.wikidoc.org/index.php/TGF_beta_1
1c5a152402c29016c807e0f3736b38517004a334	wikidoc	TGF beta 2	TGF beta 2 Transforming growth factor-beta 2 (TGF-β2) is a secreted protein known as a cytokine that performs many cellular functions and has a vital role during embryonic development (alternative names: Glioblastoma-derived T-cell suppressor factor, G-TSF, BSC-1 cell growth inhibitor, Polyergin, Cetermin). It is an extracellular glycosylated protein. It is known to suppress the effects of interleukin dependent T-cell tumors. There are two named isoforms of this protein, created by alternative splicing of the same gene. # Further reading - Clark DA, Coker R (1998). "Transforming growth factor-beta (TGF-beta)". Int. J. Biochem. Cell Biol. 30 (3): 293–8. doi:10.1016/S1357-2725(97)00128-3. PMID 9611771..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} - Wick W, Platten M, Weller M (2002). "Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta". J. Neurooncol. 53 (2): 177–85. doi:10.1023/A:1012209518843. PMID 11716069. - Bissell DM (2002). "Chronic liver injury, TGF-beta, and cancer". Experimental & Molecular Medicine. 33 (4): 179–90. doi:10.1038/emm.2001.31. PMID 11795478. - Kalluri R, Neilson EG (2004). "Epithelial-mesenchymal transition and its implications for fibrosis". J. Clin. Invest. 112 (12): 1776–84. doi:10.1172/JCI20530. PMC 297008. PMID 14679171. - Daopin S, Piez KA, Ogawa Y, Davies DR (1992). "Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily". Science. 257 (5068): 369–73. doi:10.1126/science.1631557. PMID 1631557. - Schlunegger MP, Grütter MG (1992). "An unusual feature revealed by the crystal structure at 2.2 A resolution of human transforming growth factor-beta 2". Nature. 358 (6385): 430–4. doi:10.1038/358430a0. PMID 1641027. - Noma T, Glick AB, Geiser AG, et al. (1992). "Molecular cloning and structure of the human transforming growth factor-beta 2 gene promoter". Growth Factors. 4 (4): 247–55. doi:10.3109/08977199109043910. PMID 1764261. - Bodmer S, Podlisny MB, Selkoe DJ, et al. (1990). "Transforming growth factor-beta bound to soluble derivatives of the beta amyloid precursor protein of Alzheimer's disease". Biochem. Biophys. Res. Commun. 171 (2): 890–7. doi:10.1016/0006-291X(90)91229-L. PMID 2119582. - Webb NR, Madisen L, Rose TM, Purchio AF (1989). "Structural and sequence analysis of TGF-beta 2 cDNA clones predicts two different precursor proteins produced by alternative mRNA splicing". DNA. 7 (7): 493–7. doi:10.1089/dna.1.1988.7.493. PMID 2850146. - Madisen L, Webb NR, Rose TM, et al. (1988). "Transforming growth factor-beta 2: cDNA cloning and sequence analysis". DNA. 7 (1): 1–8. doi:10.1089/dna.1988.7.1. PMID 3162414. - Barton DE, Foellmer BE, Du J, et al. (1989). "Chromosomal mapping of genes for transforming growth factors beta 2 and beta 3 in man and mouse: dispersion of TGF-beta gene family". Oncogene Res. 3 (4): 323–31. PMID 3226728. - de Martin R, Haendler B, Hofer-Warbinek R, et al. (1988). "Complementary DNA for human glioblastoma-derived T cell suppressor factor, a novel member of the transforming growth factor-beta gene family". EMBO J. 6 (12): 3673–7. PMC 553836. PMID 3322813. - Marquardt H, Lioubin MN, Ikeda T (1987). "Complete amino acid sequence of human transforming growth factor type beta 2". J. Biol. Chem. 262 (25): 12127–31. PMID 3476488. - Philip A, Bostedt L, Stigbrand T, O'Connor-McCourt MD (1994). "Binding of transforming growth factor-beta (TGF-beta) to pregnancy zone protein (PZP). Comparison to the TGF-beta-alpha 2-macroglobulin interaction". Eur. J. Biochem. 221 (2): 687–93. doi:10.1111/j.1432-1033.1994.tb18781.x. PMID 7513640. - Lin HY, Moustakas A, Knaus P, et al. (1995). "The soluble exoplasmic domain of the type II transforming growth factor (TGF)-beta receptor. A heterogeneously glycosylated protein with high affinity and selectivity for TGF-beta ligands". J. Biol. Chem. 270 (6): 2747–54. doi:10.1074/jbc.270.6.2747. PMID 7852346. - Hildebrand A, Romarís M, Rasmussen LM, et al. (1994). "Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta". Biochem. J. 302. ( Pt 2): 527–34. doi:10.1042/bj3020527. PMC 1137259. PMID 8093006. - López-Casillas F, Payne HM, Andres JL, Massagué J (1994). "Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites". J. Cell Biol. 124 (4): 557–68. doi:10.1083/jcb.124.4.557. PMC 2119924. PMID 8106553. - Fromigué O, Marie PJ, Lomri A (1998). "Bone morphogenetic protein-2 and transforming growth factor-beta2 interact to modulate human bone marrow stromal cell proliferation and differentiation". J. Cell. Biochem. 68 (4): 411–26. doi:10.1002/(SICI)1097-4644(19980315)68:43.0.CO;2-T. PMID 9493905. - Mori T, Kawara S, Shinozaki M, et al. (1999). "Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model". J. Cell. Physiol. 181 (1): 153–9. doi:10.1002/(SICI)1097-4652(199910)181:13.0.CO;2-K. PMID 10457363.	TGF beta 2 Transforming growth factor-beta 2 (TGF-β2) is a secreted protein known as a cytokine that performs many cellular functions and has a vital role during embryonic development (alternative names: Glioblastoma-derived T-cell suppressor factor, G-TSF, BSC-1 cell growth inhibitor, Polyergin, Cetermin). It is an extracellular glycosylated protein. It is known to suppress the effects of interleukin dependent T-cell tumors. There are two named isoforms of this protein, created by alternative splicing of the same gene. # Further reading - Clark DA, Coker R (1998). "Transforming growth factor-beta (TGF-beta)". Int. J. Biochem. Cell Biol. 30 (3): 293–8. doi:10.1016/S1357-2725(97)00128-3. PMID 9611771..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} - Wick W, Platten M, Weller M (2002). "Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta". J. Neurooncol. 53 (2): 177–85. doi:10.1023/A:1012209518843. PMID 11716069. - Bissell DM (2002). "Chronic liver injury, TGF-beta, and cancer". Experimental & Molecular Medicine. 33 (4): 179–90. doi:10.1038/emm.2001.31. PMID 11795478. - Kalluri R, Neilson EG (2004). "Epithelial-mesenchymal transition and its implications for fibrosis". J. Clin. Invest. 112 (12): 1776–84. doi:10.1172/JCI20530. PMC 297008. PMID 14679171. - Daopin S, Piez KA, Ogawa Y, Davies DR (1992). "Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily". Science. 257 (5068): 369–73. doi:10.1126/science.1631557. PMID 1631557. - Schlunegger MP, Grütter MG (1992). "An unusual feature revealed by the crystal structure at 2.2 A resolution of human transforming growth factor-beta 2". Nature. 358 (6385): 430–4. doi:10.1038/358430a0. PMID 1641027. - Noma T, Glick AB, Geiser AG, et al. (1992). "Molecular cloning and structure of the human transforming growth factor-beta 2 gene promoter". Growth Factors. 4 (4): 247–55. doi:10.3109/08977199109043910. PMID 1764261. - Bodmer S, Podlisny MB, Selkoe DJ, et al. (1990). "Transforming growth factor-beta bound to soluble derivatives of the beta amyloid precursor protein of Alzheimer's disease". Biochem. Biophys. Res. Commun. 171 (2): 890–7. doi:10.1016/0006-291X(90)91229-L. PMID 2119582. - Webb NR, Madisen L, Rose TM, Purchio AF (1989). "Structural and sequence analysis of TGF-beta 2 cDNA clones predicts two different precursor proteins produced by alternative mRNA splicing". DNA. 7 (7): 493–7. doi:10.1089/dna.1.1988.7.493. PMID 2850146. - Madisen L, Webb NR, Rose TM, et al. (1988). "Transforming growth factor-beta 2: cDNA cloning and sequence analysis". DNA. 7 (1): 1–8. doi:10.1089/dna.1988.7.1. PMID 3162414. - Barton DE, Foellmer BE, Du J, et al. (1989). "Chromosomal mapping of genes for transforming growth factors beta 2 and beta 3 in man and mouse: dispersion of TGF-beta gene family". Oncogene Res. 3 (4): 323–31. PMID 3226728. - de Martin R, Haendler B, Hofer-Warbinek R, et al. (1988). "Complementary DNA for human glioblastoma-derived T cell suppressor factor, a novel member of the transforming growth factor-beta gene family". EMBO J. 6 (12): 3673–7. PMC 553836. PMID 3322813. - Marquardt H, Lioubin MN, Ikeda T (1987). "Complete amino acid sequence of human transforming growth factor type beta 2". J. Biol. Chem. 262 (25): 12127–31. PMID 3476488. - Philip A, Bostedt L, Stigbrand T, O'Connor-McCourt MD (1994). "Binding of transforming growth factor-beta (TGF-beta) to pregnancy zone protein (PZP). Comparison to the TGF-beta-alpha 2-macroglobulin interaction". Eur. J. Biochem. 221 (2): 687–93. doi:10.1111/j.1432-1033.1994.tb18781.x. PMID 7513640. - Lin HY, Moustakas A, Knaus P, et al. (1995). "The soluble exoplasmic domain of the type II transforming growth factor (TGF)-beta receptor. A heterogeneously glycosylated protein with high affinity and selectivity for TGF-beta ligands". J. Biol. Chem. 270 (6): 2747–54. doi:10.1074/jbc.270.6.2747. PMID 7852346. - Hildebrand A, Romarís M, Rasmussen LM, et al. (1994). "Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta". Biochem. J. 302. ( Pt 2): 527–34. doi:10.1042/bj3020527. PMC 1137259. PMID 8093006. - López-Casillas F, Payne HM, Andres JL, Massagué J (1994). "Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites". J. Cell Biol. 124 (4): 557–68. doi:10.1083/jcb.124.4.557. PMC 2119924. PMID 8106553. - Fromigué O, Marie PJ, Lomri A (1998). "Bone morphogenetic protein-2 and transforming growth factor-beta2 interact to modulate human bone marrow stromal cell proliferation and differentiation". J. Cell. Biochem. 68 (4): 411–26. doi:10.1002/(SICI)1097-4644(19980315)68:4<411::AID-JCB2>3.0.CO;2-T. PMID 9493905. - Mori T, Kawara S, Shinozaki M, et al. (1999). "Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model". J. Cell. Physiol. 181 (1): 153–9. doi:10.1002/(SICI)1097-4652(199910)181:1<153::AID-JCP16>3.0.CO;2-K. PMID 10457363.	https://www.wikidoc.org/index.php/TGF_beta_2
7f05e5381e8e3c4b356b80b8d4c9dc3780e72cdd	wikidoc	Tenascin X	Tenascin X A member of the tenascin family, tenascin X (TN-X) also known as hexabrachion-like protein is a glycoprotein that is expressed in connective tissues including skin, joints and muscles. In humans, tenascin X is encoded by the TNXB gene. # Gene This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. # Function This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing. # Clinical significance Deficiency causes one of the types of Ehlers–Danlos syndrome where collagen density is reduced and elastic fibers are fragmentated.	Tenascin X A member of the tenascin family, tenascin X (TN-X) also known as hexabrachion-like protein is a glycoprotein that is expressed in connective tissues including skin, joints and muscles. In humans, tenascin X is encoded by the TNXB gene.[1] # Gene This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively.[2] # Function This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing.[2] # Clinical significance Deficiency causes one of the types of Ehlers–Danlos syndrome where collagen density is reduced and elastic fibers are fragmentated.[3]	https://www.wikidoc.org/index.php/TNXB
3065346965f28996ff217aafefefce57a5d5f21d	wikidoc	TRIM5alpha	TRIM5alpha Tripartite motif-containing protein 5 also known as RING finger protein 88 is a protein that in humans is encoded by the TRIM5 gene. The alpha isoform of this protein, TRIM5α, is a retrovirus restriction factor, which mediates species-specific, early block to retrovirus infection. TRIM5α is composed of 493 amino acids that is found in the cells of most primates. TRIM5α is an intrinsic immune factor important in the innate immune defense against retroviruses, along with the APOBEC family of proteins, tetherin and TRIM22. # Structure TRIM5α belongs to the TRIM protein family (TRIM stands for TRIpartite Motif); this family was first identified by Reddy in 1992 as the proteins that contain a RING finger zinc binding domain, a B-box zinc binding domain, followed by a coiled-coil region. TRIM5α bears the C-terminal PRY-SPRY or B30.2 domain in addition to the other domains. # Function When a retrovirus enters a host cell's cytoplasm, it undergoes processes such as capsid uncoating and reverse transcription. TRIM5 present in the cytoplasm recognizes motifs within the capsid proteins and interferes with the uncoating process, therefore preventing successful reverse transcription and transport to the nucleus of the viral genome. The exact mechanism of action has not been shown conclusively, but capsid protein from restricted viruses is removed by proteasome-dependent degradation. The involvement of other cellular proteins in the inhibition mediated by TRIM5α is suspected but as yet not demonstrated. However, Cyclophilin A is important for the inhibition of HIV-1 by TRIM5α in Old World monkey species. The "specificity" of restriction, that is, whether a given retrovirus can be targeted by TRIM5α, is entirely determined by the amino acid sequence of the C-terminal domain of the protein, called the B30.2/PRY-SPRY domain. Amino acid 332, which occurs within this domain, seems to play a critical role in determining the specificity of retrovirus restriction. TRIM5α may have played a critical role in the human immune defense system about 4 million years ago, when the retrovirus PtERV1 was infecting the ancestors of modern chimpanzees. While no trace of PtERV1 has yet been found in the human genome, about 130 traces of PtERV1 DNA have been found in the genome of modern chimpanzees. After recreating part of the PtERV1 retrovirus, it was reported that TRIM5α prevents the virus from entering human cells in vitro. While this cellular defense mechanism may have been very useful 4 million years ago when facing a PtERV1 epidemic, it has the side effect of leaving cells more susceptible to attack by the HIV-1 retrovirus. Recently, doubt has been cast over these conclusions. By using a PtERV1 capsid, which produces higher titer virus-like particles, Perez-Caballero et al. reported that PtERV1 is not restricted by either human or chimpanzee TRIM5α. # Clinical significance Old World monkeys cannot be infected with HIV-1, the virus that causes AIDS in humans; they can be infected, however, with SIV, a related virus. TRIM5α was isolated as a rhesus macaque protein responsible for blocking infection by HIV-1. The human version of TRIM5α does not target HIV-1, but can inhibit strains of the murine leukemia virus (MLV) as well as equine infectious anemia virus (EIAV). Prior to the discovery of TRIM5α as an antiviral protein, the inhibition phenotype had been described and coined Ref1 (in human cells) and Lv1 (in monkey cells). This terminology is now largely abandoned. A related protein, named TRIMCyp (or TRIM5-CypA), was isolated in the owl monkey, a species of New World monkey, and shown to potently inhibit infection by HIV-1. A similar protein has arisen independently in Old World monkeys and has been identified in several species of macaque. # Notes and references - ↑ Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A (May 2001). "The tripartite motif family identifies cell compartments". EMBO J. 20 (9): 2140–51. doi:10.1093/emboj/20.9.2140. PMC 125245. PMID 11331580..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} - ↑ Cullen BR (2006). "Role and mechanism of action of the APOBEC3 family of antiretroviral resistance factors". J. Virol. 80 (3): 1067–76. doi:10.1128/JVI.80.3.1067-1076.2006. PMC 1346961. PMID 16414984. - ↑ Zhang KL, Mangeat B, Ortiz M, Zoete V, Trono D, Telenti A, Michielin O (2007). Aballay A, ed. "Model structure of human APOBEC3G". PLoS ONE. 2 (4): e378. doi:10.1371/journal.pone.0000378. PMC 1849894. PMID 17440614. open access publication – free to read - ↑ Reddy BA, Etkin LD, Freemont PS (1992). "A novel zinc finger coiled-coil domain in a family of nuclear proteins". Trends Biochem. Sci. 17 (9): 344–5. doi:10.1016/0968-0004(92)90308-V. PMID 1412709. - ↑ Sebastian S, Luban J (2005). "TRIM5alpha selectively binds a restriction-sensitive retroviral capsid". Retrovirology. 2: 40. doi:10.1186/1742-4690-2-40. PMC 1166576. PMID 15967037. - ↑ Stremlau M, Perron M, Lee M, Li Y, Song B, Javanbakht H, Diaz-Griffero F, Anderson DJ, Sundquist WI, Sodroski J (2006). "Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor". Proc. Natl. Acad. Sci. U.S.A. 103 (14): 5514–9. doi:10.1073/pnas.0509996103. PMC 1459386. PMID 16540544. - ↑ Wu X, Anderson JL, Campbell EM, Joseph AM, Hope TJ (2006). "Proteasome inhibitors uncouple rhesus TRIM5alpha restriction of HIV-1 reverse transcription and infection". Proc. Natl. Acad. Sci. U.S.A. 103 (19): 7465–70. doi:10.1073/pnas.0510483103. PMC 1464362. PMID 16648264. - ↑ Berthoux L, Sebastian S, Sokolskaja E, Luban J (2005). "Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in Old World monkey cells". Proc. Natl. Acad. Sci. U.S.A. 102 (41): 14849–53. doi:10.1073/pnas.0505659102. PMC 1239943. PMID 16203999. - ↑ Ohkura S, Yap MW, Sheldon T, Stoye JP (2006). "All three variable regions of the TRIM5alpha B30.2 domain can contribute to the specificity of retrovirus restriction". J. Virol. 80 (17): 8554–65. doi:10.1128/JVI.00688-06. PMC 1563890. PMID 16912305. - ↑ Yap MW, Nisole S, Stoye JP (2005). "A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction". Curr. Biol. 15 (1): 73–8. doi:10.1016/j.cub.2004.12.042. PMID 15649369. - ↑ Jump up to: 11.0 11.1 Kaiser SM, Malik HS, Emerman M (2007). "Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein". Science. 316 (5832): 1756–8. doi:10.1126/science.1140579. PMID 17588933. - ↑ Perez-Caballero D, Soll SJ, Bieniasz PD (2008). Hope TJ, ed. "Evidence for restriction of ancient primate gammaretroviruses by APOBEC3 but not TRIM5alpha proteins". PLoS Pathog. 4 (10): e1000181. doi:10.1371/journal.ppat.1000181. PMC 2564838. PMID 18927623. open access publication – free to read - ↑ Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski J (2004). "The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys". Nature. 427 (6977): 848–53. doi:10.1038/nature02343. PMID 14985764. - ↑ Lee K, KewalRamani VN (2004). "In defense of the cell: TRIM5α interception of mammalian retroviruses". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10496–7. doi:10.1073/pnas.0404066101. PMC 489964. PMID 15252204. - ↑ Yap MW, Nisole S, Lynch C, Stoye JP (2004). "Trim5α protein restricts both HIV-1 and murine leukemia virus". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10786–91. doi:10.1073/pnas.0402876101. PMC 490012. PMID 15249690. - ↑ Hatziioannou T, Perez-Caballero D, Yang A, Cowan S, Bieniasz PD (2004). "Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5α". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10774–9. doi:10.1073/pnas.0402361101. PMC 490010. PMID 15249685. - ↑ Keckesova Z, Ylinen LM, Towers GJ (2004). "The human and African green monkey TRIM5αgenes encode Ref1 and Lv1 retroviral restriction factor activities". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10780–5. doi:10.1073/pnas.0402474101. PMC 490011. PMID 15249687. - ↑ Sayah DM, Sokolskaja E, Berthoux L, Luban J (2004). "Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1". Nature. 430 (6999): 569–73. doi:10.1038/nature02777. PMID 15243629. - ↑ Wilson SJ, Webb BL, Ylinen LM, Verschoor E, Heeney JL, Towers GJ (2008). "Independent evolution of an antiviral TRIMCyp in rhesus macaques". PNAS. 105 (9): 3557–62. doi:10.1073/pnas.0709003105. PMC 2265179. PMID 18287035. - ↑ Brennan G, Kozyrev Y, Hu SL (2008). "TRIMCyp expression in Old World primates Macaca nemestrina and Macaca fascicularis". PNAS. 105 (9): 3569–74. doi:10.1073/pnas.0709511105. PMC 2265124. PMID 18287033.	TRIM5alpha Tripartite motif-containing protein 5 also known as RING finger protein 88 is a protein that in humans is encoded by the TRIM5 gene.[1] The alpha isoform of this protein, TRIM5α, is a retrovirus restriction factor, which mediates species-specific, early block to retrovirus infection. TRIM5α is composed of 493 amino acids that is found in the cells of most primates. TRIM5α is an intrinsic immune factor important in the innate immune defense against retroviruses, along with the APOBEC family of proteins,[2][3] tetherin and TRIM22. # Structure TRIM5α belongs to the TRIM protein family (TRIM stands for TRIpartite Motif); this family was first identified by Reddy in 1992 as the proteins that contain a RING finger zinc binding domain, a B-box zinc binding domain, followed by a coiled-coil region.[4] TRIM5α bears the C-terminal PRY-SPRY or B30.2 domain in addition to the other domains. # Function When a retrovirus enters a host cell's cytoplasm, it undergoes processes such as capsid uncoating and reverse transcription. TRIM5 present in the cytoplasm recognizes motifs within the capsid proteins and interferes with the uncoating process, therefore preventing successful reverse transcription and transport to the nucleus of the viral genome.[5][6] The exact mechanism of action has not been shown conclusively, but capsid protein from restricted viruses is removed by proteasome-dependent degradation.[7] The involvement of other cellular proteins in the inhibition mediated by TRIM5α is suspected but as yet not demonstrated. However, Cyclophilin A is important for the inhibition of HIV-1 by TRIM5α in Old World monkey species.[8] The "specificity" of restriction, that is, whether a given retrovirus can be targeted by TRIM5α, is entirely determined by the amino acid sequence of the C-terminal domain of the protein, called the B30.2/PRY-SPRY domain.[9] Amino acid 332, which occurs within this domain, seems to play a critical role in determining the specificity of retrovirus restriction.[10][11] TRIM5α may have played a critical role in the human immune defense system about 4 million years ago, when the retrovirus PtERV1 was infecting the ancestors of modern chimpanzees.[11] While no trace of PtERV1 has yet been found in the human genome, about 130 traces of PtERV1 DNA have been found in the genome of modern chimpanzees. After recreating part of the PtERV1 retrovirus, it was reported that TRIM5α prevents the virus from entering human cells in vitro. While this cellular defense mechanism may have been very useful 4 million years ago when facing a PtERV1 epidemic, it has the side effect of leaving cells more susceptible to attack by the HIV-1 retrovirus. Recently, doubt has been cast over these conclusions. By using a PtERV1 capsid, which produces higher titer virus-like particles, Perez-Caballero et al. reported that PtERV1 is not restricted by either human or chimpanzee TRIM5α.[12] # Clinical significance Old World monkeys cannot be infected with HIV-1, the virus that causes AIDS in humans; they can be infected, however, with SIV, a related virus. TRIM5α was isolated as a rhesus macaque protein responsible for blocking infection by HIV-1.[13] The human version of TRIM5α does not target HIV-1, but can inhibit strains of the murine leukemia virus (MLV)[14][15] as well as equine infectious anemia virus (EIAV).[16][17] Prior to the discovery of TRIM5α as an antiviral protein, the inhibition phenotype had been described and coined Ref1 (in human cells) and Lv1 (in monkey cells). This terminology is now largely abandoned. A related protein, named TRIMCyp (or TRIM5-CypA), was isolated in the owl monkey, a species of New World monkey, and shown to potently inhibit infection by HIV-1.[18] A similar protein has arisen independently in Old World monkeys and has been identified in several species of macaque.[19][20] # Notes and references - ↑ Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A (May 2001). "The tripartite motif family identifies cell compartments". EMBO J. 20 (9): 2140–51. doi:10.1093/emboj/20.9.2140. PMC 125245. PMID 11331580..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} - ↑ Cullen BR (2006). "Role and mechanism of action of the APOBEC3 family of antiretroviral resistance factors". J. Virol. 80 (3): 1067–76. doi:10.1128/JVI.80.3.1067-1076.2006. PMC 1346961. PMID 16414984. - ↑ Zhang KL, Mangeat B, Ortiz M, Zoete V, Trono D, Telenti A, Michielin O (2007). Aballay A, ed. "Model structure of human APOBEC3G". PLoS ONE. 2 (4): e378. doi:10.1371/journal.pone.0000378. PMC 1849894. PMID 17440614. open access publication – free to read - ↑ Reddy BA, Etkin LD, Freemont PS (1992). "A novel zinc finger coiled-coil domain in a family of nuclear proteins". Trends Biochem. Sci. 17 (9): 344–5. doi:10.1016/0968-0004(92)90308-V. PMID 1412709. - ↑ Sebastian S, Luban J (2005). "TRIM5alpha selectively binds a restriction-sensitive retroviral capsid". Retrovirology. 2: 40. doi:10.1186/1742-4690-2-40. PMC 1166576. PMID 15967037. - ↑ Stremlau M, Perron M, Lee M, Li Y, Song B, Javanbakht H, Diaz-Griffero F, Anderson DJ, Sundquist WI, Sodroski J (2006). "Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor". Proc. Natl. Acad. Sci. U.S.A. 103 (14): 5514–9. doi:10.1073/pnas.0509996103. PMC 1459386. PMID 16540544. - ↑ Wu X, Anderson JL, Campbell EM, Joseph AM, Hope TJ (2006). "Proteasome inhibitors uncouple rhesus TRIM5alpha restriction of HIV-1 reverse transcription and infection". Proc. Natl. Acad. Sci. U.S.A. 103 (19): 7465–70. doi:10.1073/pnas.0510483103. PMC 1464362. PMID 16648264. - ↑ Berthoux L, Sebastian S, Sokolskaja E, Luban J (2005). "Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in Old World monkey cells". Proc. Natl. Acad. Sci. U.S.A. 102 (41): 14849–53. doi:10.1073/pnas.0505659102. PMC 1239943. PMID 16203999. - ↑ Ohkura S, Yap MW, Sheldon T, Stoye JP (2006). "All three variable regions of the TRIM5alpha B30.2 domain can contribute to the specificity of retrovirus restriction". J. Virol. 80 (17): 8554–65. doi:10.1128/JVI.00688-06. PMC 1563890. PMID 16912305. - ↑ Yap MW, Nisole S, Stoye JP (2005). "A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction". Curr. Biol. 15 (1): 73–8. doi:10.1016/j.cub.2004.12.042. PMID 15649369. - ↑ Jump up to: 11.0 11.1 Kaiser SM, Malik HS, Emerman M (2007). "Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein". Science. 316 (5832): 1756–8. doi:10.1126/science.1140579. PMID 17588933. - ↑ Perez-Caballero D, Soll SJ, Bieniasz PD (2008). Hope TJ, ed. "Evidence for restriction of ancient primate gammaretroviruses by APOBEC3 but not TRIM5alpha proteins". PLoS Pathog. 4 (10): e1000181. doi:10.1371/journal.ppat.1000181. PMC 2564838. PMID 18927623. open access publication – free to read - ↑ Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski J (2004). "The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys". Nature. 427 (6977): 848–53. doi:10.1038/nature02343. PMID 14985764. - ↑ Lee K, KewalRamani VN (2004). "In defense of the cell: TRIM5α interception of mammalian retroviruses". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10496–7. doi:10.1073/pnas.0404066101. PMC 489964. PMID 15252204. - ↑ Yap MW, Nisole S, Lynch C, Stoye JP (2004). "Trim5α protein restricts both HIV-1 and murine leukemia virus". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10786–91. doi:10.1073/pnas.0402876101. PMC 490012. PMID 15249690. - ↑ Hatziioannou T, Perez-Caballero D, Yang A, Cowan S, Bieniasz PD (2004). "Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5α". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10774–9. doi:10.1073/pnas.0402361101. PMC 490010. PMID 15249685. - ↑ Keckesova Z, Ylinen LM, Towers GJ (2004). "The human and African green monkey TRIM5αgenes encode Ref1 and Lv1 retroviral restriction factor activities". Proc. Natl. Acad. Sci. U.S.A. 101 (29): 10780–5. doi:10.1073/pnas.0402474101. PMC 490011. PMID 15249687. - ↑ Sayah DM, Sokolskaja E, Berthoux L, Luban J (2004). "Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1". Nature. 430 (6999): 569–73. doi:10.1038/nature02777. PMID 15243629. - ↑ Wilson SJ, Webb BL, Ylinen LM, Verschoor E, Heeney JL, Towers GJ (2008). "Independent evolution of an antiviral TRIMCyp in rhesus macaques". PNAS. 105 (9): 3557–62. doi:10.1073/pnas.0709003105. PMC 2265179. PMID 18287035. - ↑ Brennan G, Kozyrev Y, Hu SL (2008). "TRIMCyp expression in Old World primates Macaca nemestrina and Macaca fascicularis". PNAS. 105 (9): 3569–74. doi:10.1073/pnas.0709511105. PMC 2265124. PMID 18287033. # External links - "UniProtKB/Swiss-Prot entry Q587N7 (TRIM5_CERAE) Tripartite motif-containing protein 5". Swiss Institute of Bioinformatics. Retrieved 2008-02-19. - "NCBI Sequence Viewer v2.0". National Center for Biotechnology Information. Retrieved 2008-02-19. - Minkel JR (2007-06-21). "Defense against Ancient Virus Opened Door to HIV". Scientific American. Retrieved 2008-02-19. - Hopkin M (2007-06-26). "Access : Ancient disease resistance made us vulnerable to HIV". Nature News. Retrieved 2008-02-19.	https://www.wikidoc.org/index.php/TRIM5alpha
0e596adafda3d403fcf6bf1ccdf477a9441e75b0	wikidoc	Tablespoon	Tablespoon Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. A tablespoon is a type of spoon used for serving. # Measure of volume It is also a measure of volume used in cooking. It has various values around the world. It is abbreviated in English as T., tbs. or Tbsp., and in German and Dutch as EL (from Esslöffel and Eetlepel). Canada, Japan, New Zealand, the UK and the United States define: in line with the definition used in many other countries. In Australia, one tablespoon = 20 mL. When used for solids (such as granulated sugar), it should be measured to the flattened level of the spoon (versus a 'heaping spoonful or heaped tablespoon, which is as much as can be held in the spoon). ## Relationship to teaspoon In most jurisdictions, one tablespoon equals three teaspoons. In Australia, however, one tablespoon is four teaspoons. In Asia a tablespoon is equivalent to 2 teaspoons ## Older definitions The traditional U.S. interpretation of the tablespoon as a unit of volume was: This was considered slightly inconvenient in the context of nutrition labeling, where metric units are used even in the United States. However, this consideration does not lessen the factual relationship of a tablespoon to half of a fluid ounce, and tablespoons can be utilized to measure ingredients when other measuring devices are unavailable. For instance, 8 tablespoons is equivalent to ½ a cup. The traditional British tablespoon could vary from 1/2 to 5/8 Imperial fl. oz. (14.2 mL to 17.8 mL).	Tablespoon Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. A tablespoon is a type of spoon used for serving. # Measure of volume It is also a measure of volume used in cooking. It has various values around the world. It is abbreviated in English as T., tbs. or Tbsp., and in German and Dutch as EL (from Esslöffel and Eetlepel). Canada, Japan, New Zealand, the UK and the United States[1] define: in line with the definition used in many other countries. In Australia, one tablespoon = 20 mL. When used for solids (such as granulated sugar), it should be measured to the flattened level of the spoon (versus a 'heaping spoonful or heaped tablespoon, which is as much as can be held in the spoon). ## Relationship to teaspoon In most jurisdictions, one tablespoon equals three teaspoons. In Australia, however, one tablespoon is four teaspoons. In Asia a tablespoon is equivalent to 2 teaspoons ## Older definitions The traditional U.S. interpretation of the tablespoon as a unit of volume was:[2] This was considered slightly inconvenient in the context of nutrition labeling, where metric units are used even in the United States. However, this consideration does not lessen the factual relationship of a tablespoon to half of a fluid ounce, and tablespoons can be utilized to measure ingredients when other measuring devices are unavailable. For instance, 8 tablespoons is equivalent to ½ a cup. The traditional British tablespoon could vary from 1/2 to 5/8 Imperial fl. oz. (14.2 mL to 17.8 mL).	https://www.wikidoc.org/index.php/Tablespoon
5c683a57e571ce169d6bb7ae90c1a7ec6b02130a	wikidoc	Tafluprost	Tafluprost - Content - The recommended dose is one drop of ZIOPTAN in the conjunctival sac of the affected eye(s) once daily in the evening. - The dose should not exceed once daily since it has been shown that more frequent administration of prostaglandin analogs may lessen the intraocular pressure lowering effect. - Reduction of the intraocular pressure starts approximately 2 to 4 hours after the first administration with the maximum effect reached after 12 hours. - ZIOPTAN may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic product is being used, each one should be administered at least 5 minutes apart. - The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded immediately after administration. - Pigmentation - Tafluprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as tafluprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of tafluprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known. - Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with ZIOPTAN can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. - Eyelash Changes - ZIOPTAN may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, color, thickness, shape and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment. - Intraocular Inflammation - ZIOPTAN should be used with caution in patients with active intraocular inflammation (e.g., iritis/uveitis) because the inflammation may be exacerbated. - Macular Edema - Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin F2α analogs. ZIOPTAN should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. - Preservative-containing or preservative-free tafluprost 0.0015% was evaluated in 905 patients in five controlled clinical studies of up to 24-months duration. The most common adverse reaction observed in patients treated with tafluprost was conjunctival hyperemia which was reported in a range of 4% — 20% of patients. Approximately 1% of patients discontinued therapy due to ocular adverse reactions. - Ocular adverse reactions reported at an incidence of ≥2% in these clinical studies included ocular stinging/irritation (7%), ocular pruritus including allergic conjunctivitis (5%), cataract (3%), dry eye (3%), ocular pain (3%), eyelash darkening (2%), growth of eyelashes (2%) and vision blurred (2%). - Nonocular adverse reactions reported at an incidence of 2% — 6% in these clinical studies in patients treated with tafluprost 0.0015% were headache (6%), common cold (4%), cough (3%) and urinary tract infection (2%). Exacerbation of asthma, dyspnea Iritis/uveitis - In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid sulcus have been observed. - Teratogenic effects: In embryo-fetal development studies in rats and rabbits, tafluprost administered intravenously was teratogenic. Tafluprost caused increases in post-implantation losses in rats and rabbits and reductions in fetal body weights in rats. Tafluprost also increased the incidence of vertebral skeletal abnormalities in rats and the incidence of skull, brain and spine malformations in rabbits. In rats, there were no adverse effects on embryo-fetal development at a dose of 3 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid that were 343 times the maximum clinical exposure based on Cmax. In rabbits, effects were seen at a tafluprost dose of 0.03 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid during organogenesis that were approximately 5 times higher than the clinical exposure based on Cmax. At the no-effect dose in rabbits (0.01 mcg/kg/day), maternal plasma levels of tafluprost acid were below the lower level of quantification (20 pg/mL). - In a pre- and postnatal development study in rats, increased mortality of newborns, decreased body weights and delayed pinna unfolding were observed in offsprings. The no observed adverse effect level was at a tafluprost intravenous dose of 0.3 mcg/kg/day which is greater than 3 times the maximum recommended clinical dose based on body surface area comparison. - There are no adequate and well-controlled studies in pregnant woman. Although animal reproduction studies are not always predictive of human response, ZIOPTAN should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. - Women of childbearing age/potential should have adequate contraceptive measures in place. There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tafluprost in women who are pregnant. There is limited information regarding Chronic Overdose of Tafluprost in the drug label. Its structural formula is: - Tafluprost is a colorless to light yellow viscous liquid that is practically insoluble in water. - ZIOPTAN (tafluprost ophthalmic solution) 0.0015% is supplied as a sterile solution of tafluprost with a pH range of 5.5 — 6.7 and an Osmolality range of 260 — 300 mOsmol/kg. - ZIOPTAN contains Active: tafluprost 0.015 mg/mL; Inactives: glycerol, sodium dihydrogen phosphate dihydrate, disodium edetate, polysorbate 80, hydrochloric acid and/or sodium hydroxide (to adjust pH) and Water for Injection. - ZIOPTAN does not contain a preservative. - Following instillation, tafluprost is absorbed through the cornea and is hydrolyzed to the biologically active acid metabolite, tafluprost acid. Following instillation of one drop of the 0.0015% solution once daily into each eye of healthy volunteers, the plasma concentrations of tafluprost acid peaked at a median time of 10 minutes on both Days 1 and 8. The mean plasma Cmax of tafluprost acid were 26 pg/mL and 27 pg/mL on Day 1, and Day 8, respectively. The mean plasma AUC estimates of tafluprost acid were 394 pgmin/mL and 432 pgmin/mL on Day 1 and 8, respectively. - Metabolism - Tafluprost, an ester prodrug, is hydrolyzed to its biologically active acid metabolite in the eye. The acid metabolite is further metabolized via fatty acid β-oxidation and phase II conjugation. - Elimination - Mean plasma tafluprost acid concentrations were below the limit of quantification of the bioanalytical assay (10 pg/mL) at 30 minutes following topical ocular administration of tafluprost 0.0015% ophthalmic solution. - Tafluprost was not mutagenic or clastogenic in a battery of genetic toxicology studies, including an in vitro microbial mutagenesis assay, an in vitro chromosomal aberration assay in Chinese hamster lung cells, and an in vivo mouse micronucleus assay in bone marrow. - In rats, no adverse effects on mating performance or fertility were observed with intravenous dosing of tafluprost at a dose of 100 mcg/kg/day (over 14000 times the maximum clinical exposure based on plasma Cmax or over 3600 times based on plasma AUC). - NDC 17478-609-30; Unit-of-Use Carton of 30. - NDC 17478-609-90; Unit-of-Use Carton of 90. - Storage: - Store refrigerated at 2—8°C (36—46°F). Store in the original pouch. After the pouch is opened, the single-use containers may be stored in the opened foil pouch for up to 28 days at room temperature: 20—25°C (68—77°F). Protect from moisture. Write down the date you open the foil pouch in the space provided on the pouch. Discard any unused containers 28 days after first opening the pouch. - Advise patients to not exceed once daily dosing since more frequent administration may decrease the intraocular pressure lowering effect of ZIOPTAN. - Handling the Single-Use Container - Advise patients that ZIOPTAN is a sterile solution that does not contain a preservative. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded immediately after administration. - Potential for Pigmentation - Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Also inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of ZIOPTAN. - Potential for Eyelash Changes - Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with ZIOPTAN. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment. - When to Seek Physician Advice - Advise patients that if they develop a new ocular condition (e.g., trauma or infection), experience a sudden decrease in visual acuity, have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of ZIOPTAN. - Use with Other Ophthalmic Drugs - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications. - Storage Information - Instruct patients on proper storage of cartons, unopened foil pouches, and opened foil pouches. Recommended storage for cartons and unopened foil pouches is to store refrigerated at 2—8°C (36—46°F). After the pouch is opened, the single-use containers may be stored in the opened foil pouch for up to 28 days at room temperature: 20—25°C (68—77°F). Protect from moisture. - ↑ "ZIOPTAN tafluprost solution/ drops"..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}	Tafluprost - Content - The recommended dose is one drop of ZIOPTAN in the conjunctival sac of the affected eye(s) once daily in the evening. - The dose should not exceed once daily since it has been shown that more frequent administration of prostaglandin analogs may lessen the intraocular pressure lowering effect. - Reduction of the intraocular pressure starts approximately 2 to 4 hours after the first administration with the maximum effect reached after 12 hours. - ZIOPTAN may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic product is being used, each one should be administered at least 5 minutes apart. - The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded immediately after administration. - Pigmentation - Tafluprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as tafluprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of tafluprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known. - Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with ZIOPTAN can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. - Eyelash Changes - ZIOPTAN may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, color, thickness, shape and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment. - Intraocular Inflammation - ZIOPTAN should be used with caution in patients with active intraocular inflammation (e.g., iritis/uveitis) because the inflammation may be exacerbated. - Macular Edema - Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin F2α analogs. ZIOPTAN should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. - Preservative-containing or preservative-free tafluprost 0.0015% was evaluated in 905 patients in five controlled clinical studies of up to 24-months duration. The most common adverse reaction observed in patients treated with tafluprost was conjunctival hyperemia which was reported in a range of 4% — 20% of patients. Approximately 1% of patients discontinued therapy due to ocular adverse reactions. - Ocular adverse reactions reported at an incidence of ≥2% in these clinical studies included ocular stinging/irritation (7%), ocular pruritus including allergic conjunctivitis (5%), cataract (3%), dry eye (3%), ocular pain (3%), eyelash darkening (2%), growth of eyelashes (2%) and vision blurred (2%). - Nonocular adverse reactions reported at an incidence of 2% — 6% in these clinical studies in patients treated with tafluprost 0.0015% were headache (6%), common cold (4%), cough (3%) and urinary tract infection (2%). Exacerbation of asthma, dyspnea Iritis/uveitis - In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid sulcus have been observed. - Teratogenic effects: In embryo-fetal development studies in rats and rabbits, tafluprost administered intravenously was teratogenic. Tafluprost caused increases in post-implantation losses in rats and rabbits and reductions in fetal body weights in rats. Tafluprost also increased the incidence of vertebral skeletal abnormalities in rats and the incidence of skull, brain and spine malformations in rabbits. In rats, there were no adverse effects on embryo-fetal development at a dose of 3 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid that were 343 times the maximum clinical exposure based on Cmax. In rabbits, effects were seen at a tafluprost dose of 0.03 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid during organogenesis that were approximately 5 times higher than the clinical exposure based on Cmax. At the no-effect dose in rabbits (0.01 mcg/kg/day), maternal plasma levels of tafluprost acid were below the lower level of quantification (20 pg/mL). - In a pre- and postnatal development study in rats, increased mortality of newborns, decreased body weights and delayed pinna unfolding were observed in offsprings. The no observed adverse effect level was at a tafluprost intravenous dose of 0.3 mcg/kg/day which is greater than 3 times the maximum recommended clinical dose based on body surface area comparison. - There are no adequate and well-controlled studies in pregnant woman. Although animal reproduction studies are not always predictive of human response, ZIOPTAN should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. - Women of childbearing age/potential should have adequate contraceptive measures in place. There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tafluprost in women who are pregnant. There is limited information regarding Chronic Overdose of Tafluprost in the drug label. Its structural formula is: - Tafluprost is a colorless to light yellow viscous liquid that is practically insoluble in water. - ZIOPTAN (tafluprost ophthalmic solution) 0.0015% is supplied as a sterile solution of tafluprost with a pH range of 5.5 — 6.7 and an Osmolality range of 260 — 300 mOsmol/kg. - ZIOPTAN contains Active: tafluprost 0.015 mg/mL; Inactives: glycerol, sodium dihydrogen phosphate dihydrate, disodium edetate, polysorbate 80, hydrochloric acid and/or sodium hydroxide (to adjust pH) and Water for Injection. - ZIOPTAN does not contain a preservative. - Following instillation, tafluprost is absorbed through the cornea and is hydrolyzed to the biologically active acid metabolite, tafluprost acid. Following instillation of one drop of the 0.0015% solution once daily into each eye of healthy volunteers, the plasma concentrations of tafluprost acid peaked at a median time of 10 minutes on both Days 1 and 8. The mean plasma Cmax of tafluprost acid were 26 pg/mL and 27 pg/mL on Day 1, and Day 8, respectively. The mean plasma AUC estimates of tafluprost acid were 394 pgmin/mL and 432 pgmin/mL on Day 1 and 8, respectively. - Metabolism - Tafluprost, an ester prodrug, is hydrolyzed to its biologically active acid metabolite in the eye. The acid metabolite is further metabolized via fatty acid β-oxidation and phase II conjugation. - Elimination - Mean plasma tafluprost acid concentrations were below the limit of quantification of the bioanalytical assay (10 pg/mL) at 30 minutes following topical ocular administration of tafluprost 0.0015% ophthalmic solution. - Tafluprost was not mutagenic or clastogenic in a battery of genetic toxicology studies, including an in vitro microbial mutagenesis assay, an in vitro chromosomal aberration assay in Chinese hamster lung cells, and an in vivo mouse micronucleus assay in bone marrow. - In rats, no adverse effects on mating performance or fertility were observed with intravenous dosing of tafluprost at a dose of 100 mcg/kg/day (over 14000 times the maximum clinical exposure based on plasma Cmax or over 3600 times based on plasma AUC). - NDC 17478-609-30; Unit-of-Use Carton of 30. - NDC 17478-609-90; Unit-of-Use Carton of 90. - Storage: - Store refrigerated at 2—8°C (36—46°F). Store in the original pouch. After the pouch is opened, the single-use containers may be stored in the opened foil pouch for up to 28 days at room temperature: 20—25°C (68—77°F). Protect from moisture. Write down the date you open the foil pouch in the space provided on the pouch. Discard any unused containers 28 days after first opening the pouch. - Advise patients to not exceed once daily dosing since more frequent administration may decrease the intraocular pressure lowering effect of ZIOPTAN. - Handling the Single-Use Container - Advise patients that ZIOPTAN is a sterile solution that does not contain a preservative. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded immediately after administration. - Potential for Pigmentation - Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Also inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of ZIOPTAN. - Potential for Eyelash Changes - Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with ZIOPTAN. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment. - When to Seek Physician Advice - Advise patients that if they develop a new ocular condition (e.g., trauma or infection), experience a sudden decrease in visual acuity, have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of ZIOPTAN. - Use with Other Ophthalmic Drugs - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications. - Storage Information - Instruct patients on proper storage of cartons, unopened foil pouches, and opened foil pouches. Recommended storage for cartons and unopened foil pouches is to store refrigerated at 2—8°C (36—46°F). After the pouch is opened, the single-use containers may be stored in the opened foil pouch for up to 28 days at room temperature: 20—25°C (68—77°F). Protect from moisture. - ↑ "ZIOPTAN tafluprost solution/ drops"..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}	https://www.wikidoc.org/index.php/Tafluprost
103a94079b6599b991256971a3d8749acc68231d	wikidoc	Talk pages	Talk pages There are two types of talk pages - the first one is standard talk pages which are used to discuss an article, while user talk pages are used to communicate with other users or leave them messages. Every page has an associated talk page, except pages in the Special:namespace. If there is no discussion of a page, the link to its talk page will be red. You can still discuss the page - you will just be the first person to do so. # Accessing a talk page To access a talk page look for a link labelled Talk, Discussion or Discuss this page. These links will be found either at the top of the page or on the left hand side (near Edit this page). A talk page adds Talk: to the beginning of the main page's title. If the main page has a prefix then talk is added after this prefix. 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If a reply is made to a statement, one adds a colon to the number of colons used in the statement being replied to. This style of conversation is easier to read. Example: The above will produce this: The information on this page is attributed to WikiDoc and its contributors	Talk pages Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] There are two types of talk pages - the first one is standard talk pages which are used to discuss an article, while user talk pages are used to communicate with other users or leave them messages. Every page has an associated talk page, except pages in the Special:namespace. If there is no discussion of a page, the link to its talk page will be red. You can still discuss the page - you will just be the first person to do so. # Accessing a talk page To access a talk page look for a link labelled Talk, Discussion or Discuss this page. These links will be found either at the top of the page or on the left hand side (near Edit this page). A talk page adds Talk: to the beginning of the main page's title. If the main page has a prefix then talk is added after this prefix. For example, a talk page associated with the main article namespace simply has the prefix Talk:, while a talk page associated with the user namespace has the prefix User talk:. This article is in the Help: namespace, so the talk page for this article is [[Help talk:Talk page. The Main Page is in the main namespace (because it has no prefix), so its talk page is simply Talk:Main Page. After someone else edits your user talk page, the alert "You have new messages" is automatically displayed on all pages you view, until you view your user page. # Using talk pages You should sign your contributions by typing three or four tildes (~~~ = Username) (~~~~ = Username 19:36, 10 January 2006 (UTC)). When discussing the name of the page or discussing merging it with another page, always mention the current page name: after renaming (moving) a page, references to "this page name" would not make sense. On a talk page, "this page" usually refers to the main page (i.e. the page the talk page is associated with). If the talk page itself is referred to, write "this talk page". The "Post a comment" feature allows convenient appending of a section with the section header the same as the edit summary, and typed only once. This also works on other pages as well, though there is no link displayed, so you will need to use the URL, e.g. http://meta.wikimedia.org/w/wiki.phtml?title=Sandbox&action=edit&section=new The practice of "spamming" - posting similar messages to more than a few users' talk pages, often for the purpose of soliciting a certain action - is discouraged. ### Formatting Because the wiki software platform provides for a wide range of formatting styles, proper or at least consistent formatting is essential to maintaining readable talk pages. The depth of a message is determined by the number of colons (':') in front of the message. Each colon represents a tab, and are commonly used in discussions on user and article talk pages. If a reply is made to a statement, one adds a colon to the number of colons used in the statement being replied to. This style of conversation is easier to read. Example: The above will produce this: The information on this page is attributed to WikiDoc and its contributors Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Talk_pages
700941c1582241638c5117aac95e6adc0062c87c	wikidoc	Tapentadol	Tapentadol # 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 Tapentadol is an opioid analgesic that is FDA approved for the {{{indicationType}}} of moderate to severe acute pain in adults. Common adverse reactions include nausea, dizziness, vomiting and somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The dose is 50 mg, 75 mg, or 100 mg every 4 to 6 hours depending upon pain intensity. - On the first day of dosing, the second dose may be administered as soon as one hour after the first dose, if adequate pain relief is not attained with the first dose. Subsequent dosing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain adequate analgesia with acceptable tolerability. - Daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been studied and are not recommended. - NUCYNTA® may be given with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tapentadol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tapentadol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tapentadol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tapentadol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tapentadol in pediatric patients. # Contraindications - Patients with significant respiratory depression. - Patients with acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment. - Patients with known or suspected paralytic ileus. - Patients with hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product. - Patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels which may result in adverse cardiovascular events. # Warnings ### Precautions - Abuse Potential - NUCYNTA® contains tapentadol, an opioid agonist and a Schedule II controlled substance. Tapentadol can be abused in a manner similar to other opioid agonists legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA® in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain. - Assess each patient's risk for opioid abuse or addiction prior to prescribing NUCYNTA®. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with opioids; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use. - Misuse or abuse of NUCYNTA® by crushing, chewing, snorting or injecting will pose a significant risk that could result in overdose and death. - Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. - Life Threatening Respiratory Depression - Respiratory depression is the chief hazard of opioid agonists, including NUCYNTA®. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a "sighing" pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status. - Instruct patients against use by individuals other than the patient for whom NUCYNTA® was prescribed and to keep NUCYNTA® out of the reach of children, as such inappropriate use may result in fatal respiratory depression. - Patients with conditions accompanied by hypoxia, hypercarbia or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, central nervous system (CNS) depression, or coma may be at increased risk for increased airway resistance and decreased respiratory drive to the point of apnea even with usual therapeutic doses of NUCYNTA®. Consider the use of alternative non-mu-opioid agonist analgesics and use NUCYNTA® only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, treat the patient for mu-opioid agonist-induced respiratory depression. To reduce the risk of respiratory depression, proper dosing of NUCYNTA® is essential. - Accidental Exposure - Accidental ingestion of NUCYNTA®, especially in children, can result in a fatal overdose of tapentadol. - Interactions with Alcohol, Other Opioids, and Drugs of Abuse - Due to its mu-opioid agonist activity, NUCYNTA® may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, respiratory depression, hypotension, and profound sedation, coma or death. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol, other opioids, or drugs of abuse while on NUCYNTA® therapy. - Elderly, Cachectic, and Debilitated Patients - Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Therefore, closely monitor such patients, particularly when NUCYNTA® is given concomitantly with other drugs that depress respiration. - Use in Patients with Chronic Pulmonary Disease - Monitor for respiratory depression those patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, as in these patients, even usual therapeutic doses of NUCYNTA® may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible. - Interactions with CNS Depressants and Illicit Drugs - Hypotension, and profound sedation, coma or respiratory depression may result if NUCYNTA® is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, muscle relaxants, other opioids and illicit drugs). When considering the use of NUCYNTA® in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient's use, if any, of alcohol and/or illicit drugs that can cause CNS depression. If NUCYNTA® therapy is to be initiated in a patient taking a CNS depressant, start with a lower NUCYNTA® dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant. - Hypotensive Effect - NUCYNTA® may cause severe hypotension. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after the dose of NUCYNTA®. In patients with circulatory shock, NUCYNTA® may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA® in patients with circulatory shock. - Use in Patients with Head Injury or Increased Intracranial Pressure - Monitor patients taking NUCYNTA® who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression. NUCYNTA® may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. - Avoid the use of NUCYNTA® in patients with impaired consciousness or coma. - Seizures - NUCYNTA® has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. The active ingredient tapentadol in NUCYNTA® may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA® therapy. - Serotonin Syndrome Risk - Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (e.g. mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal . - Use in Patients with Gastrointestinal Conditions - NUCYNTA® is contraindicated in patients with GI obstruction, including paralytic ileus. The tapentadol in NUCYNTA® may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. - Withdrawal - Withdrawal symptoms may occur if NUCYNTA® is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may be reduced by tapering NUCYNTA®. - Driving and Operating Heavy Machinery - NUCYNTA® may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA® and know how they will react to the medication. - Hepatic Impairment - A study with NUCYNTA® in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA® in patients with severe hepatic impairment. Reduce the dose of NUCYNTA® in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when receiving NUCYNTA®. - Renal Impairment - Use of NUCYNTA® in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known. # 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 clinical practice. - Based on data from nine Phase 2/3 studies that administered multiple doses (seven placebo- and/or active-controlled, one noncontrolled and one Phase 3 active-controlled safety study) the most common adverse reactions (reported by ≥10% in any NUCYNTA® dose group) were: nausea, dizziness, vomiting and somnolence. - The most common reasons for discontinuation due to adverse reactions in the studies described above (reported by ≥1% in any NUCYNTA® dose group) were dizziness (2.6% vs. 0.5%), nausea (2.3% vs. 0.6%), vomiting (1.4% vs. 0.2%), somnolence (1.3% vs. 0.2%) and headache (0.9% vs. 0.2%) for NUCYNTA®- and placebo-treated patients, respectively. - Seventy-six percent of NUCYNTA®-treated patients from the nine studies experienced adverse events. - NUCYNTA® was studied in multiple-dose, active- or placebo-controlled studies, or noncontrolled studies (n = 2178), in single-dose studies (n = 870), in open-label study extension (n = 483) and in Phase 1 studies (n = 597). Of these, 2034 patients were treated with doses of 50 mg to 100 mg of NUCYNTA® dosed every 4 to 6 hours. - The data described below reflect exposure to NUCYNTA® in 3161 patients, including 449 exposed for 45 days. NUCYNTA® was studied primarily in placebo- and active-controlled studies (n = 2266, and n = 2944, respectively). The population was 18 to 85 years old (mean age 46 yea), 68% were female, 75% white and 67% were postoperative. Most patients received NUCYNTA® doses of 50 mg, 75 mg, or 100 mg every 4 to 6 hours. - The following adverse drug reactions occurred in less than 1% of NUCYNTA®-treated patients in the pooled safety data from nine Phase 2/3 clinical studies: Heart rate increased, heart rate decreased Visual disturbance Abdominal discomfort, impaired gastric emptying Irritability, edema, drug withdrawal syndrome, feeling drunk Hypersensitivity Gamma-glutamyltransferase increased, alanine aminotransferase increased, aspartate aminotransferase increased Involuntary muscle contractions, sensation of heaviness Hypoesthesia, paresthesia, disturbance in attention, sedation, dysarthria, depressed level of consciousness, memory impairment, ataxia, presyncope, syncope, coordination abnormal, seizure Euphoric mood, disorientation, restlessness, agitation, nervousness, thinking abnormal Urinary hesitation, pollakiuria Oxygen saturation decreased, cough, dyspnea, respiratory depression Urticaria Blood pressure decreased - In the pooled safety data, the overall incidence of adverse reactions increased with increased dose of NUCYNTA®, as did the percentage of patients with adverse reactions of nausea, dizziness, vomiting, somnolence, and pruritus. ## Postmarketing Experience - The following additional adverse reactions have been identified during post-approval use of NUCYNTA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably. Diarrhea Headache Hallucination, suicidal ideation, panic attack Palpitations - Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients contained in NUCYNTA®. Advise patients how to recognize such reactions and when to seek medical attention. # Drug Interactions - Alcohol, Other Opioids, and Drugs of Abuse - Due to its mu-opioid agonist activity, NUCYNTA® may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, respiratory depression, hypotension, and profound sedation, coma or death. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol, other opioids, or drugs of abuse while on NUCYNTA® therapy . - Monoamine Oxidase Inhibitors - NUCYNTA® is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels which may result in adverse cardiovascular events . - CNS Depressants - Concurrent use of NUCYNTA® and other central nervous system (CNS) depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol can increase the risk of respiratory depression, hypotension, profound sedation or coma. Monitor patients receiving CNS depressants and NUCYNTA® for signs of respiratory depression and hypotension. When such combined therapy is contemplated, start NUCYNTA® at ⅓ to ½ of the usual dosage and consider using a lower dose of the concomitant CNS depressant . - Serotonergic Drugs - There have been post-marketing reports of serotonin syndrome with the concomitant use of tapentadol and serotonergic drugs (e.g., SSRIs and SNRIs). Caution is advised when NUCYNTA® is co-administered with other drugs that may affect serotonergic neurotransmitter systems such as SSRIs, SNRIs, MAOIs, and triptans. If concomitant treatment of NUCYNTA® with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised . - Mixed Agonist/Antagonist Opioid Analgesics - The concomitant use of NUCYNTA® with mixed agonist/antagonists (e.g., butorphanol, nalbuphine, and pentazocine) and partial agonists (e.g., buprenorphine) may precipitate withdrawal symptoms. Avoid the use of agonist/antagonists and partial agonists with NUCYNTA®. - Anticholinergics - The use of NUCYNTA® with anticholinergic products may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies of NUCYNTA® in pregnant women. NUCYNTA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Tapentadol HCl was evaluated for teratogenic effects in pregnant rats and rabbits following intravenous and subcutaneous exposure during the period of embryofetal organogenesis. When tapentadol was administered twice daily by the subcutaneous route in rats at dose levels of 10, 20, or 40 mg/kg/day , no teratogenic effects were observed. Evidence of embryofetal toxicity included transient delays in skeletal maturation (i.e. reduced ossification) at the 40 mg/kg/day dose which was associated with significant maternal toxicity. Administration of tapentadol HCl in rabbits at doses of 4, 10, or 24 mg/kg/day by subcutaneous injection revealed embryofetal toxicity at doses ≥10 mg/kg/day. Findings included reduced fetal viability, skeletal delays and other variations. In addition, there were multiple malformations including gastroschisis/thoracogastroschisis, amelia/phocomelia, and cleft palate at doses ≥10 mg/kg/day and above, and ablepharia, encephalopathy, and spina bifida at the high dose of 24 mg/kg/day. Embryofetal toxicity, including malformations, may be secondary to the significant maternal toxicity observed in the study. - In a study of pre- and postnatal development in rats, oral administration of tapentadol at doses of 20, 50, 150, or 300 mg/kg/day to pregnant and lactating rats during the late gestation and early postnatal period did not influence physical or reflex development, the outcome of neurobehavioral tests or reproductive parameters. Treatment-related developmental delay was observed, including incomplete ossification, and significant reductions in pup body weights and body weight gains at doses associated with maternal toxicity (150 mg/kg/day and above). At maternal tapentadol doses ≥150 mg/kg/day, a dose-related increase in pup mortality was observed through postnatal Day 4. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tapentadol in women who are pregnant. ### Labor and Delivery - NUCYNTA® is not for use in women during and immediately prior to labor. Occasionally, opioid analgesics may prolong labor by temporarily reducing the strength, duration, and frequency of uterine contractions. However, these effects are not consistent and may be offset by an increased rate of cervical dilatation which tends to shorten labor. - Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate in such situations. ### Nursing Mothers - There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded. - Because of the potential for adverse reactions in nursing infants from NUCYNTA®, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. - Withdrawal symptoms can occur in breast-feeding infants when maternal administration of NUCYNTA® is stopped. ### Pediatric Use - The safety and effectiveness of NUCYNTA® in pediatric patients less than 18 years of age have not been established. ### Geriatic Use - Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA®, 19% were 65 and over, while 5% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The rate of constipation was higher in subjects greater than or equal to 65 years than those less than 65 years (12% vs. 7%). - In general, recommended dosing for elderly patients with normal renal and hepatic function is the same as for younger adult patients with normal renal and hepatic function. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients with the lower range of recommended doses. ### Gender There is no FDA guidance on the use of Tapentadol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tapentadol with respect to specific racial populations. ### Renal Impairment - The safety and effectiveness of NUCYNTA® has not been established in patients with severe renal impairment (CLCR <30 mL/min). Use of NUCYNTA® in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known. ### Hepatic Impairment - Administration of tapentadol resulted in higher exposures and serum levels of tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The dose of NUCYNTA® should be reduced in patients with moderate hepatic impairment (Child-Pugh Score 7 to 9). - Use of NUCYNTA® is not recommended in patients with severe hepatic impairment (Child-Pugh Score 10 to 15). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tapentadol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tapentadol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Tapentadol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tapentadol in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes pulmonary edema, bradycardia, hypotension and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations. ### Management - In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. - The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to tapentadol overdose. Such agents should be administered cautiously to patients who are known, or suspected to be, physically dependent on NUCYNTA®. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. - Because the duration of reversal would be expected to be less than the duration of action of tapentadol in NUCYNTA®, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be given as directed in the product's prescribing information. - In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. ## Chronic Overdose There is limited information regarding Chronic Overdose of Tapentadol in the drug label. # Pharmacology ## Mechanism of Action - Tapentadol is a centrally-acting synthetic analgesic. The exact mechanism of action is unknown. Although the clinical relevance is unclear, preclinical studies have shown that tapentadol is a mu-opioid receptor (MOR) agonist and a norepinephrine reuptake inhibitor (NRI). Analgesia in animal models is derived from both of these properties. ## Structure - NUCYNTA® (tapentadol) is a mu-opioid receptor agonist, supplied in immediate-release film-coated tablets for oral administration, containing 58.24, 87.36 and 116.48 mg of tapentadol hydrochloride in each tablet strength, corresponding to 50, 75, and 100 mg of tapentadol free-base, respectively. The chemical name is 3-phenol monohydrochloride. The structural formula is: - The molecular weight of tapentadol HCl is 257.80, and the molecular formula is C14H23NOHCl. The n-octanol:water partition coefficient log P value is 2.87. The pKa values are 9.34 and 10.45. - In addition to the active ingredient tapentadol HCl, NUCYNTA® tablets also contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone. The film coatings for all tablet strengths contain polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and the colorant FD&C Yellow #6 aluminum lake; the film coatings for the 50 mg and 75 mg tablets also contain the additional colorant D&C Yellow #10 aluminum lake. ## Pharmacodynamics - Tapentadol is 18 times less potent than morphine in binding to the human mu-opioid receptor and is 2–3 times less potent in producing analgesia in animal models. Tapentadol has been shown to inhibit norepinephrine reuptake in the brains of rats resulting in increased norepinephrine concentrations. In preclinical models, the analgesic activity due to the mu-opioid receptor agonist activity of tapentadol can be antagonized by selective mu-opioid antagonists (e.g., naloxone), whereas the norepinephrine reuptake inhibition is sensitive to norepinephrine modulators. Tapentadol exerts its analgesic effects without a pharmacologically active metabolite. - Concentration-Efficacy Relationships - The minimum effective plasma concentration of tapentadol for analgesia varies widely among patients, especially among patients who have been previously treated with agonist opioids. - Concentration-Adverse Experience Relationships - There is a general relationship between increasing opioid plasma concentration and increasing frequency of adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression. - Effects on the Cardiovascular System - There was no effect of therapeutic and supratherapeutic doses of tapentadol on the QT interval. In a randomized, double-blind, placebo- and positive-controlled crossover study, healthy subjects were administered five consecutive doses of NUCYNTA® 100 mg every 6 hours, NUCYNTA® 150 mg every 6 hours, placebo and a single oral dose of moxifloxacin. Similarly, NUCYNTA® had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology). - Tapentadol produces peripheral vasodilation which may result in orthostatic hypotension. - Effects on the Central Nervous System (CNS) - The principal therapeutic action of tapentadol is analgesia. Tapentadol causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Tapentadol depresses the cough reflex by direct effect on the cough center in the medulla. - Tapentadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations . Other effects of tapentadol include anxiolysis, euphoria, and feeling of relaxation, drowsiness and changes in mood. - Effects on the Gastrointestinal Tract and on Other Smooth Muscle - Gastric, biliary and pancreatic secretions are decreased by tapentadol. Tapentadol causes a reduction in motility and is associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The end result is constipation. Tapentadol can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi, and transient elevations in serum amylase. Tapentadol may also cause spasm of the sphincter of the urinary bladder. - Effects on the Endocrine System - Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. - Effects on the Immune System - Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. - CNS Depressant/Alcohol Interaction - Additive pharmacodynamic effects may be expected when NUCYNTA® is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. ## Pharmacokinetics - Absorption - The mean absolute bioavailability after single-dose administration (fasting) of NUCYNTA® is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at around 1.25 hours after dosing. - Dose-proportional increases in the Cmax and AUC values of tapentadol have been observed over the 50 to 150 mg dose range. - A multiple (every 6 hour) dose study with doses ranging from 75 to 175 mg tapentadol showed a mean accumulation factor of 1.6 for the parent drug and 1.8 for the major metabolite tapentadol-O-glucuronide, which are primarily determined by the dosing interval and apparent half-life of tapentadol and its metabolite. - Food Effect - The AUC and Cmax increased by 25% and 16%, respectively, when NUCYNTA® was administered after a high-fat, high-calorie breakfast. NUCYNTA® may be given with or without food. - Distribution - Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 L. The plasma protein binding is low and amounts to approximately 20%. - Metabolism and Elimination - In humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized via Phase 2 pathways, and only a small amount is metabolized by Phase 1 oxidative pathways. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% (55% O-glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the conjugated form. A total of 3% of drug was excreted in urine as unchanged drug. Tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Therefore, drug metabolism mediated by cytochrome P450 system is of less importance than phase 2 conjugation. - None of the metabolites contribute to the analgesic activity. - Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal half-life is on average 4 hours after oral administration. The total clearance is 1530 +/- 177 mL/min. - Special Populations - Geriatric Patients - The mean exposure (AUC) to tapentadol was similar in elderly subjects compared to young adults, with a 16% lower mean Cmax observed in the elderly subject group compared to young adult subjects. - Renal Impairment - AUC and Cmax of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild (CLCR = 50 to <80 mL/min), moderate (CLCR = 30 to <50 mL/min), and severe (CLCR = <30 mL/min) renal impairment, the AUC of tapentadol-O-glucuronide was 1.5-, 2.5-, and 5.5-fold higher compared with normal renal function, respectively. - Hepatic Impairment - Administration of NUCYNTA® resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild hepatic impairment group (Child-Pugh Score 5 to 6) and moderate hepatic impairment group (Child-Pugh Score 7 to 9) in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for Cmax; and 1.2 and 1.4, respectively, for t1/2. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment. - Pharmacokinetic Drug Interactions - Tapentadol is mainly metabolized by Phase 2 glucuronidation, a high capacity/low affinity system; therefore, clinically relevant interactions caused by Phase 2 metabolism are unlikely to occur. Naproxen and probenecid increased the AUC of tapentadol by 17% and 57%, respectively. These changes are not considered clinically relevant and no change in dose is required. - No changes in the pharmacokinetic parameters of tapentadol were observed when acetaminophen and acetylsalicylic acid were given concomitantly. - In vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Furthermore, a minor amount of NUCYNTA® is metabolized via the oxidative pathway. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur. - The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively. - Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic drug-drug interactions by displacement from the protein binding site is low. ## Nonclinical Toxicology - Carcinogenesis - Tapentadol was administered to rats (diet) and mice (oral gavage) for two years. - In mice, tapentadol HCl was administered by oral gavage at dosages of 50, 100 and 200 mg/kg/day for 2 years (up to 0.2 times the plasma exposure at the maximum recommended human dose on an area under the time-curve basis). No increase in tumor incidence was observed at any dose level. - In rats, tapentadol HCl was administered in diet at dosages of 10, 50, 125 and 250 mg/kg/day for two years (up to 0.2 times in the male rats and 0.6 times in the female rats the MRHD on an AUC basis). No increase in tumor incidence was observed at any dose level. - Mutagenesis - Tapentadol did not induce gene mutations in bacteria, but was clastogenic with metabolic activation in a chromosomal aberration test in V79 cells. The test was repeated and was negative in the presence and absence of metabolic activation. The one positive result for tapentadol was not confirmed in vivo in rats, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, when tested up to the maximum tolerated dose. - Impairment of Fertility - Tapentadol HCl was administered intravenously to male or female rats at dosages of 3, 6, or 12 mg/kg/day (representing exposures of up to approximately 0.4 times the exposure at the MRHD on an AUC basis, based on extrapolation from toxicokinetic analyses in a separate 4-week intravenous study in rats). Tapentadol did not alter fertility at any dose level. Maternal toxicity and adverse effects on embryonic development, including decreased number of implantations, decreased numbers of live conceptuses, and increased pre- and post-implantation losses occurred at dosages ≥6 mg/kg/day. # Clinical Studies - The efficacy and safety of NUCYNTA® in the treatment of moderate to severe acute pain has been established in two randomized, double-blind, placebo- and active-controlled studies of moderate to severe pain from first metatarsal bunionectomy and end-stage degenerative joint disease. - A randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study demonstrated the efficacy of 50 mg, 75 mg, and 100 mg NUCYNTA® given every 4 to 6 hours for 72 hours in patients aged 18 to 80 years experiencing moderate to severe pain following unilateral, first metatarsal bunionectomy surgery. Patients who qualified for the study with a baseline pain score of ≥4 on an 11-point rating scale ranging from 0 to 10 were randomized to 1 of 5 treatments. Patients were allowed to take a second dose of study medication as soon as 1 hour after the first dose on study Day 1, with subsequent dosing every 4 to 6 hours. If rescue analgesics were required, the patients were discontinued for lack of efficacy. Efficacy was evaluated by comparing the sum of pain intensity difference over the first 48 hours (SPID48) versus placebo. NUCYNTA® at each dose provided a greater reduction in pain compared to placebo based on SPID48 values. - For various degrees of improvement from baseline to the 48-hour endpoint, Figure 1 shows the fraction of patients achieving that level of improvement. The figures are cumulative, such that every patient that achieves a 50% reduction in pain from baseline is included in every level of improvement below 50%. Patients who did not complete the 48-hour observation period in the study were assigned 0% improvement. - The proportions of patients who showed reduction in pain intensity at 48 hours of 30% or greater, or 50% or greater were significantly higher in patients treated with NUCYNTA® at each dose versus placebo. - A randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study evaluated the efficacy and safety of 50 mg and 75 mg NUCYNTA® given every 4 to 6 hours during waking hours for 10 days in patients aged 18 to 80 years, experiencing moderate to severe pain from end stage degenerative joint disease of the hip or knee, defined as a 3-day mean pain score of ≥5 on an 11-point pain intensity scale, ranging from 0 to 10. Pain scores were assessed twice daily and assessed the pain the patient had experienced over the previous 12 hours. Patients were allowed to continue non-opioid analgesic therapy for which they had been on a stable regimen before screening throughout the study. Eighty-three percent (83%) of patients in the tapentadol treatment groups and the placebo group took such analgesia during the study. The 75 mg treatment group was dosed at 50 mg for the first day of the study, followed by 75 mg for the remaining nine days. Patients requiring rescue analgesics other than study medication were discontinued for lack of efficacy. Efficacy was evaluated by comparing the sum of pain intensity difference (SPID) versus placebo over the first five days of treatment. NUCYNTA® 50 mg and 75 mg provided improvement in pain compared with placebo based on the 5-Day SPID. - For various degrees of improvement from baseline to the Day 5 endpoint, Figure 2 shows the fraction of patients achieving that level of improvement. The figures are cumulative, such that every patient that achieves a 50% reduction in pain from baseline is included in every level of improvement below 50%. Patients who did not complete the 5-day observation period in the study were assigned 0% improvement. - The proportions of patients who showed reduction in pain intensity at 5 days of 30% or greater, or 50% or greater were significantly higher in patients treated with NUCYNTA® at each dose versus placebo. # How Supplied - NUCYNTA® Tablets are available in the following strengths and packages. All tablets are round and biconvex-shaped. - 50 mg tablets are yellow and debossed with "O-M" on one side and "50" on the other side, and are available in bottles of 100 (NDC 50458-820-04) and hospital unit dose blister packs of 10 (NDC 50458-820-02). - 75 mg tablets are yellow-orange and debossed with "O-M" on one side and "75" on the other side, and are available in bottles of 100 (NDC 50458-830-04) and hospital unit dose blister packs of 10 (NDC 50458-830-02). - 100 mg tablets are orange and debossed with "O-M" on one side and "100" on the other side, and are available in bottles of 100 (NDC 50458-840-04) and hospital unit dose blister packs of 10 (NDC 50458-840-02). - Storage and Handling - Store up to 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F) . Protect from moisture. - Keep NUCYNTA® in a secure place out of reach of children. - NUCYNTA® tablets that are no longer needed should be destroyed by flushing down the toilet. ## Storage There is limited information regarding Tapentadol Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Instruct patients to take NUCYNTA® only as prescribed. - Abuse Potential - Inform patients that NUCYNTA® contains tapentadol, a Schedule II controlled substance that is subject to abuse. Instruct patients not to share NUCYNTA® with others and to take steps to protect NUCYNTA® from theft or misuse. - Life-threatening Respiratory Depression - Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting NUCYNTA® or when the dose is increased. Advise patients how to recognize respiratory depression and to seek medical attention if they are experiencing breathing difficulties. - Accidental Exposure - Instruct patients to take steps to store NUCYNTA® securely. Accidental exposure, especially in children, may results in serious harm or death. Advise patients to dispose of unused NUCYNTA® by flushing the tablets down the toilet. - Important Administration Instructions - Instruct patients how to properly take NUCYNTA®, including the following: - Using NUCYNTA® exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression). - Not discontinuing NUCYNTA® without first discussing the need for a tapering regimen with the prescriber. - Risks from Concomitant Use of Alcohol and other CNS Depressants - Inform patients that the concomitant use of alcohol with NUCYNTA® can increase the risk of life-threatening respiratory depression. Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter drug products that contain alcohol, during treatment with NUCYNTA®. - Inform patients that potentially serious additive effects may occur if NUCYNTA® is used with other CNS depressants, and not to use such drugs unless supervised by a health care provider. - Concurrent use of MAOI - Inform patients not to take NUCYNTA® while using any drugs that inhibit monoamine oxidase. Patients should not start any new medications while taking NUCYNTA®. - Seizures - Inform patients that NUCYNTA® could cause seizures if they are at risk for seizures or have epilepsy. Patients should be advised to stop taking NUCYNTA® if they have a seizure while taking NUCYNTA® and call their healthcare provider right away. - Serotonin Syndrome - Inform patients that NUCYNTA® could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (including Serotonin Reuptake Inhibitors, Serotonin and Norepinephrine Reuptake Inhibitors and tricyclic antidepressants). Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. - Instruct patients to inform their physicians if they are taking or plan to take additional medications, including CNS Depressants, MAO inhibitors, mixed agonists/antagonist opioid analgesics, anticholinergics, SSRIs, SNRIs, or tricyclic antidepressants. - Hypotension - Inform patients that NUCYNTA® may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). - Driving or Operating Heavy Machinery - Inform patients that NUCYNTA® may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication. - Constipation - Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. - Anaphylaxis - Inform patients that anaphylaxis has been reported with ingredients contained in NUCYNTA®. Advise patients how to recognize such a reaction and when to seek medical attention. - Pregnancy - Advise female patients that NUCYNTA® can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant. # Precautions with Alcohol - Alcohol-Tapentadol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - NUCYNTA® # Look-Alike Drug Names There is limited information regarding Tapentadol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Tapentadol 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. # Overview Tapentadol is an opioid analgesic that is FDA approved for the {{{indicationType}}} of moderate to severe acute pain in adults. Common adverse reactions include nausea, dizziness, vomiting and somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The dose is 50 mg, 75 mg, or 100 mg every 4 to 6 hours depending upon pain intensity. - On the first day of dosing, the second dose may be administered as soon as one hour after the first dose, if adequate pain relief is not attained with the first dose. Subsequent dosing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain adequate analgesia with acceptable tolerability. - Daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been studied and are not recommended. - NUCYNTA® may be given with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tapentadol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tapentadol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tapentadol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tapentadol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tapentadol in pediatric patients. # Contraindications - Patients with significant respiratory depression. - Patients with acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment. - Patients with known or suspected paralytic ileus. - Patients with hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product. - Patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels which may result in adverse cardiovascular events. # Warnings ### Precautions - Abuse Potential - NUCYNTA® contains tapentadol, an opioid agonist and a Schedule II controlled substance. Tapentadol can be abused in a manner similar to other opioid agonists legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA® in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain. - Assess each patient's risk for opioid abuse or addiction prior to prescribing NUCYNTA®. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with opioids; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use. - Misuse or abuse of NUCYNTA® by crushing, chewing, snorting or injecting will pose a significant risk that could result in overdose and death. - Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. - Life Threatening Respiratory Depression - Respiratory depression is the chief hazard of opioid agonists, including NUCYNTA®. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a "sighing" pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status. - Instruct patients against use by individuals other than the patient for whom NUCYNTA® was prescribed and to keep NUCYNTA® out of the reach of children, as such inappropriate use may result in fatal respiratory depression. - Patients with conditions accompanied by hypoxia, hypercarbia or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, central nervous system (CNS) depression, or coma may be at increased risk for increased airway resistance and decreased respiratory drive to the point of apnea even with usual therapeutic doses of NUCYNTA®. Consider the use of alternative non-mu-opioid agonist analgesics and use NUCYNTA® only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, treat the patient for mu-opioid agonist-induced respiratory depression. To reduce the risk of respiratory depression, proper dosing of NUCYNTA® is essential. - Accidental Exposure - Accidental ingestion of NUCYNTA®, especially in children, can result in a fatal overdose of tapentadol. - Interactions with Alcohol, Other Opioids, and Drugs of Abuse - Due to its mu-opioid agonist activity, NUCYNTA® may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, respiratory depression, hypotension, and profound sedation, coma or death. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol, other opioids, or drugs of abuse while on NUCYNTA® therapy. - Elderly, Cachectic, and Debilitated Patients - Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Therefore, closely monitor such patients, particularly when NUCYNTA® is given concomitantly with other drugs that depress respiration. - Use in Patients with Chronic Pulmonary Disease - Monitor for respiratory depression those patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, as in these patients, even usual therapeutic doses of NUCYNTA® may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible. - Interactions with CNS Depressants and Illicit Drugs - Hypotension, and profound sedation, coma or respiratory depression may result if NUCYNTA® is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, muscle relaxants, other opioids and illicit drugs). When considering the use of NUCYNTA® in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient's use, if any, of alcohol and/or illicit drugs that can cause CNS depression. If NUCYNTA® therapy is to be initiated in a patient taking a CNS depressant, start with a lower NUCYNTA® dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant. - Hypotensive Effect - NUCYNTA® may cause severe hypotension. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after the dose of NUCYNTA®. In patients with circulatory shock, NUCYNTA® may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA® in patients with circulatory shock. - Use in Patients with Head Injury or Increased Intracranial Pressure - Monitor patients taking NUCYNTA® who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression. NUCYNTA® may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. - Avoid the use of NUCYNTA® in patients with impaired consciousness or coma. - Seizures - NUCYNTA® has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. The active ingredient tapentadol in NUCYNTA® may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA® therapy. - Serotonin Syndrome Risk - Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (e.g. mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal [see Drug Interactions (7.4)]. - Use in Patients with Gastrointestinal Conditions - NUCYNTA® is contraindicated in patients with GI obstruction, including paralytic ileus. The tapentadol in NUCYNTA® may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. - Withdrawal - Withdrawal symptoms may occur if NUCYNTA® is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may be reduced by tapering NUCYNTA®. - Driving and Operating Heavy Machinery - NUCYNTA® may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA® and know how they will react to the medication. - Hepatic Impairment - A study with NUCYNTA® in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA® in patients with severe hepatic impairment. Reduce the dose of NUCYNTA® in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when receiving NUCYNTA®. - Renal Impairment - Use of NUCYNTA® in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known. # 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 clinical practice. - Based on data from nine Phase 2/3 studies that administered multiple doses (seven placebo- and/or active-controlled, one noncontrolled and one Phase 3 active-controlled safety study) the most common adverse reactions (reported by ≥10% in any NUCYNTA® dose group) were: nausea, dizziness, vomiting and somnolence. - The most common reasons for discontinuation due to adverse reactions in the studies described above (reported by ≥1% in any NUCYNTA® dose group) were dizziness (2.6% vs. 0.5%), nausea (2.3% vs. 0.6%), vomiting (1.4% vs. 0.2%), somnolence (1.3% vs. 0.2%) and headache (0.9% vs. 0.2%) for NUCYNTA®- and placebo-treated patients, respectively. - Seventy-six percent of NUCYNTA®-treated patients from the nine studies experienced adverse events. - NUCYNTA® was studied in multiple-dose, active- or placebo-controlled studies, or noncontrolled studies (n = 2178), in single-dose studies (n = 870), in open-label study extension (n = 483) and in Phase 1 studies (n = 597). Of these, 2034 patients were treated with doses of 50 mg to 100 mg of NUCYNTA® dosed every 4 to 6 hours. - The data described below reflect exposure to NUCYNTA® in 3161 patients, including 449 exposed for 45 days. NUCYNTA® was studied primarily in placebo- and active-controlled studies (n = 2266, and n = 2944, respectively). The population was 18 to 85 years old (mean age 46 yea), 68% were female, 75% white and 67% were postoperative. Most patients received NUCYNTA® doses of 50 mg, 75 mg, or 100 mg every 4 to 6 hours. - The following adverse drug reactions occurred in less than 1% of NUCYNTA®-treated patients in the pooled safety data from nine Phase 2/3 clinical studies: Heart rate increased, heart rate decreased Visual disturbance Abdominal discomfort, impaired gastric emptying Irritability, edema, drug withdrawal syndrome, feeling drunk Hypersensitivity Gamma-glutamyltransferase increased, alanine aminotransferase increased, aspartate aminotransferase increased Involuntary muscle contractions, sensation of heaviness Hypoesthesia, paresthesia, disturbance in attention, sedation, dysarthria, depressed level of consciousness, memory impairment, ataxia, presyncope, syncope, coordination abnormal, seizure Euphoric mood, disorientation, restlessness, agitation, nervousness, thinking abnormal Urinary hesitation, pollakiuria Oxygen saturation decreased, cough, dyspnea, respiratory depression Urticaria Blood pressure decreased - In the pooled safety data, the overall incidence of adverse reactions increased with increased dose of NUCYNTA®, as did the percentage of patients with adverse reactions of nausea, dizziness, vomiting, somnolence, and pruritus. ## Postmarketing Experience - The following additional adverse reactions have been identified during post-approval use of NUCYNTA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably. Diarrhea Headache Hallucination, suicidal ideation, panic attack Palpitations - Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients contained in NUCYNTA®. Advise patients how to recognize such reactions and when to seek medical attention. # Drug Interactions - Alcohol, Other Opioids, and Drugs of Abuse - Due to its mu-opioid agonist activity, NUCYNTA® may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, respiratory depression, hypotension, and profound sedation, coma or death. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol, other opioids, or drugs of abuse while on NUCYNTA® therapy [see Warnings and Precautions (5.4)]. - Monoamine Oxidase Inhibitors - NUCYNTA® is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels which may result in adverse cardiovascular events [see Contraindications (4)]. - CNS Depressants - Concurrent use of NUCYNTA® and other central nervous system (CNS) depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol can increase the risk of respiratory depression, hypotension, profound sedation or coma. Monitor patients receiving CNS depressants and NUCYNTA® for signs of respiratory depression and hypotension. When such combined therapy is contemplated, start NUCYNTA® at ⅓ to ½ of the usual dosage and consider using a lower dose of the concomitant CNS depressant [see Warnings and Precautions (5.7)]. - Serotonergic Drugs - There have been post-marketing reports of serotonin syndrome with the concomitant use of tapentadol and serotonergic drugs (e.g., SSRIs and SNRIs). Caution is advised when NUCYNTA® is co-administered with other drugs that may affect serotonergic neurotransmitter systems such as SSRIs, SNRIs, MAOIs, and triptans. If concomitant treatment of NUCYNTA® with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised [see Warning and Precautions (5.11)]. - Mixed Agonist/Antagonist Opioid Analgesics - The concomitant use of NUCYNTA® with mixed agonist/antagonists (e.g., butorphanol, nalbuphine, and pentazocine) and partial agonists (e.g., buprenorphine) may precipitate withdrawal symptoms. Avoid the use of agonist/antagonists and partial agonists with NUCYNTA®. - Anticholinergics - The use of NUCYNTA® with anticholinergic products may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies of NUCYNTA® in pregnant women. NUCYNTA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Tapentadol HCl was evaluated for teratogenic effects in pregnant rats and rabbits following intravenous and subcutaneous exposure during the period of embryofetal organogenesis. When tapentadol was administered twice daily by the subcutaneous route in rats at dose levels of 10, 20, or 40 mg/kg/day [producing up to 1 times the plasma exposure at the maximum recommended human dose (MRHD) of 700 mg/day based on an area under the time-curve (AUC) comparison], no teratogenic effects were observed. Evidence of embryofetal toxicity included transient delays in skeletal maturation (i.e. reduced ossification) at the 40 mg/kg/day dose which was associated with significant maternal toxicity. Administration of tapentadol HCl in rabbits at doses of 4, 10, or 24 mg/kg/day by subcutaneous injection [producing 0.2, 0.6, and 1.85 times the plasma exposure at the MRHD based on an AUC comparison] revealed embryofetal toxicity at doses ≥10 mg/kg/day. Findings included reduced fetal viability, skeletal delays and other variations. In addition, there were multiple malformations including gastroschisis/thoracogastroschisis, amelia/phocomelia, and cleft palate at doses ≥10 mg/kg/day and above, and ablepharia, encephalopathy, and spina bifida at the high dose of 24 mg/kg/day. Embryofetal toxicity, including malformations, may be secondary to the significant maternal toxicity observed in the study. - In a study of pre- and postnatal development in rats, oral administration of tapentadol at doses of 20, 50, 150, or 300 mg/kg/day to pregnant and lactating rats during the late gestation and early postnatal period [resulting in up to 1.7 times the plasma exposure at the MRHD on an AUC basis] did not influence physical or reflex development, the outcome of neurobehavioral tests or reproductive parameters. Treatment-related developmental delay was observed, including incomplete ossification, and significant reductions in pup body weights and body weight gains at doses associated with maternal toxicity (150 mg/kg/day and above). At maternal tapentadol doses ≥150 mg/kg/day, a dose-related increase in pup mortality was observed through postnatal Day 4. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tapentadol in women who are pregnant. ### Labor and Delivery - NUCYNTA® is not for use in women during and immediately prior to labor. Occasionally, opioid analgesics may prolong labor by temporarily reducing the strength, duration, and frequency of uterine contractions. However, these effects are not consistent and may be offset by an increased rate of cervical dilatation which tends to shorten labor. - Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate in such situations. ### Nursing Mothers - There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded. - Because of the potential for adverse reactions in nursing infants from NUCYNTA®, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. - Withdrawal symptoms can occur in breast-feeding infants when maternal administration of NUCYNTA® is stopped. ### Pediatric Use - The safety and effectiveness of NUCYNTA® in pediatric patients less than 18 years of age have not been established. ### Geriatic Use - Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA®, 19% were 65 and over, while 5% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The rate of constipation was higher in subjects greater than or equal to 65 years than those less than 65 years (12% vs. 7%). - In general, recommended dosing for elderly patients with normal renal and hepatic function is the same as for younger adult patients with normal renal and hepatic function. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients with the lower range of recommended doses. ### Gender There is no FDA guidance on the use of Tapentadol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tapentadol with respect to specific racial populations. ### Renal Impairment - The safety and effectiveness of NUCYNTA® has not been established in patients with severe renal impairment (CLCR <30 mL/min). Use of NUCYNTA® in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known. ### Hepatic Impairment - Administration of tapentadol resulted in higher exposures and serum levels of tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The dose of NUCYNTA® should be reduced in patients with moderate hepatic impairment (Child-Pugh Score 7 to 9). - Use of NUCYNTA® is not recommended in patients with severe hepatic impairment (Child-Pugh Score 10 to 15). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tapentadol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tapentadol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Tapentadol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tapentadol in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes pulmonary edema, bradycardia, hypotension and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations. ### Management - In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. - The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to tapentadol overdose. Such agents should be administered cautiously to patients who are known, or suspected to be, physically dependent on NUCYNTA®. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. - Because the duration of reversal would be expected to be less than the duration of action of tapentadol in NUCYNTA®, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be given as directed in the product's prescribing information. - In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. ## Chronic Overdose There is limited information regarding Chronic Overdose of Tapentadol in the drug label. # Pharmacology ## Mechanism of Action - Tapentadol is a centrally-acting synthetic analgesic. The exact mechanism of action is unknown. Although the clinical relevance is unclear, preclinical studies have shown that tapentadol is a mu-opioid receptor (MOR) agonist and a norepinephrine reuptake inhibitor (NRI). Analgesia in animal models is derived from both of these properties. ## Structure - NUCYNTA® (tapentadol) is a mu-opioid receptor agonist, supplied in immediate-release film-coated tablets for oral administration, containing 58.24, 87.36 and 116.48 mg of tapentadol hydrochloride in each tablet strength, corresponding to 50, 75, and 100 mg of tapentadol free-base, respectively. The chemical name is 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride. The structural formula is: - The molecular weight of tapentadol HCl is 257.80, and the molecular formula is C14H23NO•HCl. The n-octanol:water partition coefficient log P value is 2.87. The pKa values are 9.34 and 10.45. - In addition to the active ingredient tapentadol HCl, NUCYNTA® tablets also contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone. The film coatings for all tablet strengths contain polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and the colorant FD&C Yellow #6 aluminum lake; the film coatings for the 50 mg and 75 mg tablets also contain the additional colorant D&C Yellow #10 aluminum lake. ## Pharmacodynamics - Tapentadol is 18 times less potent than morphine in binding to the human mu-opioid receptor and is 2–3 times less potent in producing analgesia in animal models. Tapentadol has been shown to inhibit norepinephrine reuptake in the brains of rats resulting in increased norepinephrine concentrations. In preclinical models, the analgesic activity due to the mu-opioid receptor agonist activity of tapentadol can be antagonized by selective mu-opioid antagonists (e.g., naloxone), whereas the norepinephrine reuptake inhibition is sensitive to norepinephrine modulators. Tapentadol exerts its analgesic effects without a pharmacologically active metabolite. - Concentration-Efficacy Relationships - The minimum effective plasma concentration of tapentadol for analgesia varies widely among patients, especially among patients who have been previously treated with agonist opioids. - Concentration-Adverse Experience Relationships - There is a general relationship between increasing opioid plasma concentration and increasing frequency of adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression. - Effects on the Cardiovascular System - There was no effect of therapeutic and supratherapeutic doses of tapentadol on the QT interval. In a randomized, double-blind, placebo- and positive-controlled crossover study, healthy subjects were administered five consecutive doses of NUCYNTA® 100 mg every 6 hours, NUCYNTA® 150 mg every 6 hours, placebo and a single oral dose of moxifloxacin. Similarly, NUCYNTA® had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology). - Tapentadol produces peripheral vasodilation which may result in orthostatic hypotension. - Effects on the Central Nervous System (CNS) - The principal therapeutic action of tapentadol is analgesia. Tapentadol causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Tapentadol depresses the cough reflex by direct effect on the cough center in the medulla. - Tapentadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Overdosage (10)]. Other effects of tapentadol include anxiolysis, euphoria, and feeling of relaxation, drowsiness and changes in mood. - Effects on the Gastrointestinal Tract and on Other Smooth Muscle - Gastric, biliary and pancreatic secretions are decreased by tapentadol. Tapentadol causes a reduction in motility and is associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The end result is constipation. Tapentadol can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi, and transient elevations in serum amylase. Tapentadol may also cause spasm of the sphincter of the urinary bladder. - Effects on the Endocrine System - Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. - Effects on the Immune System - Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. - CNS Depressant/Alcohol Interaction - Additive pharmacodynamic effects may be expected when NUCYNTA® is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. ## Pharmacokinetics - Absorption - The mean absolute bioavailability after single-dose administration (fasting) of NUCYNTA® is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at around 1.25 hours after dosing. - Dose-proportional increases in the Cmax and AUC values of tapentadol have been observed over the 50 to 150 mg dose range. - A multiple (every 6 hour) dose study with doses ranging from 75 to 175 mg tapentadol showed a mean accumulation factor of 1.6 for the parent drug and 1.8 for the major metabolite tapentadol-O-glucuronide, which are primarily determined by the dosing interval and apparent half-life of tapentadol and its metabolite. - Food Effect - The AUC and Cmax increased by 25% and 16%, respectively, when NUCYNTA® was administered after a high-fat, high-calorie breakfast. NUCYNTA® may be given with or without food. - Distribution - Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 L. The plasma protein binding is low and amounts to approximately 20%. - Metabolism and Elimination - In humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized via Phase 2 pathways, and only a small amount is metabolized by Phase 1 oxidative pathways. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% (55% O-glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the conjugated form. A total of 3% of drug was excreted in urine as unchanged drug. Tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Therefore, drug metabolism mediated by cytochrome P450 system is of less importance than phase 2 conjugation. - None of the metabolites contribute to the analgesic activity. - Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal half-life is on average 4 hours after oral administration. The total clearance is 1530 +/- 177 mL/min. - Special Populations - Geriatric Patients - The mean exposure (AUC) to tapentadol was similar in elderly subjects compared to young adults, with a 16% lower mean Cmax observed in the elderly subject group compared to young adult subjects. - Renal Impairment - AUC and Cmax of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild (CLCR = 50 to <80 mL/min), moderate (CLCR = 30 to <50 mL/min), and severe (CLCR = <30 mL/min) renal impairment, the AUC of tapentadol-O-glucuronide was 1.5-, 2.5-, and 5.5-fold higher compared with normal renal function, respectively. - Hepatic Impairment - Administration of NUCYNTA® resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild hepatic impairment group (Child-Pugh Score 5 to 6) and moderate hepatic impairment group (Child-Pugh Score 7 to 9) in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for Cmax; and 1.2 and 1.4, respectively, for t1/2. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment. - Pharmacokinetic Drug Interactions - Tapentadol is mainly metabolized by Phase 2 glucuronidation, a high capacity/low affinity system; therefore, clinically relevant interactions caused by Phase 2 metabolism are unlikely to occur. Naproxen and probenecid increased the AUC of tapentadol by 17% and 57%, respectively. These changes are not considered clinically relevant and no change in dose is required. - No changes in the pharmacokinetic parameters of tapentadol were observed when acetaminophen and acetylsalicylic acid were given concomitantly. - In vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Furthermore, a minor amount of NUCYNTA® is metabolized via the oxidative pathway. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur. - The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively. - Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic drug-drug interactions by displacement from the protein binding site is low. ## Nonclinical Toxicology - Carcinogenesis - Tapentadol was administered to rats (diet) and mice (oral gavage) for two years. - In mice, tapentadol HCl was administered by oral gavage at dosages of 50, 100 and 200 mg/kg/day for 2 years (up to 0.2 times the plasma exposure at the maximum recommended human dose [MRHD] on an area under the time-curve [AUC] basis). No increase in tumor incidence was observed at any dose level. - In rats, tapentadol HCl was administered in diet at dosages of 10, 50, 125 and 250 mg/kg/day for two years (up to 0.2 times in the male rats and 0.6 times in the female rats the MRHD on an AUC basis). No increase in tumor incidence was observed at any dose level. - Mutagenesis - Tapentadol did not induce gene mutations in bacteria, but was clastogenic with metabolic activation in a chromosomal aberration test in V79 cells. The test was repeated and was negative in the presence and absence of metabolic activation. The one positive result for tapentadol was not confirmed in vivo in rats, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, when tested up to the maximum tolerated dose. - Impairment of Fertility - Tapentadol HCl was administered intravenously to male or female rats at dosages of 3, 6, or 12 mg/kg/day (representing exposures of up to approximately 0.4 times the exposure at the MRHD on an AUC basis, based on extrapolation from toxicokinetic analyses in a separate 4-week intravenous study in rats). Tapentadol did not alter fertility at any dose level. Maternal toxicity and adverse effects on embryonic development, including decreased number of implantations, decreased numbers of live conceptuses, and increased pre- and post-implantation losses occurred at dosages ≥6 mg/kg/day. # Clinical Studies - The efficacy and safety of NUCYNTA® in the treatment of moderate to severe acute pain has been established in two randomized, double-blind, placebo- and active-controlled studies of moderate to severe pain from first metatarsal bunionectomy and end-stage degenerative joint disease. - A randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study demonstrated the efficacy of 50 mg, 75 mg, and 100 mg NUCYNTA® given every 4 to 6 hours for 72 hours in patients aged 18 to 80 years experiencing moderate to severe pain following unilateral, first metatarsal bunionectomy surgery. Patients who qualified for the study with a baseline pain score of ≥4 on an 11-point rating scale ranging from 0 to 10 were randomized to 1 of 5 treatments. Patients were allowed to take a second dose of study medication as soon as 1 hour after the first dose on study Day 1, with subsequent dosing every 4 to 6 hours. If rescue analgesics were required, the patients were discontinued for lack of efficacy. Efficacy was evaluated by comparing the sum of pain intensity difference over the first 48 hours (SPID48) versus placebo. NUCYNTA® at each dose provided a greater reduction in pain compared to placebo based on SPID48 values. - For various degrees of improvement from baseline to the 48-hour endpoint, Figure 1 shows the fraction of patients achieving that level of improvement. The figures are cumulative, such that every patient that achieves a 50% reduction in pain from baseline is included in every level of improvement below 50%. Patients who did not complete the 48-hour observation period in the study were assigned 0% improvement. - The proportions of patients who showed reduction in pain intensity at 48 hours of 30% or greater, or 50% or greater were significantly higher in patients treated with NUCYNTA® at each dose versus placebo. - A randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study evaluated the efficacy and safety of 50 mg and 75 mg NUCYNTA® given every 4 to 6 hours during waking hours for 10 days in patients aged 18 to 80 years, experiencing moderate to severe pain from end stage degenerative joint disease of the hip or knee, defined as a 3-day mean pain score of ≥5 on an 11-point pain intensity scale, ranging from 0 to 10. Pain scores were assessed twice daily and assessed the pain the patient had experienced over the previous 12 hours. Patients were allowed to continue non-opioid analgesic therapy for which they had been on a stable regimen before screening throughout the study. Eighty-three percent (83%) of patients in the tapentadol treatment groups and the placebo group took such analgesia during the study. The 75 mg treatment group was dosed at 50 mg for the first day of the study, followed by 75 mg for the remaining nine days. Patients requiring rescue analgesics other than study medication were discontinued for lack of efficacy. Efficacy was evaluated by comparing the sum of pain intensity difference (SPID) versus placebo over the first five days of treatment. NUCYNTA® 50 mg and 75 mg provided improvement in pain compared with placebo based on the 5-Day SPID. - For various degrees of improvement from baseline to the Day 5 endpoint, Figure 2 shows the fraction of patients achieving that level of improvement. The figures are cumulative, such that every patient that achieves a 50% reduction in pain from baseline is included in every level of improvement below 50%. Patients who did not complete the 5-day observation period in the study were assigned 0% improvement. - The proportions of patients who showed reduction in pain intensity at 5 days of 30% or greater, or 50% or greater were significantly higher in patients treated with NUCYNTA® at each dose versus placebo. # How Supplied - NUCYNTA® Tablets are available in the following strengths and packages. All tablets are round and biconvex-shaped. - 50 mg tablets are yellow and debossed with "O-M" on one side and "50" on the other side, and are available in bottles of 100 (NDC 50458-820-04) and hospital unit dose blister packs of 10 (NDC 50458-820-02). - 75 mg tablets are yellow-orange and debossed with "O-M" on one side and "75" on the other side, and are available in bottles of 100 (NDC 50458-830-04) and hospital unit dose blister packs of 10 (NDC 50458-830-02). - 100 mg tablets are orange and debossed with "O-M" on one side and "100" on the other side, and are available in bottles of 100 (NDC 50458-840-04) and hospital unit dose blister packs of 10 (NDC 50458-840-02). - Storage and Handling - Store up to 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature]. Protect from moisture. - Keep NUCYNTA® in a secure place out of reach of children. - NUCYNTA® tablets that are no longer needed should be destroyed by flushing down the toilet. ## Storage There is limited information regarding Tapentadol Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Instruct patients to take NUCYNTA® only as prescribed. - Abuse Potential - Inform patients that NUCYNTA® contains tapentadol, a Schedule II controlled substance that is subject to abuse. Instruct patients not to share NUCYNTA® with others and to take steps to protect NUCYNTA® from theft or misuse. - Life-threatening Respiratory Depression - Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting NUCYNTA® or when the dose is increased. Advise patients how to recognize respiratory depression and to seek medical attention if they are experiencing breathing difficulties. - Accidental Exposure - Instruct patients to take steps to store NUCYNTA® securely. Accidental exposure, especially in children, may results in serious harm or death. Advise patients to dispose of unused NUCYNTA® by flushing the tablets down the toilet. - Important Administration Instructions - Instruct patients how to properly take NUCYNTA®, including the following: - Using NUCYNTA® exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression). - Not discontinuing NUCYNTA® without first discussing the need for a tapering regimen with the prescriber. - Risks from Concomitant Use of Alcohol and other CNS Depressants - Inform patients that the concomitant use of alcohol with NUCYNTA® can increase the risk of life-threatening respiratory depression. Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter drug products that contain alcohol, during treatment with NUCYNTA®. - Inform patients that potentially serious additive effects may occur if NUCYNTA® is used with other CNS depressants, and not to use such drugs unless supervised by a health care provider. - Concurrent use of MAOI - Inform patients not to take NUCYNTA® while using any drugs that inhibit monoamine oxidase. Patients should not start any new medications while taking NUCYNTA®. - Seizures - Inform patients that NUCYNTA® could cause seizures if they are at risk for seizures or have epilepsy. Patients should be advised to stop taking NUCYNTA® if they have a seizure while taking NUCYNTA® and call their healthcare provider right away. - Serotonin Syndrome - Inform patients that NUCYNTA® could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (including Serotonin Reuptake Inhibitors, Serotonin and Norepinephrine Reuptake Inhibitors and tricyclic antidepressants). Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. - Instruct patients to inform their physicians if they are taking or plan to take additional medications, including CNS Depressants, MAO inhibitors, mixed agonists/antagonist opioid analgesics, anticholinergics, SSRIs, SNRIs, or tricyclic antidepressants. - Hypotension - Inform patients that NUCYNTA® may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). - Driving or Operating Heavy Machinery - Inform patients that NUCYNTA® may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication. - Constipation - Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. - Anaphylaxis - Inform patients that anaphylaxis has been reported with ingredients contained in NUCYNTA®. Advise patients how to recognize such a reaction and when to seek medical attention. - Pregnancy - Advise female patients that NUCYNTA® can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant. # Precautions with Alcohol - Alcohol-Tapentadol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - NUCYNTA®[3] # Look-Alike Drug Names There is limited information regarding Tapentadol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Tapentadol
90e6ae5c1629d95caf7ac70b02c948077904a590	wikidoc	Tavaborole	Tavaborole # 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 Tavaborole is an antifungal that is FDA approved for the treatment of onychomycosis of the toenails due to trichophyton rubrum or trichophyton mentagrophytes.. Common adverse reactions include Application site erythema, dermatitis, ingrowing toenail, peeling of skin.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Tavaborole topical solution, 5% is an oxaborole antifungal indicated for the treatment of onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes. - Apply Tavaboroleto affected toenails once daily for 48 weeks. - Tavaboroleshould be applied to the entire toenail surface and under the tip of each toenail being treated. - Tavaboroleis for topical use only and not for oral, ophthalmic, or intravaginal use. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tavaborole in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tavaborole in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tavaborole in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tavaborole in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tavaborole in pediatric patients. # Contraindications - None. # Warnings There is limited information regarding Tavaborole Warnings' in the drug label. # 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. - In two clinical trials, 791 subjects were treated with Tavaborole. The most commonly reported adverse reactions are listed below - A cumulative irritancy study revealed the potential for Tavaboroleto cause skin irritation. There was no evidence that Tavaborole causes contact sensitization. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Tavaborole in the drug label. # Drug Interactions - In vitro studies have shown that tavaborole, at therapeutic concentrations, neither inhibits nor induces cytochrome P450 (CYP450) enzymes. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies with Tavaborolein pregnant women. Tavaborole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Systemic embryofetal development studies were conducted in rats and rabbits and a dermal embryofetal development study was conducted in rabbits. - In an oral embryofetal development study in rats, oral doses of 30, 100, and 300 mg/kg/day tavaborole were administered during the period of organogenesis (gestational days 6-19) to pregnant female rats. In the presence of maternal toxicity, embryofetal toxicity (increased embryofetal resorption and/or deaths) and drug-related skeletal malformations and variations suggestive of delayed development (i.e., a delay in ossification) were noted in fetuses at 300 mg/kg/day tavaborole . No developmental toxicity was noted in rats at 100 mg/kg/day tavaborole (26 times the MRHD based on AUC comparisons). - In an oral embryofetal development study in rabbits, oral doses of 15, 50, and 150 mg/kg/day tavaborole were administered during the period of organogenesis (gestational days 7-19) to pregnant female rabbits. In the presence of maternal toxicity, excessive embryofetal mortality due to post-implantation loss was noted at 150 mg/kg/day tavaborole. No drug related malformations were noted in rabbits at 150 mg/kg/day tavaborole (155 times the MRHD based on AUC comparisons). No embryofetal mortality was noted in rabbits at 50 mg/kg/day tavaborole (16 times the MRHD based on AUC comparisons). - In a dermal embryofetal development study in rabbits, topical doses of 1%, 5%, and 10% tavaborole solution were administered during the period of organogenesis (gestational days 6-28) to pregnant female rabbits. A dose dependent increase in dermal irritation at the treatment site was noted at 5% and 10% tavaborole solution. A decrease in fetal bodyweight was noted at 10% tavaborole solution. No drug related malformations were noted in rabbits at 10% tavaborole solution (36 times the MRHD based on AUC comparisons). No embryofetal toxicity was noted in rabbits at 5% tavaborole solution (26 times the MRHD based on AUC comparisons).Nonteratogenic effects: - In an oral pre- and post-natal development study in rats, oral doses of 15, 60, and 100 mg/kg/day tavaborole were administered from the beginning of organogenesis (gestation day 6) through the end of lactation (lactation day 20). In the presence of minimal maternal toxicity, no embryofetal toxicity or effects on postnatal development were noted at 100 mg/kg/day (29 times the MRHD based on AUC comparisons). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tavaborole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tavaborole during labor and delivery. ### Nursing Mothers - It is not known whether tavaborole is excreted in human milk following topical application of KERYDIN. Because many drugs are excreted in human milk, caution should be exercised when Tavaboroleis administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - In clinical trials of 791 subjects who were exposed to KERYDIN, 19% were 65 years of age and over, while 4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Tavaborole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tavaborole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tavaborole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tavaborole in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tavaborole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tavaborole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Tavaborole in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tavaborole in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Tavaborole in the drug label. # Pharmacology ## Mechanism of Action - The mechanism of action of tavaborole is inhibition of fungal protein synthesis. Tavaborole inhibits protein synthesis by inhibition of an aminoacyl-transfer ribonucleic acid (tRNA) synthetase (AARS). - Tavaborole has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections : - Trichophyton rubrum - Trichophyton mentagrophytes - Trichophyton mentagrophytes and Trichophyton rubrum strains from isolates collected in the clinical trials have not demonstrated resistance following repeated exposure to tavaborole. ## Structure - Tavaborole(tavaborole) topical solution, 5% contains tavaborole, 5% (w/w) in a clear, colorless alcohol-based solution for topical use. The active ingredient, tavaborole, is an oxaborole antifungal with the chemical name of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole. The chemical formula is C7H6BFO2, the molecular weight is 151.93 and the structural formula is: - Tavaborole is a white to off-white powder. It is slightly soluble in water and freely soluble in ethanol and propylene glycol. - Each mL of Tavaborolecontains 43.5 mg of tavaborole. Inactive ingredients include alcohol, edetate calcium disodium, and propylene glycol. ## Pharmacodynamics - At therapeutic doses, Tavaboroleis not expected to prolong QTc to any clinically relevant extent. ## Pharmacokinetics - Tavaborole undergoes extensive metabolism. Renal excretion is the major route of elimination. - In a clinical pharmacology trial of six healthy adult male volunteers who received a single topical application of 5% 14C-tavaborole solution, tavaborole conjugates and metabolites were shown to be excreted primarily in the urine. - The pharmacokinetics of tavaborole was investigated in 24 subjects with distal subungual onychomycosis involving at least 4 toenails (including at least 1 great toenail) following a single dose and a 2-week daily topical application of 200 μL of a 5% solution of tavaborole to all ten toenails and 2 mm of skin surrounding each toenail. Steady state was achieved after 14 days of dosing. After a single dose, the mean (± standard deviation) peak concentration (Cmax) of tavaborole was 3.54 ± 2.26 ng/mL (n=21 with measurable concentrations, range 0.618-10.2 ng/mL, LLOQ=0.5 ng/mL), and the mean AUClast was 44.4 ± 25.5 nghr/mL (n=21). After 2 weeks of daily dosing, the mean Cmax was 5.17 ± 3.47 ng/mL (n=24, range 1.51-12.8 ng/mL), and the mean AUCτ was 75.8 ± 44.5 nghr/mL. ## Nonclinical Toxicology - In an oral carcinogenicity study in Sprague-Dawley rats, oral doses of 12.5, 25, and 50 mg/kg/day tavaborole were administered to rats once daily for 104 weeks. No drug related neoplastic findings were noted at oral doses up to 50 mg/kg/day tavaborole (14 times the MRHD based on AUC comparisons). - In a dermal carcinogenicity study in CD-1 mice, topical doses of 5%, 10%, and 15% tavaborole solution were administered to mice once daily for 104 weeks. No drug related neoplastic findings were noted at topical doses up to 15% tavaborole solution (89 times the MRHD based on AUC comparisons). - Tavaborole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Human lymphocyte chromosomal aberration assay) and one in vivo genotoxicity test (rat micronucleus assay). - No effects on fertility were observed in male and female rats that were administered oral doses up to 300 mg/kg/day tavaborole (107 times the MRHD based on AUC comparisons) prior to and during early pregnancy. # Clinical Studies - The efficacy and safety of Tavaborole was evaluated in two multicenter, double-blind, randomized, vehicle-controlled trials. Tavaboroleor vehicle was applied once daily for 48 weeks in subjects with 20% to 60% clinical involvement of the target toenail, without dermatophytomas or lunula (matrix) involvement. - A total of 1194 subjects (795 KERYDIN, 399 Vehicle) 18 to 88 years of age, 82% male, 84% white, participated in these two trials. Efficacy assessments were made at 52 weeks following a 48-week treatment period. - The Complete Cure efficacy endpoint included negative mycology (negative KOH wet mount and negative fungal culture) and Completely Clear Nail (no clinical evidence of onychomycosis as evidenced by a normal toenail plate, no onycholysis, and no subungual hyperkeratosis). Efficacy results from the two trials are summarized in # How Supplied - Tavaborole(tavaborole) topical solution, 5% is a clear, colorless solution supplied in an amber glass bottle with a screw cap. At initial use, the screw cap is replaced with the dropper assembly. - Tavaborole(tavaborole) topical solution, 5% is supplied in the following presentations: - NDC 55724-111-11: One 12 mL bottle containing 10 mL of solution with one glass pointed-tip dropper - NDC 55724-111-21: One 10 mL bottle containing 4 mL of solution with one glass pointed-tip dropper ## Storage - Store at 20–25°C (68–77°F); excursions permitted to 15–30°C (59–86°F) . - CAUTION: Flammable. Keep away from heat and flame. - Discard product within 3 months after insertion of the dropper. - Keep bottle tightly closed. Keep out of reach of children. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - The patient should be told the following: - Use Tavaborole as directed by a health care professional. - Tavaborole is for external use only. Avoid contact with eyes, mouth, or vagina. Avoid contact with skin other than skin immediately surrounding the treated nail(s). Wipe away excess solution from surrounding skin. - Clean and dry nails prior to Tavaboroleuse. Tavaborole should be applied to completely cover the nail surface and also applied under the tip of each nail being treated. Allow solution to dry following application. - Inform a health care professional if the area of application shows signs of persistent irritation (for example, redness, itching, swelling). - Forty-eight (48) weeks of daily application with tavaborole is considered the full treatment for toenail onychomycosis. - Do not use Tavaborolefor any disorder other than that for which it is prescribed - Product is flammable. Avoid use near heat or open flame. # Precautions with Alcohol - Alcohol-Tavaborole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names # Look-Alike Drug Names There is limited information regarding Tavaborole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Tavaborole Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, 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. # Overview Tavaborole is an antifungal that is FDA approved for the treatment of onychomycosis of the toenails due to trichophyton rubrum or trichophyton mentagrophytes.. Common adverse reactions include Application site erythema, dermatitis, ingrowing toenail, peeling of skin.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Tavaborole topical solution, 5% is an oxaborole antifungal indicated for the treatment of onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes. - Apply Tavaboroleto affected toenails once daily for 48 weeks. - Tavaboroleshould be applied to the entire toenail surface and under the tip of each toenail being treated. - Tavaboroleis for topical use only and not for oral, ophthalmic, or intravaginal use. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tavaborole in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tavaborole in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tavaborole in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tavaborole in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tavaborole in pediatric patients. # Contraindications - None. # Warnings There is limited information regarding Tavaborole Warnings' in the drug label. # 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. - In two clinical trials, 791 subjects were treated with Tavaborole. The most commonly reported adverse reactions are listed below - A cumulative irritancy study revealed the potential for Tavaboroleto cause skin irritation. There was no evidence that Tavaborole causes contact sensitization. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Tavaborole in the drug label. # Drug Interactions - In vitro studies have shown that tavaborole, at therapeutic concentrations, neither inhibits nor induces cytochrome P450 (CYP450) enzymes. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies with Tavaborolein pregnant women. Tavaborole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Systemic embryofetal development studies were conducted in rats and rabbits and a dermal embryofetal development study was conducted in rabbits. - In an oral embryofetal development study in rats, oral doses of 30, 100, and 300 mg/kg/day tavaborole were administered during the period of organogenesis (gestational days 6-19) to pregnant female rats. In the presence of maternal toxicity, embryofetal toxicity (increased embryofetal resorption and/or deaths) and drug-related skeletal malformations and variations suggestive of delayed development (i.e., a delay in ossification) were noted in fetuses at 300 mg/kg/day tavaborole [570 times the Maximum Recommended Human Dose (MRHD) based on Area Under the Curve (AUC) comparisons]. No developmental toxicity was noted in rats at 100 mg/kg/day tavaborole (26 times the MRHD based on AUC comparisons). - In an oral embryofetal development study in rabbits, oral doses of 15, 50, and 150 mg/kg/day tavaborole were administered during the period of organogenesis (gestational days 7-19) to pregnant female rabbits. In the presence of maternal toxicity, excessive embryofetal mortality due to post-implantation loss was noted at 150 mg/kg/day tavaborole. No drug related malformations were noted in rabbits at 150 mg/kg/day tavaborole (155 times the MRHD based on AUC comparisons). No embryofetal mortality was noted in rabbits at 50 mg/kg/day tavaborole (16 times the MRHD based on AUC comparisons). - In a dermal embryofetal development study in rabbits, topical doses of 1%, 5%, and 10% tavaborole solution were administered during the period of organogenesis (gestational days 6-28) to pregnant female rabbits. A dose dependent increase in dermal irritation at the treatment site was noted at 5% and 10% tavaborole solution. A decrease in fetal bodyweight was noted at 10% tavaborole solution. No drug related malformations were noted in rabbits at 10% tavaborole solution (36 times the MRHD based on AUC comparisons). No embryofetal toxicity was noted in rabbits at 5% tavaborole solution (26 times the MRHD based on AUC comparisons).Nonteratogenic effects: - In an oral pre- and post-natal development study in rats, oral doses of 15, 60, and 100 mg/kg/day tavaborole were administered from the beginning of organogenesis (gestation day 6) through the end of lactation (lactation day 20). In the presence of minimal maternal toxicity, no embryofetal toxicity or effects on postnatal development were noted at 100 mg/kg/day (29 times the MRHD based on AUC comparisons). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tavaborole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tavaborole during labor and delivery. ### Nursing Mothers - It is not known whether tavaborole is excreted in human milk following topical application of KERYDIN. Because many drugs are excreted in human milk, caution should be exercised when Tavaboroleis administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - In clinical trials of 791 subjects who were exposed to KERYDIN, 19% were 65 years of age and over, while 4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Tavaborole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tavaborole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tavaborole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tavaborole in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tavaborole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tavaborole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Tavaborole in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tavaborole in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Tavaborole in the drug label. # Pharmacology ## Mechanism of Action - The mechanism of action of tavaborole is inhibition of fungal protein synthesis. Tavaborole inhibits protein synthesis by inhibition of an aminoacyl-transfer ribonucleic acid (tRNA) synthetase (AARS). - Tavaborole has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections : - Trichophyton rubrum - Trichophyton mentagrophytes - Trichophyton mentagrophytes and Trichophyton rubrum strains from isolates collected in the clinical trials have not demonstrated resistance following repeated exposure to tavaborole. ## Structure - Tavaborole(tavaborole) topical solution, 5% contains tavaborole, 5% (w/w) in a clear, colorless alcohol-based solution for topical use. The active ingredient, tavaborole, is an oxaborole antifungal with the chemical name of 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole. The chemical formula is C7H6BFO2, the molecular weight is 151.93 and the structural formula is: - Tavaborole is a white to off-white powder. It is slightly soluble in water and freely soluble in ethanol and propylene glycol. - Each mL of Tavaborolecontains 43.5 mg of tavaborole. Inactive ingredients include alcohol, edetate calcium disodium, and propylene glycol. ## Pharmacodynamics - At therapeutic doses, Tavaboroleis not expected to prolong QTc to any clinically relevant extent. ## Pharmacokinetics - Tavaborole undergoes extensive metabolism. Renal excretion is the major route of elimination. - In a clinical pharmacology trial of six healthy adult male volunteers who received a single topical application of 5% 14C-tavaborole solution, tavaborole conjugates and metabolites were shown to be excreted primarily in the urine. - The pharmacokinetics of tavaborole was investigated in 24 subjects with distal subungual onychomycosis involving at least 4 toenails (including at least 1 great toenail) following a single dose and a 2-week daily topical application of 200 μL of a 5% solution of tavaborole to all ten toenails and 2 mm of skin surrounding each toenail. Steady state was achieved after 14 days of dosing. After a single dose, the mean (± standard deviation) peak concentration (Cmax) of tavaborole was 3.54 ± 2.26 ng/mL (n=21 with measurable concentrations, range 0.618-10.2 ng/mL, LLOQ=0.5 ng/mL), and the mean AUClast was 44.4 ± 25.5 nghr/mL (n=21). After 2 weeks of daily dosing, the mean Cmax was 5.17 ± 3.47 ng/mL (n=24, range 1.51-12.8 ng/mL), and the mean AUCτ was 75.8 ± 44.5 nghr/mL. ## Nonclinical Toxicology - In an oral carcinogenicity study in Sprague-Dawley rats, oral doses of 12.5, 25, and 50 mg/kg/day tavaborole were administered to rats once daily for 104 weeks. No drug related neoplastic findings were noted at oral doses up to 50 mg/kg/day tavaborole (14 times the MRHD based on AUC comparisons). - In a dermal carcinogenicity study in CD-1 mice, topical doses of 5%, 10%, and 15% tavaborole solution were administered to mice once daily for 104 weeks. No drug related neoplastic findings were noted at topical doses up to 15% tavaborole solution (89 times the MRHD based on AUC comparisons). - Tavaborole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Human lymphocyte chromosomal aberration assay) and one in vivo genotoxicity test (rat micronucleus assay). - No effects on fertility were observed in male and female rats that were administered oral doses up to 300 mg/kg/day tavaborole (107 times the MRHD based on AUC comparisons) prior to and during early pregnancy. # Clinical Studies - The efficacy and safety of Tavaborole was evaluated in two multicenter, double-blind, randomized, vehicle-controlled trials. Tavaboroleor vehicle was applied once daily for 48 weeks in subjects with 20% to 60% clinical involvement of the target toenail, without dermatophytomas or lunula (matrix) involvement. - A total of 1194 subjects (795 KERYDIN, 399 Vehicle) 18 to 88 years of age, 82% male, 84% white, participated in these two trials. Efficacy assessments were made at 52 weeks following a 48-week treatment period. - The Complete Cure efficacy endpoint included negative mycology (negative KOH wet mount and negative fungal culture) and Completely Clear Nail (no clinical evidence of onychomycosis as evidenced by a normal toenail plate, no onycholysis, and no subungual hyperkeratosis). Efficacy results from the two trials are summarized in # How Supplied - Tavaborole(tavaborole) topical solution, 5% is a clear, colorless solution supplied in an amber glass bottle with a screw cap. At initial use, the screw cap is replaced with the dropper assembly. - Tavaborole(tavaborole) topical solution, 5% is supplied in the following presentations: - NDC 55724-111-11: One 12 mL bottle containing 10 mL of solution with one glass pointed-tip dropper - NDC 55724-111-21: One 10 mL bottle containing 4 mL of solution with one glass pointed-tip dropper ## Storage - Store at 20–25°C (68–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. - CAUTION: Flammable. Keep away from heat and flame. - Discard product within 3 months after insertion of the dropper. - Keep bottle tightly closed. Keep out of reach of children. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - The patient should be told the following: - Use Tavaborole as directed by a health care professional. - Tavaborole is for external use only. Avoid contact with eyes, mouth, or vagina. Avoid contact with skin other than skin immediately surrounding the treated nail(s). Wipe away excess solution from surrounding skin. - Clean and dry nails prior to Tavaboroleuse. Tavaborole should be applied to completely cover the nail surface and also applied under the tip of each nail being treated. Allow solution to dry following application. - Inform a health care professional if the area of application shows signs of persistent irritation (for example, redness, itching, swelling). - Forty-eight (48) weeks of daily application with tavaborole is considered the full treatment for toenail onychomycosis. - Do not use Tavaborolefor any disorder other than that for which it is prescribed - Product is flammable. Avoid use near heat or open flame. # Precautions with Alcohol - Alcohol-Tavaborole 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 There is limited information regarding Tavaborole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Tavaborole
9e4cc9cf5fe7709167e8f400f0dfc242ab94254f	wikidoc	Tazarotene	Tazarotene # 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 Tazarotene is a retinoid that is FDA approved for the {{{indicationType}}} of plaque psoriasis and acne vulgaris. Common adverse reactions include pruritus, erythema, desquamation, dry skin, and burning sensation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - It is recommended that treatment starts with TAZORAC® Cream, 0.05%, with strength increased to 0.1% if tolerated and medically indicated. Apply a thin film (2 mg/cm2) of TAZORAC® Cream once per day, in the evening, to cover only the psoriatic lesions. If a bath or shower is taken prior to application, the skin should be dry before applying the cream. If emollients are used, they should be applied at least an hour before application of TAZORAC® Cream. Because unaffected skin may be more susceptible to irritation, application of TAZORAC® Cream to these areas should be carefully avoided. - Cleanse the face gently. After the skin is dry, apply a thin layer (2 mg/cm2) of TAZORAC® Cream 0.1% once per day, in the evening, to the skin areas where acne lesions appear. Use enough to cover the entire affected area. - TAZORAC® Cream is for topical use only. TAZORAC® Cream is not for ophthalmic, oral, or intravaginal use. If contact with eyes occurs, rinse thoroughly with water. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tazarotene in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tazarotene in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Cleanse the face gently. After the skin is dry, apply a thin layer (2 mg/cm2) of TAZORAC® Cream 0.1% once per day, in the evening, to the skin areas where acne lesions appear. Use enough to cover the entire affected area. - TAZORAC® Cream is for topical use only. TAZORAC® Cream is not for ophthalmic, oral, or intravaginal use. If contact with eyes occurs, rinse thoroughly with water. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tazarotene in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tazarotene in pediatric patients. # Contraindications - Pregnancy - TAZORAC® Cream may cause fetal harm when administered to a pregnant woman. Tazarotene elicits teratogenic and developmental effects associated with retinoids after topical or systemic administration in rats and rabbits. TAZORAC® Cream is contraindicated in women who are pregnant or may become pregnant. - If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential hazard to the fetus. - Hypersensitivity - TAZORAC® Cream is contraindicated in individuals who have shown hypersensitivity to any of its components. # Warnings ### Precautions - Embryofetal Toxicity - Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In patients treated topically over sufficient body surface area, exposure could be in the same order of magnitude as in orally treated animals. Although there may be less systemic exposure in the treatment of acne of the face alone due to less surface area for application, tazarotene is a teratogenic substance, and it is not known what level of exposure is required for teratogenicity in humans. - There were thirteen reported pregnancies in subjects who participated in the clinical trials for topical tazarotene. Nine of the subjects were found to have been treated with topical tazarotene, and the other four had been treated with vehicle. One of the subjects who was treated with tazarotene cream elected to terminate the pregnancy for non-medical reasons unrelated to treatment. The other eight pregnant women who were inadvertently exposed to topical tazarotene during clinical trials subsequently delivered apparently healthy babies. As the exact timing and extent of exposure in relation to the gestation times are not certain, the significance of these findings is unknown. - Females of Child-bearing Potential - Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when TAZORAC® Cream is used. The possibility that a female of child-bearing potential is pregnant at the time of institution of therapy should be considered. - A negative result for pregnancy test should be obtained within 2 weeks prior to TAZORAC® Cream therapy. TAZORAC® Cream therapy should begin during a menstrual period. - Local Irritation - Application of TAZORAC® Cream may cause excessive irritation in the skin of certain sensitive individuals. Some individuals may experience excessive pruritus, burning, skin redness or peeling. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the dosing should be reduced to an interval the patient can tolerate. However, efficacy at reduced frequency of application has not been established. Alternatively, patients with psoriasis who are being treated with the 0.1% concentration can be switched to the lower concentration. Frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Therapy can be resumed, or the drug concentration or frequency of application can be increased as the patient becomes able to tolerate treatment. - Concomitant topical medications and cosmetics that have a strong drying effect should be avoided. It is also advisable to "rest" a patient's skin until the effects of such preparations subside before use of TAZORAC® Cream is begun. - TAZORAC® Cream, should not be used on eczematous skin, as it may cause severe irritation. - Weather extremes, such as wind or cold, may be more irritating to patients using TAZORAC® Cream. - Photosensitivity and Risk for Sunburn - Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be avoided unless deemed medically necessary, and in such cases, exposure should be minimized during the use of TAZORAC® Cream. Patients must be warned to use sunscreens (minimum SPF of 15) and protective clothing when using TAZORAC® Cream. Patients with sunburn should be advised not to use TAZORAC® Cream until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using TAZORAC® Cream. - TAZORAC® Cream should be administered with caution if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity. # 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 clinical practice. - In human dermal safety trials, TAZORAC® Cream, 0.05% and 0.1% did not induce allergic contact sensitization, phototoxicity, or photoallergy. - Psoriasis - The most frequent adverse reactions reported with TAZORAC® Cream, 0.05% and 0.1% occurring in 10 to 23% of subjects, in descending order, included pruritus, erythema, and burning. Reactions occurring in greater than 1 to less than 10% of subjects, in descending order, included irritation, desquamation, stinging, contact dermatitis, dermatitis, eczema, worsening of psoriasis, skin pain, rash, hypertriglyceridemia, dry skin, skin inflammation, and peripheral edema. - TAZORAC® Cream, 0.1% was associated with a greater degree of local irritation than the 0.05% cream. The rates of irritation adverse reactions reported during psoriasis trials with TAZORAC® Cream, 0.1% were 0.1-0.4% higher than those reported for TAZORAC® Cream, 0.05%. - Acne - The most frequent adverse reactions reported during clinical trials with TAZORAC® Cream 0.1% in the treatment of acne, occurring in 10-30% of subjects, in descending order included desquamation, dry skin, erythema, and burning sensation. Reactions occurring in 1 to 5% of subjects included pruritus, irritation, face pain, and stinging. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Tazarotene in the drug label. # Drug Interactions - No formal drug-drug interaction studies were conducted with TAZORAC® Cream. - In a trial of 27 healthy female subjects between the ages of 20–55 years receiving a combination oral contraceptive tablet containing 1 mg norethindrone and 35 mcg ethinyl estradiol, concomitant use of tazarotene administered as 1.1 mg orally (mean ± SD Cmax and AUC0-24 of tazarotenic acid were 28.9 ± 9.4 ng/mL and 120.6 ± 28.5 ng∙hr/mL) did not affect the pharmacokinetics of norethindrone and ethinyl estradiol over a complete cycle. - The impact of tazarotene on the pharmacokinetics of progestin only oral contraceptives (i.e., minipills) has not been evaluated. Close # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - There are no adequate and well-controlled studies with TAZORAC® Cream in pregnant women. TAZORAC® Cream is contraindicated in women who are or may become pregnant. Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when TAZORAC® Cream is used. The possibility that a female of child-bearing potential is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy test should be obtained within 2 weeks prior to TAZORAC® Cream therapy, which should begin during a menstrual period. Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In subjects treated topically over sufficient body surface area, exposure could be in the same order of magnitude as in orally treated animals. Although there may be less systemic exposure in the treatment of acne of the face alone due to less surface area for application, tazarotene is a teratogenic substance, and it is not known what level of exposure is required for teratogenicity in humans. - In rats, a tazarotene gel, 0.05% formulation, administered topically during gestation days 6 through 17 at 0.25 mg/kg/day resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day tazarotene gel during gestation days 6 through 18 were noted with single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies. - Systemic exposure to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 1.2 and 13 times, respectively, that in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study, and 4 and 44 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - When tazarotene was given orally to experimental animals, developmental delays were seen in rats; and teratogenic effects and post-implantation loss were observed in rats and rabbits at doses producing 1.1 and 26 times, respectively, the systemic exposure seen in a psoriatic patient treated topically with tazarotene cream, 0.1% at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study and 3.5 and 85 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, a number of classic developmental effects of retinoids were observed including decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights. A low incidence of retinoid-related malformations at that dose was observed. The dose produced a systemic exposure 3.4 times that observed in a psoriatic patient treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 35% body surface area and 11 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tazarotene in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tazarotene during labor and delivery. ### Nursing Mothers - After single topical doses of 14C-tazarotene gel to the skin of lactating rats, radioactivity was detected in milk, suggesting that there would be transfer of drug-related material to the offspring via milk. It is not known whether this drug is excreted in human milk. The safe use of TAZORAC® Cream during lactation has not been established. A decision should be made whether to discontinue breast-feeding or to discontinue TAZORAC® Cream therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. ### Pediatric Use - The safety and efficacy of tazarotene have not been established in patients with psoriasis under the age of 18 years, or in patients with acne under the age of 12 years. ### Geriatic Use - TAZORAC® Cream for the treatment of acne has not been clinically tested in persons 65 years of age or older. - Of the total number of subjects in clinical trials of TAZORAC® Cream for plaque psoriasis, 120 were over the age of 65. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Currently there is no other clinical experience on the differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Tazarotene with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tazarotene with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tazarotene in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tazarotene in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tazarotene in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tazarotene in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Tazarotene in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tazarotene in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Excessive topical use of TAZORAC® Cream, 0.05% and 0.1% may lead to marked redness, peeling, or discomfort. - TAZORAC® Cream, 0.05% and 0.1% are not for oral use. Oral ingestion of the drug may lead to the same adverse effects as those associated with excessive oral intake of Vitamin A (hypervitaminosis A) or other retinoids. ### Management - If oral ingestion occurs, the patient should be monitored, and appropriate supportive measures should be administered as necessary. ## Chronic Overdose There is limited information regarding Chronic Overdose of Tazarotene in the drug label. # Pharmacology ## Mechanism of Action - Tazarotene is a retinoid prodrug which is converted to its active form, the carboxylic acid of tazarotene, by deesterification. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ, but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings is unknown. ## Structure - TAZORAC® (tazarotene) Cream, 0.05% and 0.1% is for topical use and contains the active ingredient, tazarotene. Each gram of TAZORAC® Cream, 0.05% and 0.1% contains 0.5 and 1 mg of tazarotene, respectively in a white cream base. - Tazarotene is a member of the acetylenic class of retinoids. Chemically, tazarotene is ethyl 6-nicotinate. The compound has an empirical formula of C21H21NO2S and molecular weight of 351.46. The structural formula is shown below: - TAZORAC® Cream contains the following inactive ingredients: benzyl alcohol 1%; carbomer 1342; carbomer homopolymer type B; edetate disodium; medium chain triglycerides; mineral oil; purified water; sodium hydroxide; sodium thiosulfate; and sorbitan monooleate. ## Pharmacodynamics - The pharmacodynamics of TAZORAC® Cream are unknown. ## Pharmacokinetics - Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Little parent compound could be detected in the plasma. Tazarotenic acid was highly bound to plasma proteins (greater than 99%). Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways. The half-life of tazarotenic acid was approximately 18 hours, following topical application of tazarotene to normal, acne or psoriatic skin. - In a multiple dose trial with a once daily dose for 14 consecutive days in 9 psoriatic subjects (male=5; female=4), measured doses of TAZORAC® Cream, 0.1% were applied by medical staff to involved skin without occlusion (5 to 35% of total body surface area: mean ± SD: 14 ± 11%). The Cmax of tazarotenic acid was 2.31 ± 2.78 ng/mL occurring 8 hours after the final dose, and the AUC0-24h was 31.2 ± 35.2 ng∙hr/mL on day 15 in the five subjects who were administered clinical doses of 2 mg cream/cm2. - During clinical trials with TAZORAC® Cream, 0.05% or 0.1% treatment for plaque psoriasis, three out of 139 subjects with their systemic exposure monitored had detectable plasma tazarotene concentrations, with the highest value at 0.09 ng/mL. Tazarotenic acid was detected in 78 out of 139 subjects (LLOQ = 0.05 ng/mL). Three subjects using tazarotene cream 0.1% had plasma tazarotenic acid concentrations greater than 1 ng/mL. The highest value was 2.4 ng/mL. However, because of the variations in the time of blood sampling, the area of psoriasis involvement, and the dose of tazarotene applied, actual maximal plasma levels are unknown. - TAZORAC® Cream 0.1% was applied once daily to either the face (N=8) or to 15% of body surface area (N=10) of female subjects with moderate to severe acne vulgaris. The mean Cmax and AUC values of tazarotenic acid peaked at day 15 for both dosing groups during a 29 day treatment period. Mean Cmax and AUC0-24h values of tazarotenic acid from subjects in the 15% body surface area dosing group were more than 10 times higher than those from subjects in the face-only dosing group. The single highest Cmax throughout the trial period was 1.91 ng/mL on day 15 in the exaggerated dosing group. In the face-only group, the mean ± SD values of Cmax and AUC0-24h of tazarotenic acid on day 15 were 0.10 ± 0.06 ng/mL and 1.54 ± 1.01 ng∙hr/mL, respectively, whereas in the 15% body surface area dosing group, the mean ± SD values of Cmax and AUC0-24h of tazarotenic acid on day 15 were 1.20 ± 0.41 ng/mL and 17.01 ± 6.15 ng∙hr/mL, respectively. The steady state pharmacokinetics of tazarotenic acid had been reached by day 8 in the face-only and by day 15 in the 15% body surface area dosing groups. - In a Phase 3 clinical trial, TAZORAC® Cream, 0.1% was applied once daily for 12 weeks to each of 48 subjects (22 females and 26 males) with facial acne vulgaris. The mean ± SD values of plasma tazarotenic acid at weeks 4 and 8 were 0.078 ± 0.073 ng/mL (N=47) and 0.052 ± 0.037 ng/mL (N=42), respectively. The highest observed individual plasma tazarotenic acid concentration was 0.41 ng/mL at week 4 from a female subject. The magnitude of plasma tazarotenic acid concentrations appears to be independent of gender, age, and body weight. ## Nonclinical Toxicology - Carcinogenesis - A long-term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications of increased carcinogenic risks. Based on pharmacokinetic data from a shorter term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic exposure in the rat equivalent to 0.6 times that seen in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/kg/cm2 over a 35% body surface area in a controlled pharmacokinetic study. This estimated systemic exposure in rats was 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% cream at 2 mg/cm2 over a 15% body surface area. - A long-term topical application study of up to 0.1% of tazarotene in a gel formulation in mice terminated at 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcinogenic effects when compared to vehicle control animals. Systemic exposures at the highest dose was 3.9 times that seen in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study, and 13 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - In evaluation of photo co-carcinogenicity, median time to onset of tumors was decreased, and the number of tumors increased in hairless mice following chronic topical dosing with intercurrent exposure to ultraviolet radiation at tazarotene concentrations of 0.001%, 0.005%, and 0.01% in a gel formulation for up to 40 weeks. - Mutagenesis - Tazarotene was found to be non-mutagenic in the Ames assay and did not produce structural chromosomal aberrations in a human lymphocyte assay. Tazarotene was non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in the in vivo mouse micronucleus test. - Impairment of Fertility - No impairment of fertility occurred in rats when male animals were treated for 70 days prior to mating and female animals were treated for 14 days prior to mating and continuing through gestation and lactation with topical doses of tazarotene gel up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat would be equivalent to 0.6 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study, and 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of up to 1 mg/kg/day tazarotene. That dose produced a systemic exposure that was 1.9 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area, and 6.3 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - No impairment of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuing through gestation day 7 with oral doses up to 2 mg/kg/day of tazarotene. However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at that dose . That dose produced a systemic exposure that was 3.4 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area and 11 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - Reproductive capabilities of F1 animals, including F2 survival and development, were not affected by topical administration of tazarotene gel to female F0 parental rats from gestation day 16 through lactation day 20 at the maximum tolerated dose of 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat would be equivalent to 0.6 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area, and 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. # Clinical Studies - In two 12-week vehicle-controlled clinical trials, TAZORAC® Cream, 0.05% and 0.1% was significantly more effective than vehicle in reducing the severity of stable plaque psoriasis. TAZORAC® Cream, 0.1% and 0.05% demonstrated superiority over vehicle cream as early as 1 week and 2 weeks, respectively, after starting treatment. - In these trials, the primary efficacy endpoint was “clinical success,” defined as the proportion of subjects with none, minimal, or mild overall lesional assessment at Week 12, and shown in Table 1. “Clinical success” was also significantly greater with TAZORAC® Cream, 0.05% and 0.1% versus vehicle at most follow-up visits. - At the end of 12 weeks of treatment, TAZORAC® Cream, 0.05% and 0.1% was consistently superior to vehicle in reducing the plaque thickness of psoriasis. Improvements in erythema and scaling were generally significantly greater with TAZORAC® Cream, 0.05% and 0.1% than with vehicle. TAZORAC® Cream, 0.1% was also generally more effective than TAZORAC® Cream, 0.05% in reducing the severity of the individual signs of disease. However, TAZORAC® Cream, 0.1% was associated with a greater degree of local irritation than TAZORAC® Cream, 0.05%. - Acne - In two large vehicle-controlled trials, subjects age 12 years and over with facial acne vulgaris of a severity suitable for monotherapy with a topical agent were enrolled. After face cleansing in the evening, TAZORAC® Cream, 0.1% was applied once daily to the entire face as a thin layer. TAZORAC® Cream, 0.1% was significantly more effective than vehicle in the treatment of facial acne vulgaris. Efficacy results after 12 weeks of treatment are shown in Table 3: # How Supplied - TAZORAC® Cream is a white cream available in concentrations of 0.05% and 0.1%. It is supplied in a collapsible aluminum tube with a tamper-evident aluminum membrane over the opening and a white polypropylene screw cap, in 30 g and 60 g sizes. - Storage: Store at 20°C to 25°C (68°F to 77°F). Excursions permitted from -5°C to 30°C (23°F to 86°F). ## Storage There is limited information regarding Tazarotene Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient of the following: - Fetal risk associated with TAZORAC® Cream for females of childbearing potential. Advise patients to use an effective method of contraception during treatment to avoid pregnancy. Advise the patient to stop medication if she becomes pregnant and call her doctor. - For the patient with psoriasis, apply TAZORAC® Cream only to psoriasis skin lesions, avoiding uninvolved skin. - If undue irritation (redness, peeling, or discomfort) occurs, reduce frequency of application or temporarily interrupt treatment. Treatment may be resumed once irritation subsides. - Moisturizers may be used as frequently as desired. - Patients with psoriasis may use a cream or lotion to soften or moisten skin at least 1 hour before applying TAZORAC® Cream. - Avoid exposure of the treated areas to either natural or artificial sunlight, including tanning beds and sun lamps. Use sunscreen and protective clothing if exposure to sunlight is unavoidable when using TAZORAC® Cream. - Avoid contact with the eyes. If TAZORAC® Cream gets in or near their eyes, rinse thoroughly with water. - Not for ophthalmic, oral, or intravaginal use. - Wash their hands after applying TAZORAC® Cream. # Precautions with Alcohol - Alcohol-Tazarotene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TAZORAC® # Look-Alike Drug Names There is limited information regarding Tazarotene Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Tazarotene 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. # Overview Tazarotene is a retinoid that is FDA approved for the {{{indicationType}}} of plaque psoriasis and acne vulgaris. Common adverse reactions include pruritus, erythema, desquamation, dry skin, and burning sensation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - It is recommended that treatment starts with TAZORAC® Cream, 0.05%, with strength increased to 0.1% if tolerated and medically indicated. Apply a thin film (2 mg/cm2) of TAZORAC® Cream once per day, in the evening, to cover only the psoriatic lesions. If a bath or shower is taken prior to application, the skin should be dry before applying the cream. If emollients are used, they should be applied at least an hour before application of TAZORAC® Cream. Because unaffected skin may be more susceptible to irritation, application of TAZORAC® Cream to these areas should be carefully avoided. - Cleanse the face gently. After the skin is dry, apply a thin layer (2 mg/cm2) of TAZORAC® Cream 0.1% once per day, in the evening, to the skin areas where acne lesions appear. Use enough to cover the entire affected area. - TAZORAC® Cream is for topical use only. TAZORAC® Cream is not for ophthalmic, oral, or intravaginal use. If contact with eyes occurs, rinse thoroughly with water. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tazarotene in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tazarotene in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Cleanse the face gently. After the skin is dry, apply a thin layer (2 mg/cm2) of TAZORAC® Cream 0.1% once per day, in the evening, to the skin areas where acne lesions appear. Use enough to cover the entire affected area. - TAZORAC® Cream is for topical use only. TAZORAC® Cream is not for ophthalmic, oral, or intravaginal use. If contact with eyes occurs, rinse thoroughly with water. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tazarotene in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tazarotene in pediatric patients. # Contraindications - Pregnancy - TAZORAC® Cream may cause fetal harm when administered to a pregnant woman. Tazarotene elicits teratogenic and developmental effects associated with retinoids after topical or systemic administration in rats and rabbits. TAZORAC® Cream is contraindicated in women who are pregnant or may become pregnant. - If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential hazard to the fetus. - Hypersensitivity - TAZORAC® Cream is contraindicated in individuals who have shown hypersensitivity to any of its components. # Warnings ### Precautions - Embryofetal Toxicity - Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In patients treated topically over sufficient body surface area, exposure could be in the same order of magnitude as in orally treated animals. Although there may be less systemic exposure in the treatment of acne of the face alone due to less surface area for application, tazarotene is a teratogenic substance, and it is not known what level of exposure is required for teratogenicity in humans. - There were thirteen reported pregnancies in subjects who participated in the clinical trials for topical tazarotene. Nine of the subjects were found to have been treated with topical tazarotene, and the other four had been treated with vehicle. One of the subjects who was treated with tazarotene cream elected to terminate the pregnancy for non-medical reasons unrelated to treatment. The other eight pregnant women who were inadvertently exposed to topical tazarotene during clinical trials subsequently delivered apparently healthy babies. As the exact timing and extent of exposure in relation to the gestation times are not certain, the significance of these findings is unknown. - Females of Child-bearing Potential - Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when TAZORAC® Cream is used. The possibility that a female of child-bearing potential is pregnant at the time of institution of therapy should be considered. - A negative result for pregnancy test should be obtained within 2 weeks prior to TAZORAC® Cream therapy. TAZORAC® Cream therapy should begin during a menstrual period. - Local Irritation - Application of TAZORAC® Cream may cause excessive irritation in the skin of certain sensitive individuals. Some individuals may experience excessive pruritus, burning, skin redness or peeling. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the dosing should be reduced to an interval the patient can tolerate. However, efficacy at reduced frequency of application has not been established. Alternatively, patients with psoriasis who are being treated with the 0.1% concentration can be switched to the lower concentration. Frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Therapy can be resumed, or the drug concentration or frequency of application can be increased as the patient becomes able to tolerate treatment. - Concomitant topical medications and cosmetics that have a strong drying effect should be avoided. It is also advisable to "rest" a patient's skin until the effects of such preparations subside before use of TAZORAC® Cream is begun. - TAZORAC® Cream, should not be used on eczematous skin, as it may cause severe irritation. - Weather extremes, such as wind or cold, may be more irritating to patients using TAZORAC® Cream. - Photosensitivity and Risk for Sunburn - Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be avoided unless deemed medically necessary, and in such cases, exposure should be minimized during the use of TAZORAC® Cream. Patients must be warned to use sunscreens (minimum SPF of 15) and protective clothing when using TAZORAC® Cream. Patients with sunburn should be advised not to use TAZORAC® Cream until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using TAZORAC® Cream. - TAZORAC® Cream should be administered with caution if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity. # 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 clinical practice. - In human dermal safety trials, TAZORAC® Cream, 0.05% and 0.1% did not induce allergic contact sensitization, phototoxicity, or photoallergy. - Psoriasis - The most frequent adverse reactions reported with TAZORAC® Cream, 0.05% and 0.1% occurring in 10 to 23% of subjects, in descending order, included pruritus, erythema, and burning. Reactions occurring in greater than 1 to less than 10% of subjects, in descending order, included irritation, desquamation, stinging, contact dermatitis, dermatitis, eczema, worsening of psoriasis, skin pain, rash, hypertriglyceridemia, dry skin, skin inflammation, and peripheral edema. - TAZORAC® Cream, 0.1% was associated with a greater degree of local irritation than the 0.05% cream. The rates of irritation adverse reactions reported during psoriasis trials with TAZORAC® Cream, 0.1% were 0.1-0.4% higher than those reported for TAZORAC® Cream, 0.05%. - Acne - The most frequent adverse reactions reported during clinical trials with TAZORAC® Cream 0.1% in the treatment of acne, occurring in 10-30% of subjects, in descending order included desquamation, dry skin, erythema, and burning sensation. Reactions occurring in 1 to 5% of subjects included pruritus, irritation, face pain, and stinging. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Tazarotene in the drug label. # Drug Interactions - No formal drug-drug interaction studies were conducted with TAZORAC® Cream. - In a trial of 27 healthy female subjects between the ages of 20–55 years receiving a combination oral contraceptive tablet containing 1 mg norethindrone and 35 mcg ethinyl estradiol, concomitant use of tazarotene administered as 1.1 mg orally (mean ± SD Cmax and AUC0-24 of tazarotenic acid were 28.9 ± 9.4 ng/mL and 120.6 ± 28.5 ng∙hr/mL) did not affect the pharmacokinetics of norethindrone and ethinyl estradiol over a complete cycle. - The impact of tazarotene on the pharmacokinetics of progestin only oral contraceptives (i.e., minipills) has not been evaluated. Close # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - There are no adequate and well-controlled studies with TAZORAC® Cream in pregnant women. TAZORAC® Cream is contraindicated in women who are or may become pregnant. Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when TAZORAC® Cream is used. The possibility that a female of child-bearing potential is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy test should be obtained within 2 weeks prior to TAZORAC® Cream therapy, which should begin during a menstrual period. Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In subjects treated topically over sufficient body surface area, exposure could be in the same order of magnitude as in orally treated animals. Although there may be less systemic exposure in the treatment of acne of the face alone due to less surface area for application, tazarotene is a teratogenic substance, and it is not known what level of exposure is required for teratogenicity in humans. - In rats, a tazarotene gel, 0.05% formulation, administered topically during gestation days 6 through 17 at 0.25 mg/kg/day resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day tazarotene gel during gestation days 6 through 18 were noted with single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies. - Systemic exposure to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 1.2 and 13 times, respectively, that in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study, and 4 and 44 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - When tazarotene was given orally to experimental animals, developmental delays were seen in rats; and teratogenic effects and post-implantation loss were observed in rats and rabbits at doses producing 1.1 and 26 times, respectively, the systemic exposure seen in a psoriatic patient treated topically with tazarotene cream, 0.1% at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study and 3.5 and 85 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, a number of classic developmental effects of retinoids were observed including decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights. A low incidence of retinoid-related malformations at that dose was observed. The dose produced a systemic exposure 3.4 times that observed in a psoriatic patient treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 35% body surface area and 11 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tazarotene in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tazarotene during labor and delivery. ### Nursing Mothers - After single topical doses of 14C-tazarotene gel to the skin of lactating rats, radioactivity was detected in milk, suggesting that there would be transfer of drug-related material to the offspring via milk. It is not known whether this drug is excreted in human milk. The safe use of TAZORAC® Cream during lactation has not been established. A decision should be made whether to discontinue breast-feeding or to discontinue TAZORAC® Cream therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. ### Pediatric Use - The safety and efficacy of tazarotene have not been established in patients with psoriasis under the age of 18 years, or in patients with acne under the age of 12 years. ### Geriatic Use - TAZORAC® Cream for the treatment of acne has not been clinically tested in persons 65 years of age or older. - Of the total number of subjects in clinical trials of TAZORAC® Cream for plaque psoriasis, 120 were over the age of 65. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Currently there is no other clinical experience on the differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Tazarotene with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tazarotene with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tazarotene in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tazarotene in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tazarotene in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tazarotene in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Tazarotene in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tazarotene in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Excessive topical use of TAZORAC® Cream, 0.05% and 0.1% may lead to marked redness, peeling, or discomfort. - TAZORAC® Cream, 0.05% and 0.1% are not for oral use. Oral ingestion of the drug may lead to the same adverse effects as those associated with excessive oral intake of Vitamin A (hypervitaminosis A) or other retinoids. ### Management - If oral ingestion occurs, the patient should be monitored, and appropriate supportive measures should be administered as necessary. ## Chronic Overdose There is limited information regarding Chronic Overdose of Tazarotene in the drug label. # Pharmacology ## Mechanism of Action - Tazarotene is a retinoid prodrug which is converted to its active form, the carboxylic acid of tazarotene, by deesterification. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ, but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings is unknown. ## Structure - TAZORAC® (tazarotene) Cream, 0.05% and 0.1% is for topical use and contains the active ingredient, tazarotene. Each gram of TAZORAC® Cream, 0.05% and 0.1% contains 0.5 and 1 mg of tazarotene, respectively in a white cream base. - Tazarotene is a member of the acetylenic class of retinoids. Chemically, tazarotene is ethyl 6-[(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate. The compound has an empirical formula of C21H21NO2S and molecular weight of 351.46. The structural formula is shown below: - TAZORAC® Cream contains the following inactive ingredients: benzyl alcohol 1%; carbomer 1342; carbomer homopolymer type B; edetate disodium; medium chain triglycerides; mineral oil; purified water; sodium hydroxide; sodium thiosulfate; and sorbitan monooleate. ## Pharmacodynamics - The pharmacodynamics of TAZORAC® Cream are unknown. ## Pharmacokinetics - Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Little parent compound could be detected in the plasma. Tazarotenic acid was highly bound to plasma proteins (greater than 99%). Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways. The half-life of tazarotenic acid was approximately 18 hours, following topical application of tazarotene to normal, acne or psoriatic skin. - In a multiple dose trial with a once daily dose for 14 consecutive days in 9 psoriatic subjects (male=5; female=4), measured doses of TAZORAC® Cream, 0.1% were applied by medical staff to involved skin without occlusion (5 to 35% of total body surface area: mean ± SD: 14 ± 11%). The Cmax of tazarotenic acid was 2.31 ± 2.78 ng/mL occurring 8 hours after the final dose, and the AUC0-24h was 31.2 ± 35.2 ng∙hr/mL on day 15 in the five subjects who were administered clinical doses of 2 mg cream/cm2. - During clinical trials with TAZORAC® Cream, 0.05% or 0.1% treatment for plaque psoriasis, three out of 139 subjects with their systemic exposure monitored had detectable plasma tazarotene concentrations, with the highest value at 0.09 ng/mL. Tazarotenic acid was detected in 78 out of 139 subjects (LLOQ = 0.05 ng/mL). Three subjects using tazarotene cream 0.1% had plasma tazarotenic acid concentrations greater than 1 ng/mL. The highest value was 2.4 ng/mL. However, because of the variations in the time of blood sampling, the area of psoriasis involvement, and the dose of tazarotene applied, actual maximal plasma levels are unknown. - TAZORAC® Cream 0.1% was applied once daily to either the face (N=8) or to 15% of body surface area (N=10) of female subjects with moderate to severe acne vulgaris. The mean Cmax and AUC values of tazarotenic acid peaked at day 15 for both dosing groups during a 29 day treatment period. Mean Cmax and AUC0-24h values of tazarotenic acid from subjects in the 15% body surface area dosing group were more than 10 times higher than those from subjects in the face-only dosing group. The single highest Cmax throughout the trial period was 1.91 ng/mL on day 15 in the exaggerated dosing group. In the face-only group, the mean ± SD values of Cmax and AUC0-24h of tazarotenic acid on day 15 were 0.10 ± 0.06 ng/mL and 1.54 ± 1.01 ng∙hr/mL, respectively, whereas in the 15% body surface area dosing group, the mean ± SD values of Cmax and AUC0-24h of tazarotenic acid on day 15 were 1.20 ± 0.41 ng/mL and 17.01 ± 6.15 ng∙hr/mL, respectively. The steady state pharmacokinetics of tazarotenic acid had been reached by day 8 in the face-only and by day 15 in the 15% body surface area dosing groups. - In a Phase 3 clinical trial, TAZORAC® Cream, 0.1% was applied once daily for 12 weeks to each of 48 subjects (22 females and 26 males) with facial acne vulgaris. The mean ± SD values of plasma tazarotenic acid at weeks 4 and 8 were 0.078 ± 0.073 ng/mL (N=47) and 0.052 ± 0.037 ng/mL (N=42), respectively. The highest observed individual plasma tazarotenic acid concentration was 0.41 ng/mL at week 4 from a female subject. The magnitude of plasma tazarotenic acid concentrations appears to be independent of gender, age, and body weight. ## Nonclinical Toxicology - Carcinogenesis - A long-term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications of increased carcinogenic risks. Based on pharmacokinetic data from a shorter term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic exposure in the rat equivalent to 0.6 times that seen in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/kg/cm2 over a 35% body surface area in a controlled pharmacokinetic study. This estimated systemic exposure in rats was 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% cream at 2 mg/cm2 over a 15% body surface area. - A long-term topical application study of up to 0.1% of tazarotene in a gel formulation in mice terminated at 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcinogenic effects when compared to vehicle control animals. Systemic exposures at the highest dose was 3.9 times that seen in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study, and 13 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - In evaluation of photo co-carcinogenicity, median time to onset of tumors was decreased, and the number of tumors increased in hairless mice following chronic topical dosing with intercurrent exposure to ultraviolet radiation at tazarotene concentrations of 0.001%, 0.005%, and 0.01% in a gel formulation for up to 40 weeks. - Mutagenesis - Tazarotene was found to be non-mutagenic in the Ames assay and did not produce structural chromosomal aberrations in a human lymphocyte assay. Tazarotene was non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in the in vivo mouse micronucleus test. - Impairment of Fertility - No impairment of fertility occurred in rats when male animals were treated for 70 days prior to mating and female animals were treated for 14 days prior to mating and continuing through gestation and lactation with topical doses of tazarotene gel up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat would be equivalent to 0.6 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study, and 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of up to 1 mg/kg/day tazarotene. That dose produced a systemic exposure that was 1.9 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area, and 6.3 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - No impairment of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuing through gestation day 7 with oral doses up to 2 mg/kg/day of tazarotene. However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at that dose [see Use in Specific Populations (8.1)]. That dose produced a systemic exposure that was 3.4 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area and 11 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - Reproductive capabilities of F1 animals, including F2 survival and development, were not affected by topical administration of tazarotene gel to female F0 parental rats from gestation day 16 through lactation day 20 at the maximum tolerated dose of 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat would be equivalent to 0.6 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area, and 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. # Clinical Studies - In two 12-week vehicle-controlled clinical trials, TAZORAC® Cream, 0.05% and 0.1% was significantly more effective than vehicle in reducing the severity of stable plaque psoriasis. TAZORAC® Cream, 0.1% and 0.05% demonstrated superiority over vehicle cream as early as 1 week and 2 weeks, respectively, after starting treatment. - In these trials, the primary efficacy endpoint was “clinical success,” defined as the proportion of subjects with none, minimal, or mild overall lesional assessment at Week 12, and shown in Table 1. “Clinical success” was also significantly greater with TAZORAC® Cream, 0.05% and 0.1% versus vehicle at most follow-up visits. - At the end of 12 weeks of treatment, TAZORAC® Cream, 0.05% and 0.1% was consistently superior to vehicle in reducing the plaque thickness of psoriasis. Improvements in erythema and scaling were generally significantly greater with TAZORAC® Cream, 0.05% and 0.1% than with vehicle. TAZORAC® Cream, 0.1% was also generally more effective than TAZORAC® Cream, 0.05% in reducing the severity of the individual signs of disease. However, TAZORAC® Cream, 0.1% was associated with a greater degree of local irritation than TAZORAC® Cream, 0.05%. - Acne - In two large vehicle-controlled trials, subjects age 12 years and over with facial acne vulgaris of a severity suitable for monotherapy with a topical agent were enrolled. After face cleansing in the evening, TAZORAC® Cream, 0.1% was applied once daily to the entire face as a thin layer. TAZORAC® Cream, 0.1% was significantly more effective than vehicle in the treatment of facial acne vulgaris. Efficacy results after 12 weeks of treatment are shown in Table 3: # How Supplied - TAZORAC® Cream is a white cream available in concentrations of 0.05% and 0.1%. It is supplied in a collapsible aluminum tube with a tamper-evident aluminum membrane over the opening and a white polypropylene screw cap, in 30 g and 60 g sizes. - Storage: Store at 20°C to 25°C (68°F to 77°F). Excursions permitted from -5°C to 30°C (23°F to 86°F). ## Storage There is limited information regarding Tazarotene Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient of the following: - Fetal risk associated with TAZORAC® Cream for females of childbearing potential. Advise patients to use an effective method of contraception during treatment to avoid pregnancy. Advise the patient to stop medication if she becomes pregnant and call her doctor. - For the patient with psoriasis, apply TAZORAC® Cream only to psoriasis skin lesions, avoiding uninvolved skin. - If undue irritation (redness, peeling, or discomfort) occurs, reduce frequency of application or temporarily interrupt treatment. Treatment may be resumed once irritation subsides. - Moisturizers may be used as frequently as desired. - Patients with psoriasis may use a cream or lotion to soften or moisten skin at least 1 hour before applying TAZORAC® Cream. - Avoid exposure of the treated areas to either natural or artificial sunlight, including tanning beds and sun lamps. Use sunscreen and protective clothing if exposure to sunlight is unavoidable when using TAZORAC® Cream. - Avoid contact with the eyes. If TAZORAC® Cream gets in or near their eyes, rinse thoroughly with water. - Not for ophthalmic, oral, or intravaginal use. - Wash their hands after applying TAZORAC® Cream. # Precautions with Alcohol - Alcohol-Tazarotene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TAZORAC®[1] # Look-Alike Drug Names There is limited information regarding Tazarotene Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Tazarotene
6411ffeafba9c54293a9d6c7833e4d0a90bd1c46	wikidoc	Technetium	Technetium # Overview Technetium (Template:PronEng) is the lightest chemical element with no stable isotope. It is a synthetic element. It has atomic number 43 and is given the symbol Tc. The chemical properties of this silvery grey, crystalline transition metal are intermediate between rhenium and manganese. Its short-lived gamma-emitting nuclear isomer 99mTc (technetium-99m) is used in nuclear medicine for a wide variety of diagnostic tests. 99Tc is used as a gamma ray-free source of beta particles. The pertechnetate ion (TcO4-) has been suggested as a strong anodic corrosion inhibitor for mild steel in closed cooling systems. Before the element was discovered, many of the properties of element 43 were predicted by Dmitri Mendeleev. Mendeleev noted a gap in his periodic table and called the element ekamanganese(Em). In 1937 its isotope 97Tc became the first predominantly artificial element to be produced, hence its name (from the Greek τεχνητός, meaning "artificial"). Most technetium produced on Earth is a by-product of fission of uranium-235 in nuclear reactors and is extracted from nuclear fuel rods. No isotope of technetium has a half-life longer than 4.2 million years (98Tc), so its detection in red giants in 1952 helped bolster the theory that stars can produce heavier elements. On Earth, technetium occurs in trace but measurable quantities as a product of spontaneous fission in uranium ore or by neutron capture in molybdenum ores. # Characteristics Technetium is a silvery-grey radioactive metal with an appearance similar to platinum. However, it is commonly obtained as a grey powder. Its position in the periodic table is between rhenium and manganese and as predicted by the periodic law its properties are intermediate between those two elements. Technetium is unusual among the lighter elements in that it has no stable isotopes. Only technetium and promethium have no stable isotopes, but are followed by elements which do. Technetium is therefore extremely rare on Earth. Technetium plays no natural biological role and is not normally found in the human body. The metal form of technetium slowly tarnishes in moist air. Its oxides are TcO2 and Tc2O7. Under oxidizing conditions technetium (VII) will exist as the pertechnetate ion, TcO4-. Common oxidation states of technetium include 0, +2, +4, +5, +6 and +7. Technetium will burn in oxygen when in powder form. It dissolves in aqua regia, nitric acid, and concentrated sulfuric acid, but it is not soluble in hydrochloric acid. It has characteristic spectral lines at 363 nm, 403 nm, 410 nm, 426 nm, 430 nm, and 485 nm. The metal form is slightly paramagnetic, meaning its magnetic dipoles align with external magnetic fields even though technetium is not normally magnetic. The crystal structure of the metal is hexagonal close-packed. Pure metallic single-crystal technetium becomes a type II superconductor at 7.46 K; irregular crystals and trace impurities raise this temperature to 11.2 K for 99.9% pure technetium powder. Below this temperature technetium has a very high magnetic penetration depth, the largest among the elements apart from niobium. Technetium is produced in quantity by nuclear fission, and spreads more readily than many radionuclides. In spite of the importance of understanding its toxicity in animals and humans, experimental evidence is scant. It appears to have low chemical toxicity. Its radiological toxicity (per unit of mass) is a function of compound, type of radiation for the isotope in question, and the isotope half-life. Technetium-99m is particularly attractive for medical applications, as the radiation from this isotope is a gamma ray with the same wavelength as X-rays used for common medical diagnostic X-ray applications, giving it adequate penetration while causing minimal damage for a gamma photon. This, plus the extremely short half-life of this metastable nuclear isomer, followed by the relatively long half-life of the daughter isotope Tc-99 which allows it to be eliminated from the body before it decays. This leads to a relatively low dose of administered radiation in biologically dose-equivalent amounts (sieverts) for a typical Tc-99m based nuclear scan (see more on this subject below). All isotopes of technetium must be handled carefully. The most common isotope, technetium-99, is a weak beta emitter; such radiation is stopped by the walls of laboratory glassware. Soft X-rays are emitted when the beta particles are stopped, but as long as the body is kept more than 30 cm away these should pose no problem. The primary hazard when working with technetium is inhalation of dust; such radioactive contamination in the lungs can pose a significant cancer risk. For most work, careful handling in a fume hood is sufficient; a glove box is not needed. # Applications ## Nuclear medicine 99mTc ("m" indicates that this is a metastable nuclear isomer) is used in radioactive isotope medical tests, for example as a radioactive tracer that medical equipment can detect in the human body. It is well suited to the role because it emits readily detectable 140 keV gamma rays, and its half-life is 6.01 hours (meaning that about seven eighths of it decays to 99Tc in 24 hours). Klaus Schwochau's book Technetium lists 31 radiopharmaceuticals based on 99mTc for imaging and functional studies of the brain, myocardium, thyroid, lungs, liver, gallbladder, kidneys, skeleton, blood, and tumors. Immunoscintigraphy incorporates 99mTc into a monoclonal antibody, an immune system protein capable of binding to cancer cells. A few hours after injection, medical equipment is used to detect the gamma rays emitted by the 99mTc; higher concentrations indicate where the tumor is. This technique is particularly useful for detecting hard-to-find cancers, such as those affecting the intestine. These modified antibodies are sold by the German company Hoechst (now part of Sanofi-Aventis) under the name "Scintium". When 99mTc is combined with a tin compound it binds to red blood cells and can therefore be used to map circulatory system disorders. It is commonly used to detect gastrointestinal bleeding sites. A pyrophosphate ion with 99mTc adheres to calcium deposits in damaged heart muscle, making it useful to gauge damage after a heart attack. The sulfur colloid of 99mTc is scavenged by the spleen, making it possible to image the structure of the spleen. Radiation exposure due to diagnostic treatment involving Tc-99m can be kept low. Because 99mTc has a short half-life and high energy gamma (allowing small amounts to be easily detected), its quick decay into the far-less radioactive 99Tc results in relatively less total radiation dose to the patient, per unit of initial activity after administration. In the form administered in these medical tests (usually pertechnetate) both isotopes are quickly eliminated from the body, generally within a few days. Technetium for nuclear medicine purposes is usually extracted from technetium-99m generators. 95mTc, with a half-life of 61 days, is used as a radioactive tracer to study the movement of technetium in the environment and in plant and animal systems. ## Industrial/Chemical Technetium-99 decays almost entirely by beta decay, emitting beta particles with consistent low energies and no accompanying gamma rays. Moreover, its long half-life means that this emission decreases very slowly with time. It can also be extracted to a high chemical and isotopic purity from radioactive waste. For these reasons, it is a NIST standard beta emitter, used for equipment calibration. Technetium-99 has also been proposed for use in optoelectric and nanoscale nuclear batteries. Like rhenium and palladium, technetium can serve as a catalyst. For certain reactions, for example the dehydrogenation of isopropyl alcohol, it is a far more effective catalyst than either rhenium or palladium. Of course, its radioactivity is a major problem in finding safe applications. Under certain circumstances, a small concentration (5×10−5 mol/L) of the pertechnetate ion in water can protect iron and carbon steels from corrosion. For this reason, pertechnetate has been suggested as a possible anodic corrosion inhibitor for steel, although technetium's radioactivity poses problems for strictly chemical uses such as these. While (for example) CrO42− can also inhibit corrosion, it requires a concentration ten times as high. In one experiment, a test specimen was kept in an aqueous solution of pertechnetate for 20 years and was still uncorroded. The mechanism by which pertechnetate prevents corrosion is not well-understood, but seems to involve the reversible formation of a thin surface layer. One theory holds that the pertechnetate reacts with the steel surface to form a layer of technetium dioxide which prevents further corrosion; the same effect explains how iron powder can be used to remove pertechnetate from water. (Activated carbon can also be used for the same effect.) The effect disappears rapidly if the concentration of pertechnetate falls below the minimum concentration or if too high a concentration of other ions is added. As noted, the radioactive nature of technetium (3 MBq per liter at the concentrations required) makes this corrosion protection impractical in almost all situations. Nevertheless, corrosion protection by pertechnetate ions was proposed (but never adopted) for use in boiling water reactors. # History ## Search for element 43 For a number of years there was a gap in the periodic table between molybdenum (element 42) and ruthenium (element 44). Many early researchers were eager to be the first to discover and name the missing element; its location in the table suggested that it should be easier to find than other undiscovered elements. It was first thought to have been found in platinum ores in 1828. It was given the name polinium but it turned out to be impure iridium. Then in 1846 the element ilmenium was claimed to have been discovered but was determined to be impure niobium. This mistake was repeated in 1847 with the "discovery" of pelopium. Dmitri Mendeleev predicted that this missing element, as part of other predictions, would be chemically similar to manganese and gave it the name ekamanganese. In 1877, the Russian chemist Serge Kern reported discovering the missing element in platinum ore. Kern named what he thought was the new element davyum, after the noted English chemist Sir Humphry Davy, but it was determined to be a mixture of iridium, rhodium and iron. Another candidate, lucium, followed in 1896 but it was determined to be yttrium. Then in 1908 the Japanese chemist Masataka Ogawa found evidence in the mineral thorianite which he thought indicated the presence of element 43. Ogawa named the element nipponium, after Japan (which is Nippon in Japanese). In 2004 H. K Yoshihara utilized "a record of X-ray spectrum of Ogawa's nipponium sample from thorianite was contained in a photographic plate preserved by his family. The spectrum was read and indicated the absence of the element 43 and the presence of the element 75 (rhenium)." German chemists Walter Noddack, Otto Berg and Ida Tacke (later Mrs. Noddack) reported the discovery of element 75 and element 43 in 1925 and named element 43 masurium (after Masuria in eastern Prussia, now in Poland, the region where Walter Noddack's family originated). The group bombarded columbite with a beam of electrons and deduced element 43 was present by examining X-ray diffraction spectrograms. The wavelength of the X-rays produced is related to the atomic number by a formula derived by Henry Moseley in 1913. The team claimed to detect a faint X-ray signal at a wavelength produced by element 43. Contemporary experimenters could not replicate the discovery, and in fact it was dismissed as an error for many years. In 1998 John T. Armstrong of the National Institute of Standards and Technology ran "computer simulations" of the 1925 experiments and obtained results quite close to those reported by the Noddack team. He claimed that this was further supported by work published by David Curtis of the Los Alamos National Laboratory measuring the (tiny) natural occurrence of technetium. However, the Noddack's experimental results have never been reproduced, and they were unable to isolate any element 43. Debate still exists as to whether the 1925 team actually did discover element 43. ## Official discovery and later history Discovery of element 43 was finally confirmed in a 1937 experiment at the University of Palermo in Sicily conducted by Carlo Perrier and Emilio Segrè. In the summer of 1936 Segrè and his wife visited the United States, first New York at Columbia University, where he had spent time the previous summer, and then Berkeley at Ernest O. Lawrence's Radiation Laboratory. He persuaded cyclotron inventor Lawrence to let him take back some discarded cyclotron parts that had become radioactive. In early 1937 Lawrence mailed him a molybdenum foil that had been part of the deflector in the cyclotron. Segrè enlisted his experienced chemist colleague Perrier to attempt to prove through comparative chemistry that the molybdenum activity was indeed Z = 43, an element not existent in nature because of its instability against nuclear decay. With considerable difficulty they finally succeeded in isolating three distinct decay periods (90, 80, and 50 days) that eventually turned out to be two isotopes, 95Tc and 97Tc, of technetium, the name given later by Perrier and Segrè to the first man-made element. University of Palermo officials wanted them to name their discovery panormium, after the Latin name for Palermo, Panormus. The researchers instead named element 43 after the Greek word τεχνητός, meaning "artificial", since it was the first element to be artificially produced. Segrè returned to Berkeley and immediately sought out Glenn T. Seaborg. They isolated the technetium-99m isotope which is now used in some 10,000,000 medical diagnostic procedures annually. In 1952 astronomer Paul W. Merrill in California detected the spectral signature of technetium (in particular, light at 403.1 nm, 423.8 nm, 426.8 nm, and 429.7 nm) in light from S-type red giants. These massive stars near the end of their lives were rich in this short-lived element, meaning nuclear reactions within the stars must be producing it. This evidence was used to bolster the then unproven theory that stars are where nucleosynthesis of the heavier elements occurs. More recently, such observations provided evidence that elements were being formed by neutron capture in the s-process. Since its discovery, there have been many searches in terrestrial materials for natural sources. In 1962, technetium-99 was isolated and identified in pitchblende from the Belgian Congo in extremely small quantities (about 0.2 ng/kg); there it originates as a spontaneous fission product of uranium-238. This discovery was made by B.T. Kenna and P.K. Kuroda. There is also evidence that the Oklo natural nuclear fission reactor produced significant amounts of technetium-99, which has since decayed to ruthenium-99. # Occurrence and production Since technetium is unstable, only minute traces occur naturally in the Earth's crust as a spontaneous fission product of uranium. In 1999 David Curtis (see above) estimated that a kilogram of uranium contains 1 nanogram (1×10−9 g) of technetium. Extraterrestrial technetium was found in some red giant stars (S-, M-, and N-types) that contain an absorption line in their spectrum indicating the presence of this element. ## Byproduct production of Tc-99 in fission wastes In contrast with the rare natural occurrence, bulk quantities of technetium-99 are produced each year from spent nuclear fuel rods, which contain various fission products. The fission of a gram of uranium-235 in nuclear reactors yields 27 mg of 99Tc, giving technetium a fission product yield of 6.1%. Other fissile isotopes also produce similar yields of technetium, e.g. 4.9% from uranium-233 or 6.21% from plutonium-239. It is estimated that up to 1994, about 49,000 TBq (78 metric tons) of technetium was produced in nuclear reactors, which is by far the dominant source of terrestrial technetium. However, only a fraction of the production is used commercially. As of 2005, technetium-99 is available to holders of an ORNL permit for US$83/g plus packing charges. Since the yield of technetium-99 as a product of the nuclear fission of both uranium-235 and plutonium-239 is moderate, it is present in radioactive waste of fission reactors and is produced when a fission bomb is detonated. The amount of artificially produced technetium in the environment exceeds its natural occurrence to a large extent. This is due to release by atmospheric nuclear testing along with the disposal and processing of high-level radioactive waste. Due to its high fission yield and relatively high half-life, technetium-99 is one of the main components of nuclear waste. Its decay, measured in becquerels per amount of spent fuel, is dominant at about 104 to 106 years after the creation of the nuclear waste. An estimated 160 TBq (about 250 kg) of technetium-99 was released into the environment up to 1994 by atmospheric nuclear tests. The amount of technetium-99 from nuclear reactors released into the environment up to 1986 is estimated to be on the order of 1000 TBq (about 1600 kg), primarily by nuclear fuel reprocessing; most of this was discharged into the sea. In recent years, reprocessing methods have improved to reduce emissions, but as of 2005 the primary release of technetium-99 into the environment is by the Sellafield plant, which released an estimated 550 TBq (about 900 kg) from 1995–1999 into the Irish Sea. From 2000 onwards the amount has been limited by regulation to 90 TBq (about 140 kg) per year. As a result of nuclear fuel reprocessing, technetium has been discharged into the sea in a number of locations, and some seafood contains tiny but measurable quantities. For example, lobster from west Cumbria contains small amounts of technetium. The anaerobic, spore-forming bacteria in the Clostridium genus are able to reduce Tc(VII) to Tc(IV). Clostridia bacteria play a role in reducing iron, manganese and uranium, thereby affecting these elements' solubility in soil and sediments. Their ability to reduce technetium may determine a large part of Tc's mobility in industrial wastes and other subsurface environments. The long half-life of technetium-99 and its ability to form an anionic species makes it (along with 129I) a major concern when considering long-term disposal of high-level radioactive waste. In addition, many of the processes designed to remove fission products from medium-active process streams in reprocessing plants are designed to remove cationic species like caesium (e.g., 137Cs) and strontium (e.g.,90Sr). Hence the pertechnetate is able to escape through these treatment processes. Current disposal options favor burial in geologically stable rock. The primary danger with such a course is that the waste is likely to come into contact with water, which could leach radioactive contamination into the environment. The anionic pertechnetate and iodide are less able to absorb onto the surfaces of minerals so they are likely to be more mobile. By comparison plutonium, uranium, and caesium are much more able to bind to soil particles. For this reason, the environmental chemistry of technetium is an active area of research. An alternative disposal method, transmutation, has been demonstrated at CERN for technetium-99. This transmutation process is one in which the technetium (99Tc as a metal target) is bombarded with neutrons to form the shortlived 100Tc (half life = 16 seconds) which decays by beta decay to ruthenium (100Ru). If recovery of usable ruthenium is a goal, an extremely pure technetium target is needed; if small traces of the minor actinides such as americium and curium are present in the target, they are likely to undergo fission and form more fission products which increase the radioactivity of the irradiated target. The formation of 106Ru (half life 374 days) from the fresh fission is likely to increase the activity of the final ruthenium metal, which will then require a longer cooling time after irradiation before the ruthenium can be used. The actual production of technetium-99 from spent nuclear fuel is a long process. During fuel reprocessing, it appears in the waste liquid, which is highly radioactive. After sitting for several years, the radioactivity has fallen to a point where extraction of the long-lived isotopes, including technetium-99, becomes feasible. Several chemical extraction processes are used yielding technetium-99 metal of high purity. ## Neutron activation of molybdenum or other pure elements The meta stable (a state where the nucleus is in an excited state) isotope 99mTc is produced as a fission product from the fission of uranium or plutonium in nuclear reactors. Because used fuel is allowed to stand for several years before reprocessing, all 99Mo and 99mTc will have decayed by the time that the fission products are separated from the major actinides in conventional nuclear reprocessing. The PUREX raffinate will contain a high concentration of technetium as TcO4- but almost all of this will be 99Tc. The vast majority of the 99mTc used in medical work is formed from 99Mo which is formed by the neutron activation of 98Mo. 99Mo has a half-life of 67 hours, so short-lived 99mTc (half-life: 6 hours), which results from its decay, is being constantly produced. The hospital then chemically extracts the technetium from the solution by using a technetium-99m generator ("technetium cow", also occasionally called a "molybdenum cow"). The normal technetium cow is an alumina column which contains molybdenum-98; in as much as aluminium has a small neutron cross section, it is convenient for an alumina column bearing inactive 98Mo to be irradiated with neutrons to make the radioactive Mo-99 column for the technetium cow. By working in this way, there is no need for the complex chemical steps which would be required to separate molybdenum from a fission product mixture. This alternative method requires that an enriched uranium target be irradiated with neutrons to form 99Mo as a fission product, then separated. Other technetium isotopes are not produced in significant quantities by fission; when needed, they are manufactured by neutron irradiation of parent isotopes (for example, 97Tc can be made by neutron irradiation of 96Ru). # Isotopes Technetium is one of the two elements in the first 82 that have no stable isotopes (in fact, it is the lowest-numbered element that is exclusively radioactive); the other such element is promethium. The most stable radioisotopes are 98Tc (half-life of 4.2 Ma), 97Tc (half-life: 2.6 Ma) and 99Tc (half-life: 211.1 ka). Twenty-two other radioisotopes have been characterized with atomic masses ranging from 87.933 u (88Tc) to 112.931 u (113Tc). Most of these have half-lives that are less than an hour; the exceptions are 93Tc (half-life: 2.75 hours), 94Tc (half-life: 4.883 hours), 95Tc (half-life: 20 hours), and 96Tc (half-life: 4.28 days). Technetium also has numerous meta states. 97mTc is the most stable, with a half-life of 90.1 days (0.097 MeV). This is followed by 95mTc (half life: 61 days, 0.038 MeV), and 99mTc (half-life: 6.01 hours, 0.143 MeV). 99mTc only emits gamma rays, subsequently decaying to 99Tc. For isotopes lighter than the most stable isotope, 98Tc, the primary decay mode is electron capture, giving molybdenum. For the heavier isotopes, the primary mode is beta emission, giving ruthenium, with the exception that 100Tc can decay both by beta emission and electron capture. Technetium-99 is the most common and most readily available isotope, as it is a major product of the fission of uranium-235. One gram of 99Tc produces 6.2×108 disintegrations a second (that is, 0.62 GBq/g). ## Stability of technetium isotopes Technetium and promethium are unusual light elements in that they have no stable isotopes. The reason for this is somewhat complicated. Using the liquid drop model for atomic nuclei, one can derive a semiempirical formula for the binding energy of a nucleus. This formula predicts a "valley of beta stability" along which nuclides do not undergo beta decay. Nuclides that lie "up the walls" of the valley tend to decay by beta decay towards the center (by emitting an electron, emitting a positron, or capturing an electron). For a fixed odd number of nucleons A, the graph of binding energies vs. atomic number (number of protons) is shaped like a parabola (U-shaped), with the most stable nuclide at the bottom. A single beta decay or electron captures then transforms one nuclide of mass A into the next or preceding one, if the product has a lower binding energy and the difference in energy is sufficient to drive the decay mode. When there is only one parabola, there can be only one stable isotope lying on that parabola. For a fixed even number of nucleons A, the graph is jagged and is better visualized as two separate parabolas for even and odd atomic numbers, because isotopes with an even number of protons and an even number of neutrons are more stable than isotopes with an odd number of neutrons and an odd number of protons. When there are two parabolas, that is, when the number of nucleons is even, it can happen (rarely) that there is a stable nucleus with an odd number of neutrons and an odd number of protons (although there are only 4 truly stable examples as opposed to very long-lived: the light nuclei: 2H, 6Li, 10B, 14N). However, if this happens, there can be no stable isotope with an even number of neutrons and an even number of protons. For technetium (Z=43), the valley of beta stability is centered at around 98 nucleons. However, for every number of nucleons from 95 to 102, there is already at least one stable nuclide of either molybdenum (Z=42) or ruthenium (Z=44). For the isotopes with odd numbers of nucleons, this immediately rules out a stable isotope of technetium, since there can be only one stable nuclide with a fixed odd number of nucleons. For the isotopes with an even number of nucleons, since technetium has an odd number of protons, any isotope must also have an odd number of neutrons. In such a case, the presence of a stable nuclide having the same number of nucleons and an even number of protons rules out the possibility of a stable nucleus.	Technetium Template:Infobox technetium Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Technetium (Template:PronEng) is the lightest chemical element with no stable isotope. It is a synthetic element. It has atomic number 43 and is given the symbol Tc. The chemical properties of this silvery grey, crystalline transition metal are intermediate between rhenium and manganese. Its short-lived gamma-emitting nuclear isomer 99mTc (technetium-99m) is used in nuclear medicine for a wide variety of diagnostic tests. 99Tc is used as a gamma ray-free source of beta particles. The pertechnetate ion (TcO4-) has been suggested as a strong anodic corrosion inhibitor for mild steel in closed cooling systems. Before the element was discovered, many of the properties of element 43 were predicted by Dmitri Mendeleev. Mendeleev noted a gap in his periodic table and called the element ekamanganese(Em). In 1937 its isotope 97Tc became the first predominantly artificial element to be produced, hence its name (from the Greek τεχνητός, meaning "artificial"). Most technetium produced on Earth is a by-product of fission of uranium-235 in nuclear reactors and is extracted from nuclear fuel rods. No isotope of technetium has a half-life longer than 4.2 million years (98Tc), so its detection in red giants in 1952 helped bolster the theory that stars can produce heavier elements. On Earth, technetium occurs in trace but measurable quantities as a product of spontaneous fission in uranium ore or by neutron capture in molybdenum ores. # Characteristics Technetium is a silvery-grey radioactive metal with an appearance similar to platinum. However, it is commonly obtained as a grey powder. Its position in the periodic table is between rhenium and manganese and as predicted by the periodic law its properties are intermediate between those two elements. Technetium is unusual among the lighter elements in that it has no stable isotopes. Only technetium and promethium have no stable isotopes, but are followed by elements which do. Technetium is therefore extremely rare on Earth. Technetium plays no natural biological role and is not normally found in the human body. The metal form of technetium slowly tarnishes in moist air. Its oxides are TcO2 and Tc2O7. Under oxidizing conditions technetium (VII) will exist as the pertechnetate ion, TcO4-.[1] Common oxidation states of technetium include 0, +2, +4, +5, +6 and +7.[2] Technetium will burn in oxygen when in powder form.[3] It dissolves in aqua regia, nitric acid, and concentrated sulfuric acid, but it is not soluble in hydrochloric acid. It has characteristic spectral lines at 363 nm, 403 nm, 410 nm, 426 nm, 430 nm, and 485 nm.[4] The metal form is slightly paramagnetic, meaning its magnetic dipoles align with external magnetic fields even though technetium is not normally magnetic.[5] The crystal structure of the metal is hexagonal close-packed. Pure metallic single-crystal technetium becomes a type II superconductor at 7.46 K; irregular crystals and trace impurities raise this temperature to 11.2 K for 99.9% pure technetium powder.[6] Below this temperature technetium has a very high magnetic penetration depth, the largest among the elements apart from niobium.[7] Technetium is produced in quantity by nuclear fission, and spreads more readily than many radionuclides. In spite of the importance of understanding its toxicity in animals and humans, experimental evidence is scant. It appears to have low chemical toxicity. Its radiological toxicity (per unit of mass) is a function of compound, type of radiation for the isotope in question, and the isotope half-life. Technetium-99m is particularly attractive for medical applications, as the radiation from this isotope is a gamma ray with the same wavelength as X-rays used for common medical diagnostic X-ray applications, giving it adequate penetration while causing minimal damage for a gamma photon. This, plus the extremely short half-life of this metastable nuclear isomer, followed by the relatively long half-life of the daughter isotope Tc-99 which allows it to be eliminated from the body before it decays. This leads to a relatively low dose of administered radiation in biologically dose-equivalent amounts (sieverts) for a typical Tc-99m based nuclear scan (see more on this subject below).[6] All isotopes of technetium must be handled carefully. The most common isotope, technetium-99, is a weak beta emitter; such radiation is stopped by the walls of laboratory glassware. Soft X-rays are emitted when the beta particles are stopped, but as long as the body is kept more than 30 cm away these should pose no problem. The primary hazard when working with technetium is inhalation of dust; such radioactive contamination in the lungs can pose a significant cancer risk. For most work, careful handling in a fume hood is sufficient; a glove box is not needed.[6] # Applications ## Nuclear medicine 99mTc ("m" indicates that this is a metastable nuclear isomer) is used in radioactive isotope medical tests, for example as a radioactive tracer that medical equipment can detect in the human body.[8] It is well suited to the role because it emits readily detectable 140 keV gamma rays, and its half-life is 6.01 hours (meaning that about seven eighths of it decays to 99Tc in 24 hours).[9] Klaus Schwochau's book Technetium lists 31 radiopharmaceuticals based on 99mTc for imaging and functional studies of the brain, myocardium, thyroid, lungs, liver, gallbladder, kidneys, skeleton, blood, and tumors.[6] Immunoscintigraphy incorporates 99mTc into a monoclonal antibody, an immune system protein capable of binding to cancer cells. A few hours after injection, medical equipment is used to detect the gamma rays emitted by the 99mTc; higher concentrations indicate where the tumor is. This technique is particularly useful for detecting hard-to-find cancers, such as those affecting the intestine. These modified antibodies are sold by the German company Hoechst (now part of Sanofi-Aventis) under the name "Scintium".[10] When 99mTc is combined with a tin compound it binds to red blood cells and can therefore be used to map circulatory system disorders. It is commonly used to detect gastrointestinal bleeding sites. A pyrophosphate ion with 99mTc adheres to calcium deposits in damaged heart muscle, making it useful to gauge damage after a heart attack.[11] The sulfur colloid of 99mTc is scavenged by the spleen, making it possible to image the structure of the spleen.[12] Radiation exposure due to diagnostic treatment involving Tc-99m can be kept low. Because 99mTc has a short half-life and high energy gamma (allowing small amounts to be easily detected), its quick decay into the far-less radioactive 99Tc results in relatively less total radiation dose to the patient, per unit of initial activity after administration. In the form administered in these medical tests (usually pertechnetate) both isotopes are quickly eliminated from the body, generally within a few days.[11] Technetium for nuclear medicine purposes is usually extracted from technetium-99m generators. 95mTc, with a half-life of 61 days, is used as a radioactive tracer to study the movement of technetium in the environment and in plant and animal systems.[6] ## Industrial/Chemical Technetium-99 decays almost entirely by beta decay, emitting beta particles with consistent low energies and no accompanying gamma rays. Moreover, its long half-life means that this emission decreases very slowly with time. It can also be extracted to a high chemical and isotopic purity from radioactive waste. For these reasons, it is a NIST standard beta emitter, used for equipment calibration.[6] Technetium-99 has also been proposed for use in optoelectric and nanoscale nuclear batteries.[13] Like rhenium and palladium, technetium can serve as a catalyst. For certain reactions, for example the dehydrogenation of isopropyl alcohol, it is a far more effective catalyst than either rhenium or palladium. Of course, its radioactivity is a major problem in finding safe applications.[6] Under certain circumstances, a small concentration (5×10−5 mol/L) of the pertechnetate ion in water can protect iron and carbon steels from corrosion. For this reason, pertechnetate has been suggested as a possible anodic corrosion inhibitor for steel, although technetium's radioactivity poses problems for strictly chemical uses such as these. While (for example) CrO42− can also inhibit corrosion, it requires a concentration ten times as high. In one experiment, a test specimen was kept in an aqueous solution of pertechnetate for 20 years and was still uncorroded. The mechanism by which pertechnetate prevents corrosion is not well-understood, but seems to involve the reversible formation of a thin surface layer. One theory holds that the pertechnetate reacts with the steel surface to form a layer of technetium dioxide which prevents further corrosion; the same effect explains how iron powder can be used to remove pertechnetate from water. (Activated carbon can also be used for the same effect.) The effect disappears rapidly if the concentration of pertechnetate falls below the minimum concentration or if too high a concentration of other ions is added. As noted, the radioactive nature of technetium (3 MBq per liter at the concentrations required) makes this corrosion protection impractical in almost all situations. Nevertheless, corrosion protection by pertechnetate ions was proposed (but never adopted) for use in boiling water reactors.[6] # History ## Search for element 43 For a number of years there was a gap in the periodic table between molybdenum (element 42) and ruthenium (element 44). Many early researchers were eager to be the first to discover and name the missing element; its location in the table suggested that it should be easier to find than other undiscovered elements. It was first thought to have been found in platinum ores in 1828. It was given the name polinium but it turned out to be impure iridium. Then in 1846 the element ilmenium was claimed to have been discovered but was determined to be impure niobium. This mistake was repeated in 1847 with the "discovery" of pelopium.[14] Dmitri Mendeleev predicted that this missing element, as part of other predictions, would be chemically similar to manganese and gave it the name ekamanganese. In 1877, the Russian chemist Serge Kern reported discovering the missing element in platinum ore. Kern named what he thought was the new element davyum, after the noted English chemist Sir Humphry Davy, but it was determined to be a mixture of iridium, rhodium and iron. Another candidate, lucium, followed in 1896 but it was determined to be yttrium. Then in 1908 the Japanese chemist Masataka Ogawa found evidence in the mineral thorianite which he thought indicated the presence of element 43. Ogawa named the element nipponium, after Japan (which is Nippon in Japanese). In 2004 H. K Yoshihara utilized "a record of X-ray spectrum of Ogawa's nipponium sample from thorianite [which] was contained in a photographic plate preserved by his family. The spectrum was read and indicated the absence of the element 43 and the presence of the element 75 (rhenium)."[15] German chemists Walter Noddack, Otto Berg and Ida Tacke (later Mrs. Noddack) reported the discovery of element 75 and element 43 in 1925 and named element 43 masurium (after Masuria in eastern Prussia, now in Poland, the region where Walter Noddack's family originated).[16] The group bombarded columbite with a beam of electrons and deduced element 43 was present by examining X-ray diffraction spectrograms. The wavelength of the X-rays produced is related to the atomic number by a formula derived by Henry Moseley in 1913. The team claimed to detect a faint X-ray signal at a wavelength produced by element 43. Contemporary experimenters could not replicate the discovery, and in fact it was dismissed as an error for many years.[17][18] In 1998 John T. Armstrong of the National Institute of Standards and Technology ran "computer simulations" of the 1925 experiments and obtained results quite close to those reported by the Noddack team. He claimed that this was further supported by work published by David Curtis of the Los Alamos National Laboratory measuring the (tiny) natural occurrence of technetium.[17][19] However, the Noddack's experimental results have never been reproduced, and they were unable to isolate any element 43. Debate still exists as to whether the 1925 team actually did discover element 43. ## Official discovery and later history Discovery of element 43 was finally confirmed in a 1937 experiment at the University of Palermo in Sicily conducted by Carlo Perrier and Emilio Segrè. In the summer of 1936 Segrè and his wife visited the United States, first New York at Columbia University, where he had spent time the previous summer, and then Berkeley at Ernest O. Lawrence's Radiation Laboratory. He persuaded cyclotron inventor Lawrence to let him take back some discarded cyclotron parts that had become radioactive. In early 1937 Lawrence mailed him a molybdenum foil that had been part of the deflector in the cyclotron. Segrè enlisted his experienced chemist colleague Perrier to attempt to prove through comparative chemistry that the molybdenum activity was indeed Z = 43, an element not existent in nature because of its instability against nuclear decay. With considerable difficulty they finally succeeded in isolating three distinct decay periods (90, 80, and 50 days) that eventually turned out to be two isotopes, 95Tc and 97Tc, of technetium, the name given later by Perrier and Segrè to the first man-made element.[20] University of Palermo officials wanted them to name their discovery panormium, after the Latin name for Palermo, Panormus. The researchers instead named element 43 after the Greek word τεχνητός, meaning "artificial", since it was the first element to be artificially produced.[16][14] Segrè returned to Berkeley and immediately sought out Glenn T. Seaborg. They isolated the technetium-99m isotope which is now used in some 10,000,000 medical diagnostic procedures annually.[21] In 1952 astronomer Paul W. Merrill in California detected the spectral signature of technetium (in particular, light at 403.1 nm, 423.8 nm, 426.8 nm, and 429.7 nm) in light from S-type red giants.[6] These massive stars near the end of their lives were rich in this short-lived element, meaning nuclear reactions within the stars must be producing it. This evidence was used to bolster the then unproven theory that stars are where nucleosynthesis of the heavier elements occurs.[22] More recently, such observations provided evidence that elements were being formed by neutron capture in the s-process.[6] Since its discovery, there have been many searches in terrestrial materials for natural sources. In 1962, technetium-99 was isolated and identified in pitchblende from the Belgian Congo in extremely small quantities (about 0.2 ng/kg);[6] there it originates as a spontaneous fission product of uranium-238. This discovery was made by B.T. Kenna and P.K. Kuroda.[23] There is also evidence that the Oklo natural nuclear fission reactor produced significant amounts of technetium-99, which has since decayed to ruthenium-99.[6] # Occurrence and production Since technetium is unstable, only minute traces occur naturally in the Earth's crust as a spontaneous fission product of uranium. In 1999 David Curtis (see above) estimated that a kilogram of uranium contains 1 nanogram (1×10−9 g) of technetium.[24] Extraterrestrial technetium was found in some red giant stars (S-, M-, and N-types) that contain an absorption line in their spectrum indicating the presence of this element.[25] ## Byproduct production of Tc-99 in fission wastes In contrast with the rare natural occurrence, bulk quantities of technetium-99 are produced each year from spent nuclear fuel rods, which contain various fission products. The fission of a gram of uranium-235 in nuclear reactors yields 27 mg of 99Tc, giving technetium a fission product yield of 6.1%.[26] Other fissile isotopes also produce similar yields of technetium,[6] e.g. 4.9% from uranium-233 or 6.21% from plutonium-239. It is estimated that up to 1994, about 49,000 TBq (78 metric tons) of technetium was produced in nuclear reactors, which is by far the dominant source of terrestrial technetium.[27] However, only a fraction of the production is used commercially. As of 2005, technetium-99 is available to holders of an ORNL permit for US$83/g plus packing charges.[28] Since the yield of technetium-99 as a product of the nuclear fission of both uranium-235 and plutonium-239 is moderate, it is present in radioactive waste of fission reactors and is produced when a fission bomb is detonated. The amount of artificially produced technetium in the environment exceeds its natural occurrence to a large extent. This is due to release by atmospheric nuclear testing along with the disposal and processing of high-level radioactive waste. Due to its high fission yield and relatively high half-life, technetium-99 is one of the main components of nuclear waste. Its decay, measured in becquerels per amount of spent fuel, is dominant at about 104 to 106 years after the creation of the nuclear waste.[27] An estimated 160 TBq (about 250 kg) of technetium-99 was released into the environment up to 1994 by atmospheric nuclear tests.[27] The amount of technetium-99 from nuclear reactors released into the environment up to 1986 is estimated to be on the order of 1000 TBq (about 1600 kg), primarily by nuclear fuel reprocessing; most of this was discharged into the sea. In recent years, reprocessing methods have improved to reduce emissions, but as of 2005 the primary release of technetium-99 into the environment is by the Sellafield plant, which released an estimated 550 TBq (about 900 kg) from 1995–1999 into the Irish Sea. From 2000 onwards the amount has been limited by regulation to 90 TBq (about 140 kg) per year.[29] As a result of nuclear fuel reprocessing, technetium has been discharged into the sea in a number of locations, and some seafood contains tiny but measurable quantities. For example, lobster from west Cumbria contains small amounts of technetium.[30] The anaerobic, spore-forming bacteria in the Clostridium genus are able to reduce Tc(VII) to Tc(IV). Clostridia bacteria play a role in reducing iron, manganese and uranium, thereby affecting these elements' solubility in soil and sediments. Their ability to reduce technetium may determine a large part of Tc's mobility in industrial wastes and other subsurface environments.[31] The long half-life of technetium-99 and its ability to form an anionic species makes it (along with 129I) a major concern when considering long-term disposal of high-level radioactive waste. In addition, many of the processes designed to remove fission products from medium-active process streams in reprocessing plants are designed to remove cationic species like caesium (e.g., 137Cs) and strontium (e.g.,90Sr). Hence the pertechnetate is able to escape through these treatment processes. Current disposal options favor burial in geologically stable rock. The primary danger with such a course is that the waste is likely to come into contact with water, which could leach radioactive contamination into the environment. The anionic pertechnetate and iodide are less able to absorb onto the surfaces of minerals so they are likely to be more mobile. By comparison plutonium, uranium, and caesium are much more able to bind to soil particles. For this reason, the environmental chemistry of technetium is an active area of research. An alternative disposal method, transmutation, has been demonstrated at CERN for technetium-99. This transmutation process is one in which the technetium (99Tc as a metal target) is bombarded with neutrons to form the shortlived 100Tc (half life = 16 seconds) which decays by beta decay to ruthenium (100Ru). If recovery of usable ruthenium is a goal, an extremely pure technetium target is needed; if small traces of the minor actinides such as americium and curium are present in the target, they are likely to undergo fission and form more fission products which increase the radioactivity of the irradiated target. The formation of 106Ru (half life 374 days) from the fresh fission is likely to increase the activity of the final ruthenium metal, which will then require a longer cooling time after irradiation before the ruthenium can be used. The actual production of technetium-99 from spent nuclear fuel is a long process. During fuel reprocessing, it appears in the waste liquid, which is highly radioactive. After sitting for several years, the radioactivity has fallen to a point where extraction of the long-lived isotopes, including technetium-99, becomes feasible. Several chemical extraction processes are used yielding technetium-99 metal of high purity.[6] ## Neutron activation of molybdenum or other pure elements The meta stable (a state where the nucleus is in an excited state) isotope 99mTc is produced as a fission product from the fission of uranium or plutonium in nuclear reactors. Because used fuel is allowed to stand for several years before reprocessing, all 99Mo and 99mTc will have decayed by the time that the fission products are separated from the major actinides in conventional nuclear reprocessing. The PUREX raffinate will contain a high concentration of technetium as TcO4- but almost all of this will be 99Tc. The vast majority of the 99mTc used in medical work is formed from 99Mo which is formed by the neutron activation of 98Mo. 99Mo has a half-life of 67 hours, so short-lived 99mTc (half-life: 6 hours), which results from its decay, is being constantly produced.[32] The hospital then chemically extracts the technetium from the solution by using a technetium-99m generator ("technetium cow", also occasionally called a "molybdenum cow"). The normal technetium cow is an alumina column which contains molybdenum-98; in as much as aluminium has a small neutron cross section, it is convenient for an alumina column bearing inactive 98Mo to be irradiated with neutrons to make the radioactive Mo-99 column for the technetium cow.[33] By working in this way, there is no need for the complex chemical steps which would be required to separate molybdenum from a fission product mixture. This alternative method requires that an enriched uranium target be irradiated with neutrons to form 99Mo as a fission product, then separated.[34] Other technetium isotopes are not produced in significant quantities by fission; when needed, they are manufactured by neutron irradiation of parent isotopes (for example, 97Tc can be made by neutron irradiation of 96Ru). # Isotopes Technetium is one of the two elements in the first 82 that have no stable isotopes (in fact, it is the lowest-numbered element that is exclusively radioactive); the other such element is promethium.[35] The most stable radioisotopes are 98Tc (half-life of 4.2 Ma), 97Tc (half-life: 2.6 Ma) and 99Tc (half-life: 211.1 ka).[36] Twenty-two other radioisotopes have been characterized with atomic masses ranging from 87.933 u (88Tc) to 112.931 u (113Tc). Most of these have half-lives that are less than an hour; the exceptions are 93Tc (half-life: 2.75 hours), 94Tc (half-life: 4.883 hours), 95Tc (half-life: 20 hours), and 96Tc (half-life: 4.28 days).[36] Technetium also has numerous meta states. 97mTc is the most stable, with a half-life of 90.1 days (0.097 MeV). This is followed by 95mTc (half life: 61 days, 0.038 MeV), and 99mTc (half-life: 6.01 hours, 0.143 MeV). 99mTc only emits gamma rays, subsequently decaying to 99Tc.[36] For isotopes lighter than the most stable isotope, 98Tc, the primary decay mode is electron capture, giving molybdenum. For the heavier isotopes, the primary mode is beta emission, giving ruthenium, with the exception that 100Tc can decay both by beta emission and electron capture.[36][37] Technetium-99 is the most common and most readily available isotope, as it is a major product of the fission of uranium-235. One gram of 99Tc produces 6.2×108 disintegrations a second (that is, 0.62 GBq/g).[38] ## Stability of technetium isotopes Technetium and promethium are unusual light elements in that they have no stable isotopes. The reason for this is somewhat complicated. [39] Using the liquid drop model for atomic nuclei, one can derive a semiempirical formula for the binding energy of a nucleus. This formula predicts a "valley of beta stability" along which nuclides do not undergo beta decay. Nuclides that lie "up the walls" of the valley tend to decay by beta decay towards the center (by emitting an electron, emitting a positron, or capturing an electron). For a fixed odd number of nucleons A, the graph of binding energies vs. atomic number (number of protons) is shaped like a parabola (U-shaped), with the most stable nuclide at the bottom. A single beta decay or electron captures then transforms one nuclide of mass A into the next or preceding one, if the product has a lower binding energy and the difference in energy is sufficient to drive the decay mode. When there is only one parabola, there can be only one stable isotope lying on that parabola. For a fixed even number of nucleons A, the graph is jagged and is better visualized as two separate parabolas for even and odd atomic numbers, because isotopes with an even number of protons and an even number of neutrons are more stable than isotopes with an odd number of neutrons and an odd number of protons. When there are two parabolas, that is, when the number of nucleons is even, it can happen (rarely) that there is a stable nucleus with an odd number of neutrons and an odd number of protons (although there are only 4 truly stable examples as opposed to very long-lived: the light nuclei: 2H, 6Li, 10B, 14N). However, if this happens, there can be no stable isotope with an even number of neutrons and an even number of protons. For technetium (Z=43), the valley of beta stability is centered at around 98 nucleons. However, for every number of nucleons from 95 to 102, there is already at least one stable nuclide of either molybdenum (Z=42) or ruthenium (Z=44). For the isotopes with odd numbers of nucleons, this immediately rules out a stable isotope of technetium, since there can be only one stable nuclide with a fixed odd number of nucleons. For the isotopes with an even number of nucleons, since technetium has an odd number of protons, any isotope must also have an odd number of neutrons. In such a case, the presence of a stable nuclide having the same number of nucleons and an even number of protons rules out the possibility of a stable nucleus.[40]	https://www.wikidoc.org/index.php/Technetium
448196af47f7ac151a4c2f93e4414e9361866ade	wikidoc	TeenScreen	TeenScreen TeenScreen is a national mental health and suicide risk screening program for students and adolescents in the United States. The screening itself generally consists of a short (usually around ten minutes) questionnaire and is conducted in public and private schools, doctor's offices, clinics, youth groups, shelters, and other youth-serving organizations and settings. As of October 2005, TeenScreen has 460 active screening sites in 42 states. Missing from the list of states where TeenScreen has been established are: Hawaii, Utah, Wyoming, South Dakota, Kansas, Alabama, New Hampshire and Maryland. # Controversy TeenScreen has become the subject of much controversy. It has been criticized by many family groups, professional associations, education groups, legislators, doctors, and watch-dog organizations publicly opposing mental health screening in general and TeenScreen in particular. These groups include the Association of American Physicians and Surgeons (AAPS), Eagle Forum, the International Center for the Study of Psychiatry and Psychology, Alliance for Human Research Protection, the Liberty Coalition, Citizens Commission on Human Rights (CCHR), EdWatch, the Rutherford Institute, Texans for Safe Education and the Citizens for Health. These groups spoke up in opposition of screenings that were being conducted without explicit parental consent that relied instead on passive consent, whereby consent is assumed if it is not explicitly denied. On June 5, 2006, TeenScreen changed their consent procedures for public schools so that active parental consent - meaning that parents have to sign and turn in a permission slip - is now a requirement of TeenScreen in public schools. Passive consent is still being used in some private schools, in teen shelters and the juvenile justice system. TeenScreen is the subject of a lawsuit in a case in Indiana. ## No evidence of effectiveness TeenScreen officials admit that there have been no studies that show that their program reduces suicide. After an in-depth investigation, the U.S. Preventive Services Task Force report of May of 2004 states: A. There is no evidence that screening for suicide risk reduces suicide attempts or mortality. B. There is limited evidence on the accuracy of screening tools to identify suicide risk. C. There is insufficient evidence that treatment of those at high risk reduces suicide attempts or mortality. D. No studies were found that directly address the harms of screening and treatment for suicide risk. Two years later, on June 16, 2006, Ned Calonge, the chairman of the Task Force, and the chief medical officer for the Colorado Department of Public Health and Environment, spoke to the Washington Post and said the same findings apply to screening today: “The panel would reach the same conclusion today… Whether or not we like to admit it, there are no interventions that have no harms… There is weak evidence that screening can distinguish people who will commit suicide from those who will not… And screening inevitably leads to treating some people who do not need it. Such interventions have consequences beyond side effects from drugs or other treatments… Unnecessary care drives up the cost of insurance, causing some people to lose coverage altogether.” ## Referral to treatment Before screening takes place, TeenScreen partners with local mental health providers. This has become a source of controversy as some have alleged that TeenScreen is merely a scheme to market psychiatric drugs. In addition, critics show that some of TeenScreen's executives and advisory board members have ties to pharmaceutical companies. Some of the symptoms that TeenScreen uses as indicators of mental illness can also be caused by physical illnesses, allergies, poor nutrition, lack of sleep, drug abuse, and toxic exposure. TeenScreen refers students flagged by the screening process to psychiatric professionals only. ## TeenScreen refutes controversial claims On its website, TeenScreen provides information aimed at "Setting the Record Straight About TeenScreen" to refute these claims and emphasize the voluntary nature of the TeenScreen program. One critic says they are side-stepping the real issues.	TeenScreen TeenScreen is a national mental health and suicide risk screening program for students and adolescents in the United States. The screening itself generally consists of a short (usually around ten minutes) questionnaire[1][2] and is conducted in public and private schools, doctor's offices, clinics, youth groups, shelters, and other youth-serving organizations and settings.[3] As of October 2005, TeenScreen has 460 active screening sites in 42 states. Missing from the list of states where TeenScreen has been established are: Hawaii, Utah, Wyoming, South Dakota, Kansas, Alabama, New Hampshire and Maryland.[4] # Controversy TeenScreen has become the subject of much controversy. It has been criticized by many family groups, professional associations, education groups, legislators, doctors, and watch-dog organizations publicly opposing mental health screening in general and TeenScreen in particular. These groups include the Association of American Physicians and Surgeons (AAPS), Eagle Forum, the International Center for the Study of Psychiatry and Psychology, Alliance for Human Research Protection, the Liberty Coalition, Citizens Commission on Human Rights (CCHR), EdWatch, the Rutherford Institute, Texans for Safe Education and the Citizens for Health. These groups spoke up in opposition of screenings that were being conducted without explicit parental consent that relied instead on passive consent, whereby consent is assumed if it is not explicitly denied.[5] [6] [7] [8] [9] [10] [11] [12] On June 5, 2006, TeenScreen changed their consent procedures for public schools so that active parental consent - meaning that parents have to sign and turn in a permission slip - is now a requirement of TeenScreen in public schools.[13] Passive consent is still being used in some private schools, in teen shelters and the juvenile justice system. TeenScreen is the subject of a lawsuit in a case in Indiana.[14][15] ## No evidence of effectiveness TeenScreen officials admit that there have been no studies that show that their program reduces suicide.[16] After an in-depth investigation, the U.S. Preventive Services Task Force report of May of 2004 states: [17] A. There is no evidence that screening for suicide risk reduces suicide attempts or mortality. B. There is limited evidence on the accuracy of screening tools to identify suicide risk. C. There is insufficient evidence that treatment of those at high risk reduces suicide attempts or mortality. D. No studies were found that directly address the harms of screening and treatment for suicide risk. Two years later, on June 16, 2006, Ned Calonge, the chairman of the Task Force, and the chief medical officer for the Colorado Department of Public Health and Environment, spoke to the Washington Post and said the same findings apply to screening today:[18] “The panel would reach the same conclusion today… Whether or not we like to admit it, there are no interventions that have no harms… There is weak evidence that screening can distinguish people who will commit suicide from those who will not… And screening inevitably leads to treating some people who do not need it. Such interventions have consequences beyond side effects from drugs or other treatments… Unnecessary care drives up the cost of insurance, causing some people to lose coverage altogether.” ## Referral to treatment Before screening takes place, TeenScreen partners with local mental health providers. This has become a source of controversy as some have alleged that TeenScreen is merely a scheme to market psychiatric drugs.[19] In addition, critics show that some of TeenScreen's executives and advisory board members have ties to pharmaceutical companies.[20] Some of the symptoms that TeenScreen uses as indicators of mental illness can also be caused by physical illnesses, allergies, poor nutrition, lack of sleep, drug abuse, and toxic exposure.[21] TeenScreen refers students flagged by the screening process to psychiatric professionals only.[22] ## TeenScreen refutes controversial claims On its website, TeenScreen provides information aimed at "Setting the Record Straight About TeenScreen" to refute these claims and emphasize the voluntary nature of the TeenScreen program.[23] One critic says they are side-stepping the real issues.[citation needed]	https://www.wikidoc.org/index.php/TeenScreen
27bcbf86e202f6e834f741f142c654225a4b798b	wikidoc	Telaprevir	Telaprevir # Overview Telaprevir (INN) is a protease inhibitor being studied as a treatment for hepatitis C. Telaprevir is currently being marketed as Incivek. It has completed its phase III trials (ADVANCE; A New Direction in HCV Care: A Study of Treatment-naïve Hepatitis C Patients with Telaprevir) in previously untreated patients with genotype 1, the most common strain in North American and Europe It is an orally bioavailable inhibitor of the nonstructural 3/4A (NS3/4A) HCV serine protease. It was approved by the FDA on May 23rd, 2011 as a hepatitis C virus protease inhibitor, making it the second direct-acting antiviral HCV drug therapy to be approved behind boceprevir. Telaprevir is most successful in patients who have not yet been previously treated for the condition.2 Currently, it is reported by the World Health Organization that 170-180 million people worldwide suffer from the hepatitis C virus (HCV ) and it is considered to be a serious global health crisis. It is the most common blood born infection worldwide.5 Of this population, at least 130 million patients are estimated to be chronic HCV carriers who are at severe risk of developing liver cirrhosis and liver cancer.4, 6 The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases, and then viral assembly occurs.4 The previously leading treatment therapy, a regimen of pegylated interferon and ribavirin, was only effective in about 38% - 46% of patients.2 It was administered for 24 weeks in patients with genotypes 2 or 3, or for 48 weeks in patients with genotype 1, the most common strain in Europe and North America.2 Fortunately, the recently FDA approved telaprevir is a significant and improved development in the successful treatment of HCV. Telaprevir is a polymerase-inhibiting direct-acting antiviral (DAA) agent that is to be administered to the patients in combination with peginterferon and ribavirin.1 DAA drug agents work to attack the virus directly; they work by different mechanisms of action than previous treatments which indirectly fought the virus by trying to boost the immune system.4, The introduction of this drug has broadened treatment options for patients suffering HCV considerably with the main goal of treatment being the achievement of a sustained virologic response (SVR), defined as an undetectable serum HCV RNA level 24 weeks after cessation of therapy.2 The achievement of SVR means that the virus has been eradicated and will further complications such as cirrhosis and hepatocellular carcinoma (HCC) are prevented.1,4 Serine protease inhibitors such as telaprevir used in the treatment of HCV for post-translational processing and the inhibition viral replication. It is most successful when given in combination with peginterferon and ribavirin at achieving sustained virologic responses in most patients who have genotype 1. However, when used as monotherapy, without the combination of the other standard drugs, the body quickly develops resistance.6 # Category Antiviral # US Brand Names INCIVEK® # FDA Package Insert Description # Mechanism of Action Telaprevir is an inhibitor of the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication. In a biochemical assay, telaprevir inhibited the proteolytic activity of the recombinant HCV NS3 protease domain with an IC50 value of 10 nM.	Telaprevir Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2] # Overview Telaprevir (INN) is a protease inhibitor being studied as a treatment for hepatitis C. Telaprevir is currently being marketed as Incivek. It has completed its phase III trials (ADVANCE; A New Direction in HCV Care: A Study of Treatment-naïve Hepatitis C Patients with Telaprevir) in previously untreated patients with genotype 1, the most common strain in North American and Europe It is an orally bioavailable inhibitor of the nonstructural 3/4A (NS3/4A) HCV serine protease. [1] [2] It was approved by the FDA on May 23rd, 2011 as a hepatitis C virus protease inhibitor, making it the second direct-acting antiviral HCV drug therapy to be approved behind boceprevir. [3] Telaprevir is most successful in patients who have not yet been previously treated for the condition.2 Currently, it is reported by the World Health Organization that 170-180 million people worldwide suffer from the hepatitis C virus (HCV ) and it is considered to be a serious global health crisis. [4] [5] [6] It is the most common blood born infection worldwide.5 Of this population, at least 130 million patients are estimated to be chronic HCV carriers who are at severe risk of developing liver cirrhosis and liver cancer.4, 6 The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases, and then viral assembly occurs.4 The previously leading treatment therapy, a regimen of pegylated interferon and ribavirin, was only effective in about 38% - 46% of patients.2[7] [8] It was administered for 24 weeks in patients with genotypes 2 or 3, or for 48 weeks in patients with genotype 1, the most common strain in Europe and North America.2 Fortunately, the recently FDA approved telaprevir is a significant and improved development in the successful treatment of HCV. Telaprevir is a polymerase-inhibiting direct-acting antiviral (DAA) agent that is to be administered to the patients in combination with peginterferon and ribavirin.1 DAA drug agents work to attack the virus directly; they work by different mechanisms of action than previous treatments which indirectly fought the virus by trying to boost the immune system.4, [9] The introduction of this drug has broadened treatment options for patients suffering HCV considerably with the main goal of treatment being the achievement of a sustained virologic response (SVR), defined as an undetectable serum HCV RNA level 24 weeks after cessation of therapy.2 The achievement of SVR means that the virus has been eradicated and will further complications such as cirrhosis and hepatocellular carcinoma (HCC) are prevented.1,4 Serine protease inhibitors such as telaprevir used in the treatment of HCV for post-translational processing and the inhibition viral replication. It is most successful when given in combination with peginterferon and ribavirin at achieving sustained virologic responses in most patients who have genotype 1. However, when used as monotherapy, without the combination of the other standard drugs, the body quickly develops resistance.6 # Category Antiviral # US Brand Names INCIVEK® # FDA Package Insert Description # Mechanism of Action Telaprevir is an inhibitor of the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication. In a biochemical assay, telaprevir inhibited the proteolytic activity of the recombinant HCV NS3 protease domain with an IC50 value of 10 nM.	https://www.wikidoc.org/index.php/Telaprevir
8015f18bdfdc3a0272708a15e23bc8093a540c4c	wikidoc	Telehealth	Telehealth Should this page be merged with telemedicine? These are synonymous per the National Library of Medicine Telehealth is the delivery of health-related services and information via telecommunications technologies. Telehealth delivery could be as simple as two health professionals discussing a case over the telephone, or as sophisticated as using videoconferencing to between providers at facilities in two countries, or even as complex as robotic technology. Telehealth is an expansion of telemedicine, and unlike telemedicine (which more narrowly focuses on the curative aspect) it encompasses preventive, promotive and curative aspects. Originally used to describe administrative or educational functions related to telemedicine, today telehealth stresses a myriad of technology solutions. For example, physicians use email to communicate with patients, order drug prescriptions and provide other health services. ## Clinical uses of telehealth technologies - Transmission of medical images for diagnosis (often referred to as store and forward telehealth) - Groups or individuals exchanging health services or education live via videoconference (real-time telehealth) - Transmission of medical data for diagnosis or disease management (sometimes referred to as remote monitoring or remote sensing technology) - Advice on prevention of diseases and promotion of good health by patient monitoring and followup. - Health advice by telephone in emergent cases(referred to as teletriage) ## Nonclinical uses of telehealth technologies - Distance education including continuing medical education, grand rounds, and patient education - Administrative uses including meetings among telehealth networks, supervision, and presentations - Research - Online information and health data management - heathcare sytem integration - asset identification, listing, and patient to asset matching, and movement - overall healtcare system management - patient movement and remote admission # Telehealth modes ## Store-and-forward telehealth In store-and-forward telehealth, digital images, video, audio and clinical data are captured and "stored" on the client computer; then at a convenient time transmitted securely ("forwarded") to a clinic at another location where they are studied by relevant specialists. The opinion of the specialist is then transmitted back. Based on the requirements of the participating healthcare entities, this roundtrip could take between 2 to 48 hours. In many store-and-forward specialties, such as teleradiology, an immediate response is not critical. Dermatology, radiology and pathology are common specialties that are conducive to store-and-forward technologies. ## Real-time telehealth In real-time telehealth, a telecommunications link allows instantaneous interaction. Video-conferencing equipment is one of the most common forms of synchronous telemedicine. Peripheral devices can also be attached to computers or the video-conferencing equipment which can aid in an interactive examination. With the availability of better and cheaper communication channels, direct two-way audio and video streaming between centers through computers is leading to lower costs. Examples of real-time clinical telehealth include" - Telemental health -- the use of videoconferencing technology to connect a psychiatrist with a mental health client - Telerehabilitation - Telecardiology - Teleneurology - Telenursing - Teleradiology ## Remote monitoring In remote monitoring, sensors are used to capture and transmit biometric data. For example, a tele-eeg device monitors the electrical activity of a patients brain and then transmits that data to a specialist. This could be done in either real time or the data could be stored and then forwarded. Examples of remote monitoring include: - Home-based nocturnal dialysis - Cardiac and multi-parameter monitoring of remote ICUs - Home telehealth - Disease management # Benefits of telehealth Telehealth benefits patients in countries where traditional delivery of health services are affected by distance and lack of local specialist clinicians to deliver services. The rate of adoption of telehealth services in any jurisdiction is frequently influenced by factors such as the adequacy and cost of existing conventional health services in meeting patient needs; the policies of governments and/or insurers with respect to coverage and payment for telehealth services; and medical licensing requirements that may inhibit or deter the provision of telehealth second opinions or primary consultations by physicians.	Telehealth Should this page be merged with telemedicine? These are synonymous per the National Library of Medicine[1] Telehealth is the delivery of health-related services and information via telecommunications technologies. Telehealth delivery could be as simple as two health professionals discussing a case over the telephone, or as sophisticated as using videoconferencing to between providers at facilities in two countries, or even as complex as robotic technology. Telehealth is an expansion of telemedicine, and unlike telemedicine (which more narrowly focuses on the curative aspect) it encompasses preventive, promotive and curative aspects. Originally used to describe administrative or educational functions related to telemedicine, today telehealth stresses a myriad of technology solutions. For example, physicians use email to communicate with patients, order drug prescriptions and provide other health services. ## Clinical uses of telehealth technologies - Transmission of medical images for diagnosis (often referred to as store and forward telehealth) - Groups or individuals exchanging health services or education live via videoconference (real-time telehealth) - Transmission of medical data for diagnosis or disease management (sometimes referred to as remote monitoring or remote sensing technology) - Advice on prevention of diseases and promotion of good health by patient monitoring and followup. - Health advice by telephone in emergent cases(referred to as teletriage) ## Nonclinical uses of telehealth technologies - Distance education including continuing medical education, grand rounds, and patient education - Administrative uses including meetings among telehealth networks, supervision, and presentations - Research - Online information and health data management - heathcare sytem integration - asset identification, listing, and patient to asset matching, and movement - overall healtcare system management - patient movement and remote admission # Telehealth modes ## Store-and-forward telehealth In store-and-forward telehealth, digital images, video, audio and clinical data are captured and "stored" on the client computer; then at a convenient time transmitted securely ("forwarded") to a clinic at another location where they are studied by relevant specialists. The opinion of the specialist is then transmitted back. Based on the requirements of the participating healthcare entities, this roundtrip could take between 2 to 48 hours. In many store-and-forward specialties, such as teleradiology, an immediate response is not critical. Dermatology, radiology and pathology are common specialties that are conducive to store-and-forward technologies. ## Real-time telehealth In real-time telehealth, a telecommunications link allows instantaneous interaction. Video-conferencing equipment is one of the most common forms of synchronous telemedicine. Peripheral devices can also be attached to computers or the video-conferencing equipment which can aid in an interactive examination. With the availability of better and cheaper communication channels, direct two-way audio and video streaming between centers through computers is leading to lower costs. Examples of real-time clinical telehealth include" - Telemental health -- the use of videoconferencing technology to connect a psychiatrist with a mental health client - Telerehabilitation - Telecardiology - Teleneurology - Telenursing - Teleradiology ## Remote monitoring In remote monitoring, sensors are used to capture and transmit biometric data. For example, a tele-eeg device monitors the electrical activity of a patients brain and then transmits that data to a specialist. This could be done in either real time or the data could be stored and then forwarded. Examples of remote monitoring include: - Home-based nocturnal dialysis [1] - Cardiac and multi-parameter monitoring of remote ICUs - Home telehealth - Disease management # Benefits of telehealth Telehealth benefits patients in countries where traditional delivery of health services are affected by distance and lack of local specialist clinicians to deliver services. The rate of adoption of telehealth services in any jurisdiction is frequently influenced by factors such as the adequacy and cost of existing conventional health services in meeting patient needs; the policies of governments and/or insurers with respect to coverage and payment for telehealth services; and medical licensing requirements that may inhibit or deter the provision of telehealth second opinions or primary consultations by physicians. # External links - UCLA Telehealth - American Telemedicine Association - Telemedicine Information Exchange - Telehealth Ontario - NORTH Network -- Ontario Telemedicine Network - Tasmanian government - Office for the Advancement of Telehealth (established by the Health Resources and Services Administration) - NHS Direct, the UK National Health Service information service - Association of Telehealth Service Providers - Center for Telehealth & E-Health Law (CTeL) - International Society for Telemedicine & eHealth - Med-e-Tel - The International Trade Event & Conference for eHealth, Telemedicine and Health ICT - University of Florida Center for Telehealth - National Rural Health Association - Community for Teledermatology # Further reading - Telemedicine,Telehealth, and the Consumer Online introduction and primer to telehealth and telemedicine from the Telemedicine Information Exchange - Norris, A. C. (2002). Essentials of Telemedicine and Telecare. West Sussex, England; New York: John Wiley & Sons, Ltd. ISBN 0-471-53151-0. - Maheu, Marlene M.; Whitten, Pamela; & Allen, Ace (2001). E-Health, Telehealth, and Telemedicine: A Guide to Start-up and Success. San Francisco: Jossey Bass. ISBN 0-7879-4420-3. - Telehealth Technical Assistance Manual - A document to assist in the planning of telehealth and telemedicine projects for rural community and migrant health centers and other health care organizations. By Samuel G. Burgess, Ph.D. October 2006	https://www.wikidoc.org/index.php/Telehealth
06f9efc357d08c06f766948516b9f9b0aa5a2a0b	wikidoc	Telethonin	Telethonin Telethonin, also known as Tcap, is a protein that in humans is encoded by the TCAP gene. Telethonin is expressed in cardiac and skeletal muscle at Z-discs and functions to regulate sarcomere assembly, T-tubule function and apoptosis. Telethonin has been implicated in several diseases, including limb-girdle muscular dystrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy and idiopathic cardiomyopathy. # Structure Telethonin is a 19.0 kDa protein composed of 167 amino acids. Telethonin has a unique β-sheet structure, which enables antiparallel association with the Titin Z1-Z2 domains in cardiac and skeletal muscle. Structural analysis of full-length Telethonin with the N-terminal region of Titin indicate that the C-terminus of Telethonin is critical for the dimerization of two Telethonin/Titin complexes into a higher oligomeric structure. # Function Telethonin expression is developmentally regulated in both cardiac and skeletal muscle and is thought to be critical to sarcomere assembly. Telethonin was found to be a late assembling protein only present in mature myofibrils at Z-discs. Telethonin forms a complex with MLP at Z-discs, which constitutes part of the cardiomyocyte stretch sensory mechanism. It has also been shown that Telethonin binds to the beta-subunit of the slow activating component of the delayed rectifier potassium channel, MinK, in areas localized to T-tubule membranes surrounding Z-lines in the inner myocardium. In addition, Telethonin interacts with the sodium channel Na(v)1.5, and alters the activation kinetics via doubling the window current. These data suggest that Telethonin may constitute a mechano-electrical links between Z-lines and T-tubules. Further functional evidence for this has come from studies utilizing a Telethonin-knockout mouse (KO), which have shown that Telethonin is involved in T-tubule structure and function, as well as apoptosis in the heart. Telethonin KO animals showed preserved Titin anchoring at baseline, and instead showed a profound deficit during nuclear biomechanical stress in modulating the turnover of the proapoptotic p53 protein. Telethonin KO animals also displayed calcium transient dysynchrony, T-tubule loss and depressed L-type calcium channel function. Telethonin is a substrate of titin kinase, protein kinase D (PKD) and CaM Kinase II. Telethonin, as well as TNNI3, MYBPC3 and MYOM2 are phosphorylated by PKD in cardiomyocytes, and this leads to a reduction in calcium sensitivity of myofilaments, as well as accelerated crossbridge kinetics. Bis-phosphorylation of Telethonin specifically at sites Serine-157 and Serine-161 has been shown to be essential for normal T-tubule organization and intracellular calcium transient kinetics. The intracellular degradation of Telethonin is regulated by MDM2 in a proteasomal-dependent yet ubiquitin-independent manner. Telethonin specifically interacts with the pro-apoptotic protein Siva, suggesting that Telethonin may be involved in the mechanism underlying Coxsackievirus B3 infection in acute and chronic myocarditis Telethonin was also identified to be targeted and regulated by transcriptional activators CLOCK and BMAL1, thus demonstrating that TCAP is a circadian regulated gene. # Clinical Significance Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G, hypertrophic cardiomyopathy, dilated cardiomyopathy, idiopathic cardiomyopathy, and gastrointestinal smooth muscle-related diseases. Two mutations in Telethonin, Thr137Ile and Arg153His have been associated with hypertrophic cardiomyopathy, which enhance the binding of Telethonin with Titin and MYOZ2. The Glu132Gln mutation has been associated with dilated cardiomyopathy, which has the opposite effect in that it impairs the binding of Telethonin with Titin and MYOZ2. Mutations in Titin associated with dilated cardiomyopathy, including Val54Met, have been shown specifically to impair binding of Titin with Telethonin. In a mouse model of dilated cardiomyopathy, recapitulating the human dilated cardiomyopathy mutation in MLP, Trp4Arg, studies have found that this mutation disrupts normal binding and localization of MLP with Telethonin. In a rat model of hypertension-induced cardiomyopathy, a human variant of BMP10, Thr326Ile, showed decreased binding to Telethonin and increased extracellular secretion. # Interactions Telethonin has been shown to interact with: - ANKRD2, - BMP10, - MLP, - MinK, - MDM2, - MSTN, - MYOZ1, - MYOZ2, - PRKD1, - SCN5A, - SIVA, and - Titin,	Telethonin Telethonin, also known as Tcap, is a protein that in humans is encoded by the TCAP gene.[1][2][3] Telethonin is expressed in cardiac and skeletal muscle at Z-discs and functions to regulate sarcomere assembly, T-tubule function and apoptosis. Telethonin has been implicated in several diseases, including limb-girdle muscular dystrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy and idiopathic cardiomyopathy. # Structure Telethonin is a 19.0 kDa protein composed of 167 amino acids.[4] Telethonin has a unique β-sheet structure, which enables antiparallel association with the Titin Z1-Z2 domains in cardiac and skeletal muscle.[5] Structural analysis of full-length Telethonin with the N-terminal region of Titin indicate that the C-terminus of Telethonin is critical for the dimerization of two Telethonin/Titin complexes into a higher oligomeric structure.[6] # Function Telethonin expression is developmentally regulated in both cardiac and skeletal muscle and is thought to be critical to sarcomere assembly.[7] Telethonin was found to be a late assembling protein only present in mature myofibrils at Z-discs.[8] Telethonin forms a complex with MLP at Z-discs, which constitutes part of the cardiomyocyte stretch sensory mechanism.[9] It has also been shown that Telethonin binds to the beta-subunit of the slow activating component of the delayed rectifier potassium channel, MinK, in areas localized to T-tubule membranes surrounding Z-lines in the inner myocardium.[10] In addition, Telethonin interacts with the sodium channel Na(v)1.5, and alters the activation kinetics via doubling the window current.[11] These data suggest that Telethonin may constitute a mechano-electrical links between Z-lines and T-tubules. Further functional evidence for this has come from studies utilizing a Telethonin-knockout mouse (KO), which have shown that Telethonin is involved in T-tubule structure and function, as well as apoptosis in the heart. Telethonin KO animals showed preserved Titin anchoring at baseline, and instead showed a profound deficit during nuclear biomechanical stress in modulating the turnover of the proapoptotic p53 protein.[12] Telethonin KO animals also displayed calcium transient dysynchrony, T-tubule loss and depressed L-type calcium channel function.[13] Telethonin is a substrate of titin kinase,[14] protein kinase D (PKD) and CaM Kinase II.[15] Telethonin, as well as TNNI3, MYBPC3 and MYOM2 are phosphorylated by PKD in cardiomyocytes, and this leads to a reduction in calcium sensitivity of myofilaments, as well as accelerated crossbridge kinetics.[16] Bis-phosphorylation of Telethonin specifically at sites Serine-157 and Serine-161 has been shown to be essential for normal T-tubule organization and intracellular calcium transient kinetics.[15] The intracellular degradation of Telethonin is regulated by MDM2 in a proteasomal-dependent yet ubiquitin-independent manner.[17] Telethonin specifically interacts with the pro-apoptotic protein Siva, suggesting that Telethonin may be involved in the mechanism underlying Coxsackievirus B3 infection in acute and chronic myocarditis[18] Telethonin was also identified to be targeted and regulated by transcriptional activators CLOCK and BMAL1, thus demonstrating that TCAP is a circadian regulated gene.[19] # Clinical Significance Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G,[20] hypertrophic cardiomyopathy,[21][22][23] dilated cardiomyopathy,[24][25] idiopathic cardiomyopathy,[26] and gastrointestinal smooth muscle-related diseases.[11] Two mutations in Telethonin, Thr137Ile and Arg153His have been associated with hypertrophic cardiomyopathy, which enhance the binding of Telethonin with Titin and MYOZ2. The Glu132Gln mutation has been associated with dilated cardiomyopathy, which has the opposite effect in that it impairs the binding of Telethonin with Titin and MYOZ2.[27] Mutations in Titin associated with dilated cardiomyopathy, including Val54Met, have been shown specifically to impair binding of Titin with Telethonin.[28] In a mouse model of dilated cardiomyopathy, recapitulating the human dilated cardiomyopathy mutation in MLP, Trp4Arg, studies have found that this mutation disrupts normal binding and localization of MLP with Telethonin.[9] In a rat model of hypertension-induced cardiomyopathy, a human variant of BMP10, Thr326Ile, showed decreased binding to Telethonin and increased extracellular secretion.[29] # Interactions Telethonin has been shown to interact with: - ANKRD2,[30] - BMP10,[31] - MLP,[9] - MinK,[10] - MDM2,[32] - MSTN,[33] - MYOZ1,[34][35] - MYOZ2,[34] - PRKD1,[36] - SCN5A,[11] - SIVA,[37] and - Titin,[2][14][38][39]	https://www.wikidoc.org/index.php/Telethonin
1341252bcd5dfb7e17c0d604ce4078bc9b23a76a	wikidoc	Temocillin	Temocillin # Overview Temocillin is a β-lactamase-resistant penicillin introduced by Beecham, marketed by Eumedica Pharmaceuticals as Negaban. It is used primarily for the treatment of multiple drug-resistant, Gram-negative bacteria. It is a carboxypenicillin. # Pharmacology Temocillin is a β-lactamase-resistant penicillin. It is not active against Gram-positive bacteria or bacteria with altered penicillin-binding proteins. It is normally active against Moraxella catarrhalis, Brucella abortus, Burkholderia cepacia, Citrobacter species, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Pasteurella multocida, Proteus mirabilis, Salmonella typhimurium, and Yersinia enterocolitica. It is also active against some Enterobacter species, Morganella morganii, and Serratia species. Temocillin has no useful activity against Acinetobacter species or Pseudomonas aeruginosa. Its primary use is against Enterobacteriaceae, and in particular against strains producing extended-spectrum β-lactamase or AmpC β-lactamase. # Dosage The common dose is 2 g intravenously every 12 hours. Theoretical reasons exist for giving temocillin as a continuous intravenous infusion in severe disease: a single loading dose of 2 g is given intravenously followed by a 4-g infusion over 24 hours. Temocillin for intravenous injection is diluted in 20 ml of sterile water; it is diluted in less than 2.7 ml of sterile water when being prepared for intramuscular injection; the continuous infusion is diluted in 48 ml of sterile water for ease of administration (1 ml per half hour). To reduce pain, the intramuscular injection may be made up using sterile 1% lignocaine instead of sterile water. Temocillin may be given to patients with impaired renal function. No adjustment needs to be made to the dose in mild to moderate renal impairment (creatinine clearance greater than 30 ml/min). Temocillin is cleared by haemodialysis, so in dialysis patients, the dose should be given after dialysis. No oral preparation of temocillin is licensed. # Adverse effects The undesirable effects of temocillin are those of any β-lactam antibiotic. In particular, it has been associated with angioedema and anaphylaxis in penicillin-allergic patients. Animal studies have not shown any induction of Clostridium difficile infection. As with any other penicillin, convulsions can occur if very high doses are given. # Synthesis	Temocillin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Temocillin is a β-lactamase-resistant penicillin[1][2] introduced by Beecham, marketed by Eumedica Pharmaceuticals as Negaban. It is used primarily for the treatment of multiple drug-resistant, Gram-negative bacteria. It is a carboxypenicillin.[3] # Pharmacology Temocillin is a β-lactamase-resistant penicillin. It is not active against Gram-positive bacteria or bacteria with altered penicillin-binding proteins. It is normally active against Moraxella catarrhalis, Brucella abortus, Burkholderia cepacia, Citrobacter species, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Pasteurella multocida, Proteus mirabilis, Salmonella typhimurium, and Yersinia enterocolitica. It is also active against some Enterobacter species, Morganella morganii, and Serratia species. Temocillin has no useful activity against Acinetobacter species or Pseudomonas aeruginosa. Its primary use is against Enterobacteriaceae, and in particular against strains producing extended-spectrum β-lactamase or AmpC β-lactamase.[4] # Dosage The common dose is 2 g intravenously every 12 hours. Theoretical reasons exist for giving temocillin as a continuous intravenous infusion in severe disease:[5] a single loading dose of 2 g is given intravenously followed by a 4-g infusion over 24 hours. Temocillin for intravenous injection is diluted in 20 ml of sterile water; it is diluted in less than 2.7 ml of sterile water when being prepared for intramuscular injection; the continuous infusion is diluted in 48 ml of sterile water for ease of administration (1 ml per half hour). To reduce pain, the intramuscular injection may be made up using sterile 1% lignocaine instead of sterile water. Temocillin may be given to patients with impaired renal function. No adjustment needs to be made to the dose in mild to moderate renal impairment (creatinine clearance greater than 30 ml/min). Temocillin is cleared by haemodialysis, so in dialysis patients, the dose should be given after dialysis. No oral preparation of temocillin is licensed. # Adverse effects The undesirable effects of temocillin are those of any β-lactam antibiotic. In particular, it has been associated with angioedema and anaphylaxis in penicillin-allergic patients. Animal studies have not shown any induction of Clostridium difficile infection.[6] As with any other penicillin, convulsions can occur if very high doses are given. # Synthesis	https://www.wikidoc.org/index.php/Temocillin
2e7f41082e3774b1484d7009b1f7ac09f0841f36	wikidoc	Temoporfin	Temoporfin # Overview Temoporfin (INN) is a photosensitizer (based on chlorin) used in photodynamic therapy for the treatment of squamous cell carcinoma of the head and neck It is marketed in the European Union under the brand name Foscan. The U.S. Food and Drug Administration (FDA) declined to approve Foscan in 2000. The EU approved its use in June 2001. Good results were obtained in 21 of 35 patients treated in Germany. It is photoactivated at 652 nm i.e. by red light. Patients can remain photosensitive for several weeks after treatment. # Further reading - Relationship between subcellular localisation of Foscan and caspase activation in photosensitised MCF-7 cells. Marchal et al. 2007	Temoporfin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Temoporfin (INN) is a photosensitizer (based on chlorin) used in photodynamic therapy for the treatment of squamous cell carcinoma of the head and neck[1] .[2] It is marketed in the European Union under the brand name Foscan. The U.S. Food and Drug Administration (FDA) declined to approve Foscan in 2000. The EU approved its use in June 2001.[3] Good results were obtained in 21 of 35 patients treated in Germany.[4] It is photoactivated at 652 nm[5] i.e. by red light. Patients can remain photosensitive for several weeks after treatment.[2] # Further reading - Relationship between subcellular localisation of Foscan and caspase activation in photosensitised MCF-7 cells. Marchal et al. 2007	https://www.wikidoc.org/index.php/Temoporfin
8fd9281f566e2bbfa51b95349f408f46de8176ed	wikidoc	Tenascin C	Tenascin C Tenascin C (TN-C) is a glycoprotein that in humans is encoded by the TNC gene. It is expressed in the extracellular matrix of various tissues during development, disease or injury, and in restricted neurogenic areas of the central nervous system. Tenascin-C is the founding member of the tenascin protein family. In the embryo it is made by migrating cells like the neural crest; it is also abundant in developing tendons, bone and cartilage. # Gene and expression The human tenascin C gene, TN-C, is located on chromosome 9 with location of the cytogenic band at the 9q33. The entire Tenascin family coding region spans approximately 80 kilobases translating into 2203 amino acids. Expression of TN-C changes from development to adulthood. TN-C is highly expressed during embryogenesis and is briefly expressed during organogenesis, while in developed organs, expression is absent or in trace amounts. TN-C has been shown to be upregulated under pathological conditions caused by inflammation, infection, tumorigenesis, and at sites that are subject to unique biomechanics forces. The regulation of TN-C is induced or repressed by a number of different factors that are expressed during embryonic tissue, as well as developed tissues during remodeling, injured, or neoplastic. TGF-β1, tumor necrosis factor-α, interleukin-1, nerve growth factor, and keratinocyte growth factor are factors that have been shown to regulate TN-C. Other extracellular matrix components such as matrix metalloproteins and integrins are also frequently co-expressed with TN-C. In the developing central nervous system, TN-C is involved in regulating the proliferation of both oligodendrocyte precursor cells and astrocytes. Expression of TN-C by radial glia precedes the onset of gliogenesis, during which time it is thought to drive the differentiation of astrocytes. In the adult brain, TN-C expression is downregulated except for the areas that maintain neurogenesis into adulthood and the hypothalamus. TN-C is also present in central nervous system injuries and gliomas. # Structure Tenascin C is an oligomeric glycoprotein composed of individual polypeptides with molecular weights ranging from 180 to ~300kDa. The Tenascin family of proteins shares a similar structural pattern. These similar modules include heptad repeats, EGF-like repeats, fibronectin type III domains, and a C-terminal globular domain shared with fibrinogens. These protein modules are lined up like beads on a string and give rise to long and extended molecules. At the N-terminus each Tenascin has an oligomerization domain which in the case of TN-C leads to the formation of hexamers. TN-C and -R are known to be subject to alternative splicing. In human TN-C there exists, in addition to the eight constant repeats, nine extra repeats subject to alternative splicing. This results in a multitude of TN-C subunits differing in the number and identity of fibronectin type III domain repeats. # Interactions Tenascin-C has been shown to interact with fibronectin. This interaction is shown to have the potential to modify cell adhesion. A solid-state interaction between fibronectin and TN-C results in cellular upregulation of matrix metalloproteinase expression. TN-C also interacts with one or more TN-C receptors on cells which activate and repress the same signal transduction pathway. An example of this interaction is the adhesion of SW80 carcinoma cells to the third FN-III repeat of TN-C via the αvβ3 integrin receptor leads to cell spreading, phosphorylation of focal adhesion kinase, paxillin and ERK2 MAPK, and proliferation. In contrast, when these same cells use either α9β1 or αvβ6 integrins to adhere to the same third FN type III repeat, cell spreading is attenuated and activation of these signaling mediators and cell growth is suppressed or fails to occur. # Function Tenascin C is a very diverse protein that can produce different functions within the same cell type. This myriad of functions is accomplished through alternative splicing of mRNA as well as the temporal activation of signal transduction pathways and/or target genes at different stages of growth or differentiation. TN-C is classified as an adhesion-modulating protein, because it has been found to inhibit cellular adhesion to fibronectin. Much of the functional studies are inferred from various TN-C knockout mice models. TN-C clearly plays a role in cell signaling as evidenced by its ability to be induced during events such as trauma, inflammation, or cancer development. Also, TN-C is important in regulating cell proliferation and migration, especially during developmental differentiation and wound healing. # Clinical significance Tenascin C continues to be researched as a potential biomarker for a number of diseases such as myocarditis and different forms of cancer. The numerous involvements with cellular functioning and signaling make TN-C a popular protein to study in developing new therapies and detection methods. Recent work has shown that TN-C inhibits HIV infection in immune cells by binding to a chemokine coreceptor site on the HIV-1 envelope protein, blocking the virus' entry into the host cells. ## Role in cancer Tenascin C is implicated in a number of different cancers such as osteosarcomas, chondrosarcomas, bladder cancer, and glioblastomas. In glioblastoma cells, Tenascin-C expression provides much clinical and functional significance in terms of cancer prognosis and tumor progression. The endogenous pool of tenascin-C isoforms in gliomas supports both tumor cell proliferation and migration. Because tenascin-C is essential to the survival of these various forms of cancers, tenascin-c expression could be a potential biomarker for cancer detection. Also, tenascin-C antibodies have been used to diagnose and create therapies for many different types of cancers.	Tenascin C Tenascin C (TN-C) is a glycoprotein that in humans is encoded by the TNC gene.[1][2] It is expressed in the extracellular matrix of various tissues during development, disease or injury, and in restricted neurogenic areas of the central nervous system.[3][4] Tenascin-C is the founding member of the tenascin protein family. In the embryo it is made by migrating cells like the neural crest; it is also abundant in developing tendons, bone and cartilage. # Gene and expression The human tenascin C gene, TN-C, is located on chromosome 9 with location of the cytogenic band at the 9q33. The entire Tenascin family coding region spans approximately 80 kilobases translating into 2203 amino acids.[5] Expression of TN-C changes from development to adulthood. TN-C is highly expressed during embryogenesis and is briefly expressed during organogenesis, while in developed organs, expression is absent or in trace amounts.[6] TN-C has been shown to be upregulated under pathological conditions caused by inflammation, infection, tumorigenesis, and at sites that are subject to unique biomechanics forces.[6][7] The regulation of TN-C is induced or repressed by a number of different factors that are expressed during embryonic tissue, as well as developed tissues during remodeling, injured, or neoplastic.[8] TGF-β1, tumor necrosis factor-α, interleukin-1, nerve growth factor, and keratinocyte growth factor are factors that have been shown to regulate TN-C.[9] Other extracellular matrix components such as matrix metalloproteins and integrins are also frequently co-expressed with TN-C.[10] In the developing central nervous system, TN-C is involved in regulating the proliferation of both oligodendrocyte precursor cells and astrocytes. Expression of TN-C by radial glia precedes the onset of gliogenesis, during which time it is thought to drive the differentiation of astrocytes.[4] In the adult brain, TN-C expression is downregulated except for the areas that maintain neurogenesis into adulthood and the hypothalamus.[4] TN-C is also present in central nervous system injuries and gliomas.[4] # Structure Tenascin C is an oligomeric glycoprotein composed of individual polypeptides with molecular weights ranging from 180 to ~300kDa. The Tenascin family of proteins shares a similar structural pattern. These similar modules include heptad repeats, EGF-like repeats, fibronectin type III domains, and a C-terminal globular domain shared with fibrinogens. These protein modules are lined up like beads on a string and give rise to long and extended molecules.[5] At the N-terminus each Tenascin has an oligomerization domain which in the case of TN-C leads to the formation of hexamers.[5] TN-C and -R are known to be subject to alternative splicing. In human TN-C there exists, in addition to the eight constant repeats, nine extra repeats subject to alternative splicing. This results in a multitude of TN-C subunits differing in the number and identity of fibronectin type III domain repeats.[6] # Interactions Tenascin-C has been shown to interact with fibronectin.[11] This interaction is shown to have the potential to modify cell adhesion.[12] A solid-state interaction between fibronectin and TN-C results in cellular upregulation of matrix metalloproteinase expression.[13] TN-C also interacts with one or more TN-C receptors on cells which activate and repress the same signal transduction pathway. An example of this interaction is the adhesion of SW80 carcinoma cells to the third FN-III repeat of TN-C via the αvβ3 integrin receptor leads to cell spreading, phosphorylation of focal adhesion kinase, paxillin and ERK2 MAPK, and proliferation.[14] In contrast, when these same cells use either α9β1 or αvβ6 integrins to adhere to the same third FN type III repeat, cell spreading is attenuated and activation of these signaling mediators and cell growth is suppressed or fails to occur. # Function Tenascin C is a very diverse protein that can produce different functions within the same cell type. This myriad of functions is accomplished through alternative splicing of mRNA as well as the temporal activation of signal transduction pathways and/or target genes at different stages of growth or differentiation.[8] TN-C is classified as an adhesion-modulating protein, because it has been found to inhibit cellular adhesion to fibronectin.[6] Much of the functional studies are inferred from various TN-C knockout mice models. TN-C clearly plays a role in cell signaling as evidenced by its ability to be induced during events such as trauma, inflammation, or cancer development. Also, TN-C is important in regulating cell proliferation and migration, especially during developmental differentiation and wound healing.[15] # Clinical significance Tenascin C continues to be researched as a potential biomarker for a number of diseases such as myocarditis[16] and different forms of cancer. The numerous involvements with cellular functioning and signaling make TN-C a popular protein to study in developing new therapies and detection methods. Recent work has shown that TN-C inhibits HIV infection in immune cells by binding to a chemokine coreceptor site on the HIV-1 envelope protein, blocking the virus' entry into the host cells.[17] ## Role in cancer Tenascin C is implicated in a number of different cancers such as osteosarcomas,[18] chondrosarcomas,[19] bladder cancer,[20] and glioblastomas.[21] In glioblastoma cells, Tenascin-C expression provides much clinical and functional significance in terms of cancer prognosis and tumor progression. The endogenous pool of tenascin-C isoforms in gliomas supports both tumor cell proliferation and migration.[21] Because tenascin-C is essential to the survival of these various forms of cancers, tenascin-c expression could be a potential biomarker for cancer detection. Also, tenascin-C antibodies have been used to diagnose and create therapies for many different types of cancers.[22][23]	https://www.wikidoc.org/index.php/Tenascin_C
d7e713c73b4cba7129b1ff1058ee3d45cd8deea1	wikidoc	Tendinitis	Tendinitis Synonyms and keywords: Tendinosis; tendonitis # Overview Tendinitis (also with the nonmedical spelling tendonitis) is a painful disorder of a tendon. Generally tendinitis is referred to by the body part involved, such as Achilles tendinitis (affecting the Achilles tendon), or patellar tendinitis (jumper's knee, affecting the patellar tendon). It was believed that tendinitis was due to inflammation of a tendon, although this is coming into doubt. Chronic overuse of tendons leads to microscopic tears within the collagen matrix, which gradually weakens the tissue. # Common areas of tendinitis Tendinous injuries are common in the upper and lower limbs (including the rotator cuff attachments), and are less common in the hips and torso. Individual variation in frequency and severity of tendinitis will vary depending on the type, frequency and severity of exercise or use; for example, rock climbers tend to develop tendinitis in their fingers, swimmers in their shoulders. Achilles tendinitis is a common injury, particularly in sports that involve lunging and jumping while patellar tendinitis is a common among basketball and volleyball players owing to the amount of jumping and landing. # Causes - Drug side effect - Ciprofloxacin - Gemifloxacin mesylate - Levofloxacin - Norfloxacin # Diagnosis Swelling in a region of micro damage or partial tear can be detected visually or by touch. Increased water content and disorganized collagen matrix in tendon lesions may be detected by ultrasonography or magnetic resonance imaging. Symptoms can vary from an ache or pain and stiffness to the local area of the tendon, or a burning that surrounds the whole joint around the inflamed tendon. With this condition, the pain is usually worse during and after activity, and the tendon and joint area can become stiffer the following day as swelling impinges on the movement of the tendon. Many patients report stressful situations in their life in correlation with the beginnings of pain which may contribute to the symptoms. # Treatment Due to their highly specialized ultra-structure, low level of vascularization and slow collagen turnover, tendons and ligaments are very slow to heal if injured, and rarely regain their original strength. Partial tears heal by the rapid production of disorganized type-III collagen, which is weaker than normal tendon. Recurrence of injury in the damaged region of tendon is common. Standard treatment of tendon injuries is largely palliative. Use of non-steroidal anti-inflammatory drugs combined with rest and gradual return to exercise is a common therapy, although there is evidence to suggest that tendinitis is not an inflammatory disorder, and that anti-inflammatory drugs are not an effective treatment and that inflammation does not cause tendon dysfunction. ## On-going research Both eccentric loading and extracorporeal shockwave therapy are currently being researched as possible treatments for tendinitis. One study found both modalities to be equally effective in treating tendinosis of the Achilles tendon and more effective than a 'wait and see' approach. Other treatments for which research is on-going includes vitamin E, nitric oxide and stem cell injections. ## Eccentric loading Perhaps the most promising avenue of therapy is indicated in a line of research finding dramatic rates of recovery including complete remodeling of chronically damaged tendon tissue with eccentric loading, though eccentric loading may be less effective among non-athletes. However, a 2007 meta-analysis suggested that there is insufficient research to support the use of eccentric loading for the treatment of damage to tendons. ## Inflatable brace The use of an inflatable brace (AirHeel) was shown to be as effective as eccentric loading in the treatment of chronic Achilles tendinopathy. Both modalities produced significant reduction in pain scores, but their combination was no more effective than either treatment alone. ## Shock-wave therapy Shock-wave therapy (SWT) may be effective in treating calcific tendinitis in both humans and rats. In rat subjects, SWT increased levels of healing hormones and proteins leading to increased cell proliferation and tissue regeneration in tendons. Another study found no evidence that SWT was useful in treating chronic pain in the Achilles tendon. ## Vitamin E Vitamin E has been found to increase the activity of fibroblasts, leading to increased collagen fibrils and synthesis, which seems to speed up the regeneration and increase the regenerative capacity of tendons. ## Nitric oxide Nitric oxide (NO) also appears to play a role in tendon healing and inhibition of NO synthesis impairs tendon healing. Supplementing with arginine, the amino acid that the body uses to form NO, may be useful in tendon healing. The use of a NO delivery system (glyceryl trinitrate patches) applied over the area of maximal tenderness was tested in three clinical trials for the treatment of tendinopathies and was found to significantly reduce pain and increase range of motion and strength. # Related Chapters - Repetitive strain injury - Stenosing tenosynovitis - Tenosynovitis - Tendinosis - Orthopedic surgery - Tennis elbow - Tension myositis syndrome	Tendinitis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2] Synonyms and keywords: Tendinosis; tendonitis # Overview Tendinitis (also with the nonmedical spelling tendonitis) is a painful disorder of a tendon. Generally tendinitis is referred to by the body part involved, such as Achilles tendinitis (affecting the Achilles tendon), or patellar tendinitis (jumper's knee, affecting the patellar tendon). It was believed that tendinitis was due to inflammation of a tendon, although this is coming into doubt. Chronic overuse of tendons leads to microscopic tears within the collagen matrix, which gradually weakens the tissue. # Common areas of tendinitis Tendinous injuries are common in the upper and lower limbs (including the rotator cuff attachments), and are less common in the hips and torso. Individual variation in frequency and severity of tendinitis will vary depending on the type, frequency and severity of exercise or use; for example, rock climbers tend to develop tendinitis in their fingers, swimmers in their shoulders. Achilles tendinitis is a common injury, particularly in sports that involve lunging and jumping while patellar tendinitis is a common among basketball and volleyball players owing to the amount of jumping and landing.[1] # Causes - Drug side effect - Ciprofloxacin - Gemifloxacin mesylate - Levofloxacin - Norfloxacin # Diagnosis Swelling in a region of micro damage or partial tear can be detected visually or by touch. Increased water content and disorganized collagen matrix in tendon lesions may be detected by ultrasonography or magnetic resonance imaging. Symptoms can vary from an ache or pain and stiffness to the local area of the tendon, or a burning that surrounds the whole joint around the inflamed tendon. With this condition, the pain is usually worse during and after activity, and the tendon and joint area can become stiffer the following day as swelling impinges on the movement of the tendon. Many patients report stressful situations in their life in correlation with the beginnings of pain which may contribute to the symptoms. # Treatment Due to their highly specialized ultra-structure, low level of vascularization and slow collagen turnover, tendons and ligaments are very slow to heal if injured, and rarely regain their original strength. Partial tears heal by the rapid production of disorganized type-III collagen, which is weaker than normal tendon. Recurrence of injury in the damaged region of tendon is common. Standard treatment of tendon injuries is largely palliative. Use of non-steroidal anti-inflammatory drugs combined with rest and gradual return to exercise is a common therapy, although there is evidence to suggest that tendinitis is not an inflammatory disorder, and that anti-inflammatory drugs are not an effective treatment[2] and that inflammation does not cause tendon dysfunction.[3] ## On-going research Both eccentric loading and extracorporeal shockwave therapy are currently being researched as possible treatments for tendinitis. One study found both modalities to be equally effective in treating tendinosis of the Achilles tendon and more effective than a 'wait and see' approach.[4] Other treatments for which research is on-going includes vitamin E, nitric oxide and stem cell injections. ## Eccentric loading Perhaps the most promising avenue of therapy is indicated in a line of research finding dramatic rates of recovery including complete remodeling of chronically damaged tendon tissue with eccentric loading,[5][6][7][8][9][10][11][12] though eccentric loading may be less effective among non-athletes.[13] However, a 2007 meta-analysis suggested that there is insufficient research to support the use of eccentric loading for the treatment of damage to tendons.[14] ## Inflatable brace The use of an inflatable brace (AirHeel) was shown to be as effective as eccentric loading in the treatment of chronic Achilles tendinopathy. Both modalities produced significant reduction in pain scores, but their combination was no more effective than either treatment alone.[15] ## Shock-wave therapy Shock-wave therapy (SWT) may be effective in treating calcific tendinitis in both humans[16] and rats.[17] In rat subjects, SWT increased levels of healing hormones and proteins leading to increased cell proliferation and tissue regeneration in tendons. Another study found no evidence that SWT was useful in treating chronic pain in the Achilles tendon.[18] ## Vitamin E Vitamin E has been found to increase the activity of fibroblasts, leading to increased collagen fibrils and synthesis, which seems to speed up the regeneration and increase the regenerative capacity of tendons.[19][20] ## Nitric oxide Nitric oxide (NO) also appears to play a role in tendon healing[21] and inhibition of NO synthesis impairs tendon healing.[22] Supplementing with arginine, the amino acid that the body uses to form NO, may be useful in tendon healing.[23] The use of a NO delivery system (glyceryl trinitrate patches) applied over the area of maximal tenderness was tested in three clinical trials for the treatment of tendinopathies and was found to significantly reduce pain and increase range of motion and strength.[24] # Related Chapters - Repetitive strain injury - Stenosing tenosynovitis - Tenosynovitis - Tendinosis - Orthopedic surgery - Tennis elbow - Tension myositis syndrome	https://www.wikidoc.org/index.php/Tendinitis
3a1fda5352231272d294f574d359dadd3010beb1	wikidoc	Tendinosis	Tendinosis Tendinosis, sometimes called chronic tendinitis, chronic tendinopathy or chronic tendon injury, is damage to a tendon at a cellular level. It is thought to be caused by microtears in the connective tissue in and around the tendon. Tendinosis is typically diagnosed as tendinitis due to the limited understanding of tendinopathies by the medical community. The suffix 'itis' means inflammation leading to anti-inflammatories being prescribed, despite there being limited support for this treatment in clinical trials. The strongest evidence for treatment of tendinosis is for nitric oxide patches and for forms of resistance training exercises that 'load' the affected tendon.	Tendinosis Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Tendinosis, sometimes called chronic tendinitis, chronic tendinopathy or chronic tendon injury, is damage to a tendon at a cellular level. It is thought to be caused by microtears in the connective tissue in and around the tendon. Tendinosis is typically diagnosed as tendinitis due to the limited understanding of tendinopathies by the medical community.[1] The suffix 'itis' means inflammation leading to anti-inflammatories being prescribed, despite there being limited support for this treatment in clinical trials.[2] The strongest evidence for treatment of tendinosis is for nitric oxide patches and for forms of resistance training exercises that 'load' the affected tendon.	https://www.wikidoc.org/index.php/Tendinosis
494e963906681ed5f5ef32cb05bbb41e9e1b7f42	wikidoc	Teniposide	Teniposide # 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 Teniposide is an antineoplastic and a mitotic inhibitor that is FDA approved for the treatment of childhood acute lymphoblastic leukemia. Common adverse reactions include diarrhea, inflammatory disease of mucous membrane, nausea, vomiting, anemia, leukopenia, thrombocytopenia and infectious disease. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) NOTE: Contact of undiluted teniposide with plastic equipment or devices used to prepare solutions for infusion may result in softening or cracking and possible drug product leakage. This effect has not been reported with diluted solutions of teniposide. - In order to prevent extraction of the plasticizer DEHP , solutions of teniposide should be prepared in non-DEHP containing LVP containers such as glass or polyolefin plastic bags or containers. - Teniposide solutions should be administered with non-DEHP containing intravenous administration sets. - In one study, childhood ALL patients failing induction therapy with a cytarabine-containing regimen were treated with the combination of teniposide 165 mg/m2 and cytarabine 300 mg/m2 intravenously, twice weekly for 8 to 9 doses. In another study, patients with childhood ALL refractory to vincristine/prednisone-containing regimens were treated with the combination of teniposide 250 mg/m2 and vincristine 1.5 mg/m2 intravenously, weekly for 4 to 8 weeks and prednisone 40 mg/m2 orally for 28 days. - Adequate data in patients with hepatic insufficiency and/or renal insufficiency are lacking, but dose adjustments may be necessary for patients with significant renal or hepatic impairment. ### Preparation and Administration Precautions - Caution should be exercised in handling and preparing the solution of teniposide. Several guidelines on proper handling and disposal of anticancer drugs have been published.1-4 Skin reactions associated with accidental exposure to teniposide may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling ampules containing teniposide. If teniposide solution contacts the skin, immediately wash the skin thoroughly with soap and water. If teniposide contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below. ### Preparation for Intravenous Administration - Teniposide must be diluted with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, to give final teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, or 1.0 mg/mL. Solutions prepared in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP at teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, or 0.4 mg/mL are stable at room temperature for up to 24 hours after preparation. Teniposide solutions prepared at a final teniposide concentration of 1.0 mg/mL should be administered within 4 hours of preparation to reduce the potential for precipitation. Refrigeration of teniposide solutions is not recommended. Stability and use times are identical in glass and plastic parenteral solution containers. - Although solutions are chemically stable under the conditions indicated, precipitation of teniposide may occur at the recommended concentrations, especially if the diluted solution is subjected to more agitation than is recommended to prepare the drug solution for parenteral administration. In addition, storage time prior to administration should be minimized and care should be taken to avoid contact of the diluted solution with other drugs or fluids. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Precipitation has been reported during 24-hour infusions of teniposide diluted to teniposide concentrations of 0.1 to 0.2 mg/mL, resulting in occlusion of central venous access catheters in several patients. Heparin solution can cause precipitation of teniposide, therefore, the administration apparatus should be flushed thoroughly with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP before and after administration of teniposide. Hypotension has been reported following rapid intravenous administration; it is recommended that the teniposide solution be administered over at least a 30- to 60-minute period. Teniposide should not be given by rapid intravenous injection. - In a 24-hour study under simulated conditions of actual use of the product relative to dilution strength, diluent and administration rates, dilutions at 0.1 to 1.0 mg/mL were chemically stable for at least 24 hours. Data collected for the presence of the extractable DEHP from PVC containers show that levels increased with time and concentration of the solutions. The data appeared similar for 0.9% Sodium Chloride Injection, USP, and 5% Dextrose Injection, USP. Consequently, the use of PVC containers is not recommended. - Similarly, the use of non-DEHP intravenous administration sets is recommended. Lipid administration sets or low DEHP-containing nitroglycerin sets will keep patient’s exposure to DEHP at low levels and are suitable for use. The diluted solutions are chemically and physically compatible with the recommended intravenous administration sets and LVP containers for up to 24 hours at ambient room temperature and lighting conditions. Because of the potential for precipitation, compatibility with other drugs, infusion materials, or intravenous pumps cannot be assured. ### Stability - Unopened ampules of teniposide are stable until the date indicated on the package when stored under refrigeration 2° to 8°C (36° to 46°F) in the original package. Freezing does not adversely affect the product. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Teniposide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Teniposide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Teniposide 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 Teniposide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Teniposide in pediatric patients. # Contraindications - Teniposide is generally contraindicated in patients who have demonstrated a previous hypersensitivity to teniposide and/or polyoxyl 35 castor oil. # Warnings - Teniposide is a potent drug and should be used only by physicians experienced in the administration of cancer chemotherapeutic drugs. Blood counts, as well as renal and hepatic function tests, should be carefully monitored prior to and during therapy. - Patients being treated with teniposide injection should be observed frequently for myelosuppression both during and after therapy. Dose-limiting bone marrow suppression is the most significant toxicity associated with teniposide therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent dose of teniposide: hemoglobin, white blood cell count and differential, and platelet count. If necessary, repeat bone marrow examination should be performed prior to the decision to continue therapy in the setting of severe myelosuppression. Physicians should be aware of the possible occurrence of a hypersensitivity reaction variably manifested by chills, fever, urticaria, tachycardia, bronchospasm, dyspnea, hypertension, orhypotension, rash, and facial flushing. This reaction may occur with the first dose of teniposide and may be life threatening if not treated promptly with antihistamines, corticosteroids, epinephrine, intravenous fluids, and other supportive measures as clinically indicated. The exact cause of these reactions is unknown. They may be due to the polyoxyl 35 castor oil componentof the vehicle or to teniposide itself. Patients who have experienced prior hypersensitivity reactions to teniposide are at risk for recurrence of symptoms and should only be retreatedreactions has been accomplished using measures described above. To date, there is no evidence to suggest cross-sensitization between teniposide and etoposide. One episode of sudden death, attributed to probable arrhythmia and intractable hypotension, has been reported in an elderly patient receiving teniposide combination therapy for a nonleukemicmalignancy. - Patients receiving teniposide treatment should be under continuous observation for at least the first 60 minutes following the start ofthe infusion and at frequent intervals thereafter. If symptoms or signs of anaphylaxis occur, the infusion should be stopped immediately, followed by the administration of epinephrine, corticosteroids, antihistamines, pressor agents, or volume expanders at the discretion of the physician. An aqueous solution of epinephrine 1:1000 and a source of oxygen should beavailable at the bedside. - For parenteral administration, teniposide should be given only by slow intravenous infusion (lasting at least 30 to 60 minutes) since hypotension has been reported as a possible side effect of rapid intravenous injection, perhaps due to a direct effect of polyoxyl 35 castor oil. If clinically significant hypotension develops, the teniposide infusion should be discontinued. The blood pressure usually normalizes within hours in response to cessation of the infusion and administration of fluids or other supportive therapy as appropriate. If the infusion is restarted, a slower administration rate should be used and the patient should be carefully monitored. - Acute central nervous system depression, hypotension, and metabolic acidosis have been observed in patients receiving investigational infusions of high-dose teniposide who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the teniposide formulation may place patients receiving higher than recommended doses of teniposide a risk for central nervous system depression. # Adverse Reactions ## Clinical Trials Experience The table below presents the incidences of adverse reactions derived from an analysis of data contained within literature reports of 7 studies involving 303 pediatric patients in which teniposide was administered by injection as a single agent in a variety of doses and schedules for a variety of hematologic malignancies and solid tumors. The total number of patients evaluable for a given event was not 303 since the individual studies did not address the occurrence of each event listed. Five of these 7 studies assessed teniposide activity in hematologic malignancies, such as leukemia. Thus, many of these patients had abnormal hematologic status at start of therapy with teniposide and were expected to develop significant myelosuppression as an endpoint of treatment. ### Hematologic Toxicity - Teniposide, when used with other chemotherapeutic agents for the treatment of ALL, results in severe myelosuppression. Sepsis, sometimes fatal, may be a consequence of severe myelosuppression. Early onset of profound myelosuppression with delayed recovery can be expected when using the doses and schedules of teniposide necessary for treatment of refractory ALL, since bone marrow hypoplasia is a desired endpoint of therapy. The occurrence of acute non-lymphocytic leukemia (ANLL), with or without a preleukemic phase, has been reported in patients treated with teniposide in combination with other antineoplastic agents. ### Gastrointestinal Toxicity - Nausea and vomiting are the most common gastrointestinal toxicities, having occurred in 29% of evaluable pediatric patients. The severity of this nausea and vomiting is generally mild to moderate. ### Hypotension - Transient hypotension following rapid intravenous administration has been reported in 2% of evaluable pediatric patients. One episode of sudden death, attributed to probable arrhythmia and intractable hypotension, has been reported in an elderly patient receiving teniposide combination therapy for a non-leukemic malignancy. - No other cardiac toxicity or electrocardiographic changes have been documented. No delayed hypotension has been noted. ### Allergic Reactions - Hypersensitivity reactions characterized by chills, fever, tachycardia, flushing, bronchospasm, dyspnea, rash, and blood pressure changes (hypertension or hypotension) have been reported to occur in approximately 5% of evaluable pediatric patients receiving intravenous teniposide. The incidence of hypersensitivity reactions to teniposide appears to be increased in patients with brain tumors and in patients with neuroblastoma. ### Central Nervous System - Neurotoxicity has been reported, including severe cases of neuropathy, in patients receiving vincristine sulfate and teniposide concomitantly. - Acute central nervous system depression and hypotension have been observed in patients receiving investigational infusions of high-dose teniposide who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the teniposide formulation may place patients receiving higher than recommended doses of teniposide at risk for central nervous system depression. ### Alopecia - Alopecia, sometimes progressing to total baldness, was observed in 9% of evaluable pediatric patients who received teniposide as single-agent therapy. It was usually reversible. ### Other Adverse Reactions - The following adverse reactions have been reported: headache, confusion, and asthenia. Headache and confusion were associated with hypersensitivity reactions. ## Postmarketing Experience There is limited information regarding Teniposide Postmarketing Experience in the drug label. # Drug Interactions - In a study in which 34 different drugs were tested, therapeutically relevant concentrations of tolbutamide, sodium salicylate, and sulfamethizole displaced protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering teniposide to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Teniposide may cause fetal harm when administered to a pregnant woman. Teniposide has been shown to be teratogenic and embryotoxic in laboratory animals. In pregnant rats, intravenous admin- istration of teniposide 0.1 to 3 mg/kg (0.6-18 mg/m2), every second day from day 6 to day 16 post coitum caused dose-related embryotoxicity and teratogenicity. Major anomalies included spinal and rib defects, deformed extremities, anophthalmia, and celosomia. - There are no adequate and well-controlled studies in pregnant women. If teniposide 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. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with teniposide. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Teniposide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Teniposide during labor and delivery. ### Nursing Mothers - It is not known whether this drug 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 the drug, taking into account the importance of teniposide therapy to the mother. ### Pediatric Use - Adverse events were evaluated in 7 studies involving 303 patients (age range 0.5 months to 20 years) who received teniposide as a single agent. No association between any particular age group and adverse effects was reported in any of these investigations. ### Geriatic Use There is no FDA guidance on the use of Teniposide in geriatric settings. ### Gender There is no FDA guidance on the use of Teniposide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Teniposide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Teniposide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Teniposide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Teniposide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Teniposide in patients who are immunocompromised. ### Patients With Down Syndrome - Patients with both Down syndrome and leukemia may be especially sensitive to myelosuppressive chemotherapy, therefore, initial dosing with teniposide should be reduced in these patients. It is suggested that the first course of teniposide should be given at half the usual dose. Subsequent courses may be administered at higher dosages depending on the degree of myelosuppression and mucositis encountered in earlier courses in an individual patient. # Administration and Monitoring ### Administration There is limited information regarding Teniposide Administration in the drug label. ### Monitoring There is limited information regarding Teniposide Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Teniposide and IV administrations. # Overdosage - Acute central nervous system depression, hypotension, and metabolic acidosis have been observed in patients who were receiving higher than recommended doses of teniposide, and who were also pretreated with antiemetic drugs. - There is no known antidote for teniposide overdosage. The anticipated complications of overdosage are secondary to bone marrow suppression. Treatment should consist of supportive care, including blood products and antibiotics as indicated. # Pharmacology ## Mechanism of Action - Teniposide is a phase-specific cytotoxic drug, acting in the late S phase or early G2 phase of the cell cycle, thus preventing cells from entering mitosis. - Teniposide causes dose-dependent single- and double-stranded breaks in DNA and DNA-protein cross-links. The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate. ## Structure - Teniposide is a semisynthetic derivative of podophyllotoxin. The chemical name for teniposide is 4-demethylepipodophyllotoxin 9-4,6-0-(R)-2-thenylidene-β-D-glucopyranoside. - Teniposide differs from etoposide, another podophyllotoxin derivative, by the substitution of a thenylidene group on the glucopyranoside ring. - Teniposide has the following structural formula: ## Pharmacodynamics There is limited information regarding Teniposide Pharmacodynamics in the drug label. ## Pharmacokinetics Plasma drug levels declined biexponentially following intravenous infusion (155 mg/m2 over 1 to 2.5 hours) of teniposide given to 8 children (4-11 years old) with newly diagnosed acute lymphoblastic leukemia (ALL). The observed average pharmacokinetic parameters and associated coefficients of variation (CV%) based on a two-compartmental model analysis of the data are as follows: - There appears to be some association between an increase in serum alkaline phosphatase or gamma glutamyl-transpeptidase and a decrease in plasma clearance of teniposide. Therefore, caution should be exercised if teniposide is to be administered to patients with hepatic dysfunction. - In adults, at doses of 100 to 333 mg/m2/day, plasma levels increased linearly with dose. Drug accumulation in adult patients did not occur after daily administration of teniposide for 3 days. In pediatric patients, maximum plasma concentrations (Cmax) after infusions of 137 to 203 mg/m2 over a period of 1 to 2 hours exceeded 40 mcg/mL; by 20 to 24 hours after infusion plasma levels were generally <2 mcg/mL. - Renal clearance of parent teniposide accounts for about 10% of total body clearance. In adults, after intravenous administration of 10 mg/kg or 67 mg/m2 of tritium-labeled teniposide, 44% of the radiolabel was recovered in urine (parent drug and metabolites) within 120 hours after dosing. From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose. - Mean steady-state volumes of distribution range from 8 to 44 L/m2 for adults and 3 to 11 L/m2 for children. The blood-brain barrier appears to limit diffusion of teniposide into the brain, although in a study in patients with brain tumors, CSF levels of teniposide were higher than CSF levels reported in other studies of patients who did not have brain tumors. - Teniposide is highly protein bound. In vitro plasma protein binding of teniposide is >99%. The high affinity of teniposide for plasma proteins may be an important factor in limiting distribution of drug within the body. Steady-state volume of distribution of the drug increases with a decrease in plasma albumin levels. Therefore, careful monitoring of children with hypoalbuminemia is indicated during therapy. Levels of teniposide in saliva, CSF, and malignant ascites fluid are low relative to simultaneously measured plasma levels. - The pharmacokinetic characteristics of teniposide differ from those of etoposide, another podophyllotoxin. Teniposide is more extensively bound to plasma proteins and its cellular uptake is greater. - Teniposide also has a lower systemic clearance, a longer elimination half-life, and is excreted in the urine as parent drug to a lesser extent than etoposide. - In a study at St. Jude Children’s Research Hospital (SJCRH), 9 children with acute lymphocytic leukemia (ALL) failing induction therapy with a cytarabine-containing regimen, were treated with teniposide plus cytarabine. Three of these patients were induced into complete remission with durations of remission of 30 weeks, 59 weeks, and 13 years. In another study at SJCRH, 16 children with ALL rrefractory to vincristine/prednisone-containing regimens were treated with teniposide plus vincristine and prednisone. Three of these patients were induced into complete remission with durations of remission of 5.5, 37, and 73 weeks. In these 2 studies, patients served as their own control based on the premise that long-term complete remissions could not be achieved by re-treatment with drugs to which they had previously failed to respond. ## Nonclinical Toxicology There is limited information regarding Teniposide Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Teniposide Clinical Studies in the drug label. # How Supplied ## Storage - Store the unopened ampules under refrigeration 2° to 8°C (36° to 46°F). Retain in original package to protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Teniposide Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Teniposide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Vumon # Look-Alike Drug Names There is limited information regarding Teniposide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Teniposide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [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 Teniposide is an antineoplastic and a mitotic inhibitor that is FDA approved for the treatment of childhood acute lymphoblastic leukemia. Common adverse reactions include diarrhea, inflammatory disease of mucous membrane, nausea, vomiting, anemia, leukopenia, thrombocytopenia and infectious disease. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) NOTE: Contact of undiluted teniposide with plastic equipment or devices used to prepare solutions for infusion may result in softening or cracking and possible drug product leakage. This effect has not been reported with diluted solutions of teniposide. - In order to prevent extraction of the plasticizer DEHP [di(2-ethylhexyl) phthalate], solutions of teniposide should be prepared in non-DEHP containing LVP containers such as glass or polyolefin plastic bags or containers. - Teniposide solutions should be administered with non-DEHP containing intravenous administration sets. - In one study, childhood ALL patients failing induction therapy with a cytarabine-containing regimen were treated with the combination of teniposide 165 mg/m2 and cytarabine 300 mg/m2 intravenously, twice weekly for 8 to 9 doses. In another study, patients with childhood ALL refractory to vincristine/prednisone-containing regimens were treated with the combination of teniposide 250 mg/m2 and vincristine 1.5 mg/m2 intravenously, weekly for 4 to 8 weeks and prednisone 40 mg/m2 orally for 28 days. - Adequate data in patients with hepatic insufficiency and/or renal insufficiency are lacking, but dose adjustments may be necessary for patients with significant renal or hepatic impairment. ### Preparation and Administration Precautions - Caution should be exercised in handling and preparing the solution of teniposide. Several guidelines on proper handling and disposal of anticancer drugs have been published.1-4 Skin reactions associated with accidental exposure to teniposide may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling ampules containing teniposide. If teniposide solution contacts the skin, immediately wash the skin thoroughly with soap and water. If teniposide contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below. ### Preparation for Intravenous Administration - Teniposide must be diluted with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, to give final teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, or 1.0 mg/mL. Solutions prepared in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP at teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, or 0.4 mg/mL are stable at room temperature for up to 24 hours after preparation. Teniposide solutions prepared at a final teniposide concentration of 1.0 mg/mL should be administered within 4 hours of preparation to reduce the potential for precipitation. Refrigeration of teniposide solutions is not recommended. Stability and use times are identical in glass and plastic parenteral solution containers. - Although solutions are chemically stable under the conditions indicated, precipitation of teniposide may occur at the recommended concentrations, especially if the diluted solution is subjected to more agitation than is recommended to prepare the drug solution for parenteral administration. In addition, storage time prior to administration should be minimized and care should be taken to avoid contact of the diluted solution with other drugs or fluids. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Precipitation has been reported during 24-hour infusions of teniposide diluted to teniposide concentrations of 0.1 to 0.2 mg/mL, resulting in occlusion of central venous access catheters in several patients. Heparin solution can cause precipitation of teniposide, therefore, the administration apparatus should be flushed thoroughly with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP before and after administration of teniposide. Hypotension has been reported following rapid intravenous administration; it is recommended that the teniposide solution be administered over at least a 30- to 60-minute period. Teniposide should not be given by rapid intravenous injection. - In a 24-hour study under simulated conditions of actual use of the product relative to dilution strength, diluent and administration rates, dilutions at 0.1 to 1.0 mg/mL were chemically stable for at least 24 hours. Data collected for the presence of the extractable DEHP [di(2-ethylhexyl) phthalate] from PVC containers show that levels increased with time and concentration of the solutions. The data appeared similar for 0.9% Sodium Chloride Injection, USP, and 5% Dextrose Injection, USP. Consequently, the use of PVC containers is not recommended. - Similarly, the use of non-DEHP intravenous administration sets is recommended. Lipid administration sets or low DEHP-containing nitroglycerin sets will keep patient’s exposure to DEHP at low levels and are suitable for use. The diluted solutions are chemically and physically compatible with the recommended intravenous administration sets and LVP containers for up to 24 hours at ambient room temperature and lighting conditions. Because of the potential for precipitation, compatibility with other drugs, infusion materials, or intravenous pumps cannot be assured. ### Stability - Unopened ampules of teniposide are stable until the date indicated on the package when stored under refrigeration 2° to 8°C (36° to 46°F) in the original package. Freezing does not adversely affect the product. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Teniposide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Teniposide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Teniposide 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 Teniposide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Teniposide in pediatric patients. # Contraindications - Teniposide is generally contraindicated in patients who have demonstrated a previous hypersensitivity to teniposide and/or polyoxyl 35 castor oil. # Warnings - Teniposide is a potent drug and should be used only by physicians experienced in the administration of cancer chemotherapeutic drugs. Blood counts, as well as renal and hepatic function tests, should be carefully monitored prior to and during therapy. - Patients being treated with teniposide injection should be observed frequently for myelosuppression both during and after therapy. Dose-limiting bone marrow suppression is the most significant toxicity associated with teniposide therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent dose of teniposide: hemoglobin, white blood cell count and differential, and platelet count. If necessary, repeat bone marrow examination should be performed prior to the decision to continue therapy in the setting of severe myelosuppression. Physicians should be aware of the possible occurrence of a hypersensitivity reaction variably manifested by chills, fever, urticaria, tachycardia, bronchospasm, dyspnea, hypertension, orhypotension, rash, and facial flushing. This reaction may occur with the first dose of teniposide and may be life threatening if not treated promptly with antihistamines, corticosteroids, epinephrine, intravenous fluids, and other supportive measures as clinically indicated. The exact cause of these reactions is unknown. They may be due to the polyoxyl 35 castor oil componentof the vehicle or to teniposide itself. Patients who have experienced prior hypersensitivity reactions to teniposide are at risk for recurrence of symptoms and should only be retreatedreactions has been accomplished using measures described above. To date, there is no evidence to suggest cross-sensitization between teniposide and etoposide. One episode of sudden death, attributed to probable arrhythmia and intractable hypotension, has been reported in an elderly patient receiving teniposide combination therapy for a nonleukemicmalignancy. - Patients receiving teniposide treatment should be under continuous observation for at least the first 60 minutes following the start ofthe infusion and at frequent intervals thereafter. If symptoms or signs of anaphylaxis occur, the infusion should be stopped immediately, followed by the administration of epinephrine, corticosteroids, antihistamines, pressor agents, or volume expanders at the discretion of the physician. An aqueous solution of epinephrine 1:1000 and a source of oxygen should beavailable at the bedside. - For parenteral administration, teniposide should be given only by slow intravenous infusion (lasting at least 30 to 60 minutes) since hypotension has been reported as a possible side effect of rapid intravenous injection, perhaps due to a direct effect of polyoxyl 35 castor oil. If clinically significant hypotension develops, the teniposide infusion should be discontinued. The blood pressure usually normalizes within hours in response to cessation of the infusion and administration of fluids or other supportive therapy as appropriate. If the infusion is restarted, a slower administration rate should be used and the patient should be carefully monitored. - Acute central nervous system depression, hypotension, and metabolic acidosis have been observed in patients receiving investigational infusions of high-dose teniposide who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the teniposide formulation may place patients receiving higher than recommended doses of teniposide a risk for central nervous system depression. # Adverse Reactions ## Clinical Trials Experience The table below presents the incidences of adverse reactions derived from an analysis of data contained within literature reports of 7 studies involving 303 pediatric patients in which teniposide was administered by injection as a single agent in a variety of doses and schedules for a variety of hematologic malignancies and solid tumors. The total number of patients evaluable for a given event was not 303 since the individual studies did not address the occurrence of each event listed. Five of these 7 studies assessed teniposide activity in hematologic malignancies, such as leukemia. Thus, many of these patients had abnormal hematologic status at start of therapy with teniposide and were expected to develop significant myelosuppression as an endpoint of treatment. ### Hematologic Toxicity - Teniposide, when used with other chemotherapeutic agents for the treatment of ALL, results in severe myelosuppression. Sepsis, sometimes fatal, may be a consequence of severe myelosuppression. Early onset of profound myelosuppression with delayed recovery can be expected when using the doses and schedules of teniposide necessary for treatment of refractory ALL, since bone marrow hypoplasia is a desired endpoint of therapy. The occurrence of acute non-lymphocytic leukemia (ANLL), with or without a preleukemic phase, has been reported in patients treated with teniposide in combination with other antineoplastic agents. ### Gastrointestinal Toxicity - Nausea and vomiting are the most common gastrointestinal toxicities, having occurred in 29% of evaluable pediatric patients. The severity of this nausea and vomiting is generally mild to moderate. ### Hypotension - Transient hypotension following rapid intravenous administration has been reported in 2% of evaluable pediatric patients. One episode of sudden death, attributed to probable arrhythmia and intractable hypotension, has been reported in an elderly patient receiving teniposide combination therapy for a non-leukemic malignancy. - No other cardiac toxicity or electrocardiographic changes have been documented. No delayed hypotension has been noted. ### Allergic Reactions - Hypersensitivity reactions characterized by chills, fever, tachycardia, flushing, bronchospasm, dyspnea, rash, and blood pressure changes (hypertension or hypotension) have been reported to occur in approximately 5% of evaluable pediatric patients receiving intravenous teniposide. The incidence of hypersensitivity reactions to teniposide appears to be increased in patients with brain tumors and in patients with neuroblastoma. ### Central Nervous System - Neurotoxicity has been reported, including severe cases of neuropathy, in patients receiving vincristine sulfate and teniposide concomitantly. - Acute central nervous system depression and hypotension have been observed in patients receiving investigational infusions of high-dose teniposide who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the teniposide formulation may place patients receiving higher than recommended doses of teniposide at risk for central nervous system depression. ### Alopecia - Alopecia, sometimes progressing to total baldness, was observed in 9% of evaluable pediatric patients who received teniposide as single-agent therapy. It was usually reversible. ### Other Adverse Reactions - The following adverse reactions have been reported: headache, confusion, and asthenia. Headache and confusion were associated with hypersensitivity reactions. ## Postmarketing Experience There is limited information regarding Teniposide Postmarketing Experience in the drug label. # Drug Interactions - In a study in which 34 different drugs were tested, therapeutically relevant concentrations of tolbutamide, sodium salicylate, and sulfamethizole displaced protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering teniposide to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Teniposide may cause fetal harm when administered to a pregnant woman. Teniposide has been shown to be teratogenic and embryotoxic in laboratory animals. In pregnant rats, intravenous admin- istration of teniposide 0.1 to 3 mg/kg (0.6-18 mg/m2), every second day from day 6 to day 16 post coitum caused dose-related embryotoxicity and teratogenicity. Major anomalies included spinal and rib defects, deformed extremities, anophthalmia, and celosomia. - There are no adequate and well-controlled studies in pregnant women. If teniposide 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. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with teniposide. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Teniposide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Teniposide during labor and delivery. ### Nursing Mothers - It is not known whether this drug 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 the drug, taking into account the importance of teniposide therapy to the mother. ### Pediatric Use - Adverse events were evaluated in 7 studies involving 303 patients (age range 0.5 months to 20 years) who received teniposide as a single agent. No association between any particular age group and adverse effects was reported in any of these investigations. ### Geriatic Use There is no FDA guidance on the use of Teniposide in geriatric settings. ### Gender There is no FDA guidance on the use of Teniposide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Teniposide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Teniposide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Teniposide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Teniposide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Teniposide in patients who are immunocompromised. ### Patients With Down Syndrome - Patients with both Down syndrome and leukemia may be especially sensitive to myelosuppressive chemotherapy, therefore, initial dosing with teniposide should be reduced in these patients. It is suggested that the first course of teniposide should be given at half the usual dose. Subsequent courses may be administered at higher dosages depending on the degree of myelosuppression and mucositis encountered in earlier courses in an individual patient. # Administration and Monitoring ### Administration There is limited information regarding Teniposide Administration in the drug label. ### Monitoring There is limited information regarding Teniposide Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Teniposide and IV administrations. # Overdosage - Acute central nervous system depression, hypotension, and metabolic acidosis have been observed in patients who were receiving higher than recommended doses of teniposide, and who were also pretreated with antiemetic drugs. - There is no known antidote for teniposide overdosage. The anticipated complications of overdosage are secondary to bone marrow suppression. Treatment should consist of supportive care, including blood products and antibiotics as indicated. # Pharmacology ## Mechanism of Action - Teniposide is a phase-specific cytotoxic drug, acting in the late S phase or early G2 phase of the cell cycle, thus preventing cells from entering mitosis. - Teniposide causes dose-dependent single- and double-stranded breaks in DNA and DNA-protein cross-links. The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate. ## Structure - Teniposide is a semisynthetic derivative of podophyllotoxin. The chemical name for teniposide is 4-demethylepipodophyllotoxin 9-4,6-0-(R)-2-thenylidene-β-D-glucopyranoside. - Teniposide differs from etoposide, another podophyllotoxin derivative, by the substitution of a thenylidene group on the glucopyranoside ring. - Teniposide has the following structural formula: ## Pharmacodynamics There is limited information regarding Teniposide Pharmacodynamics in the drug label. ## Pharmacokinetics Plasma drug levels declined biexponentially following intravenous infusion (155 mg/m2 over 1 to 2.5 hours) of teniposide given to 8 children (4-11 years old) with newly diagnosed acute lymphoblastic leukemia (ALL). The observed average pharmacokinetic parameters and associated coefficients of variation (CV%) based on a two-compartmental model analysis of the data are as follows: - There appears to be some association between an increase in serum alkaline phosphatase or gamma glutamyl-transpeptidase and a decrease in plasma clearance of teniposide. Therefore, caution should be exercised if teniposide is to be administered to patients with hepatic dysfunction. - In adults, at doses of 100 to 333 mg/m2/day, plasma levels increased linearly with dose. Drug accumulation in adult patients did not occur after daily administration of teniposide for 3 days. In pediatric patients, maximum plasma concentrations (Cmax) after infusions of 137 to 203 mg/m2 over a period of 1 to 2 hours exceeded 40 mcg/mL; by 20 to 24 hours after infusion plasma levels were generally <2 mcg/mL. - Renal clearance of parent teniposide accounts for about 10% of total body clearance. In adults, after intravenous administration of 10 mg/kg or 67 mg/m2 of tritium-labeled teniposide, 44% of the radiolabel was recovered in urine (parent drug and metabolites) within 120 hours after dosing. From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose. - Mean steady-state volumes of distribution range from 8 to 44 L/m2 for adults and 3 to 11 L/m2 for children. The blood-brain barrier appears to limit diffusion of teniposide into the brain, although in a study in patients with brain tumors, CSF levels of teniposide were higher than CSF levels reported in other studies of patients who did not have brain tumors. - Teniposide is highly protein bound. In vitro plasma protein binding of teniposide is >99%. The high affinity of teniposide for plasma proteins may be an important factor in limiting distribution of drug within the body. Steady-state volume of distribution of the drug increases with a decrease in plasma albumin levels. Therefore, careful monitoring of children with hypoalbuminemia is indicated during therapy. Levels of teniposide in saliva, CSF, and malignant ascites fluid are low relative to simultaneously measured plasma levels. - The pharmacokinetic characteristics of teniposide differ from those of etoposide, another podophyllotoxin. Teniposide is more extensively bound to plasma proteins and its cellular uptake is greater. - Teniposide also has a lower systemic clearance, a longer elimination half-life, and is excreted in the urine as parent drug to a lesser extent than etoposide. - In a study at St. Jude Children’s Research Hospital (SJCRH), 9 children with acute lymphocytic leukemia (ALL) failing induction therapy with a cytarabine-containing regimen, were treated with teniposide plus cytarabine. Three of these patients were induced into complete remission with durations of remission of 30 weeks, 59 weeks, and 13 years. In another study at SJCRH, 16 children with ALL rrefractory to vincristine/prednisone-containing regimens were treated with teniposide plus vincristine and prednisone. Three of these patients were induced into complete remission with durations of remission of 5.5, 37, and 73 weeks. In these 2 studies, patients served as their own control based on the premise that long-term complete remissions could not be achieved by re-treatment with drugs to which they had previously failed to respond. ## Nonclinical Toxicology There is limited information regarding Teniposide Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Teniposide Clinical Studies in the drug label. # How Supplied ## Storage - Store the unopened ampules under refrigeration 2° to 8°C (36° to 46°F). Retain in original package to protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Teniposide Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Teniposide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Vumon # Look-Alike Drug Names There is limited information regarding Teniposide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Teniposide
228ab916178100fcc0d445885d646d49cd61a976	wikidoc	Teratology	Teratology # Background Teratology (from the Greek Template:Polytonic (genitive Template:Polytonic), meaning monster, or marvel and Template:Polytonic, meaning word, speech) In contemporary usage, the term teratology generally refers to disfiguring birth defects or malformations. Another term for this is dysmorphology, meaning "the study of abnormal form." # Etymology Teratology as early as 17th century referred to a discourse on prodigies and marvels, of anything so extraordinary as to seem abnormal. In 19th century, it acquired a meaning closer related to biological deformities, mostly in the field of botany. Currently, its most instrumental meaning is that of the medical study of teratogenesis, congenital malformations or grossly deformed individuals. Monster is a pejorative term for a grossly deformed individual, although it is interesting to note that, etymologically, this word is related to demonstration, and used to simply mean something worth looking at, for being unusual, without necessarily being pejorative. Teratology as a medical term was popularized in the 1960s by Dr. David W. Smith of the University of Washington Medical School, one of the researchers who became known in 1973 for the discovery of Fetal alcohol syndrome. With greater understanding of the origins of birth defects, the field of teratology now overlaps with other fields of basic science, including developmental biology, embryology, and genetics. # Teratogenesis and teratology Birth defects are known to occur in 3-5% of all newborns. They are the leading cause of infant mortality in the United States, accounting for more than 20% of all infant deaths. Seven to ten percent of all children will require extensive medical care to diagnose or treat a birth defect. Although significant progress has been made in identifying etiologic causes of some birth defects, approximately 65% have no known or identifiable cause. It was previously believed that the mammalian embryo developed in the impervious uterus of the mother, protected from all extrinsic factors. However, after the thalidomide disaster of the 1960's, it became apparent and more accepted that the developing embryo could be highly vulnerable to certain environmental agents that have negligible or non-toxic effects to adult individuals. ## Wilson's 6 principles Along with this new awareness of the in utero vulnerability of the developing mammalian embryo came the development and refinement of The Six Principles of Teratology which are still applied today. These principles of teratology were put forth by Jim Wilson in 1959 and in his monograph Environment and Birth Defects. These principles guide the study and understanding of teratogenic agents and their effects on developing organisms - Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors. - Susceptibility to teratogenesis varies with the developmental stage at the time of exposure to an adverse influence. There are critical periods of susceptibility to agents and organ systems affected by these agents. - Teratogenic agents act in specific ways on developing cells and tissues to initiate sequences of abnormal developmental events. - The access of adverse influences to developing tissues depends on the nature of the influence. Several factors affect the ability of a teratogen to contact a developing conceptus, such as the nature of the agent itself, route and degree of maternal exposure, rate of placental transfer and systemic absorption, and composition of the maternal and embryonic/fetal genotypes. - There are four manifestations of deviant development (Death, Malformation, Growth Retardation and Functional Defect). - Manifestations of deviant development increase in frequency and degree as dosage increases from the No Observable Adverse Effect Level (NOAEL) to a dose producing 100% Lethality (LD100). Studies designed to test the teratogenic potential of environmental agents use animal model systems (e.g., rat, mouse, rabbit, dog, and monkey). Early teratologists exposed pregnant animals to environmental agents and observed the fetuses for gross visceral and skeletal abnormalities. While this is still part of the teratological evaluation procedures today, the field of Teratology is moving to a more molecular level, seeking the mechanism(s) of action by which these agents act. Genetically modified mice are commonly used for this purpose. In addition, pregnancy registries are large, prospective studies that monitor exposures women receive during their pregnancies and record the outcome of their births. These studies provide information about possible risks of medications or other exposures in human pregnancies. Understanding how a teratogen causes its effect is not only important in preventing congenital abnormalities but also has the potential for developing new therapeutic drugs safe for use with pregnant women. # Teratology education It is estimated that 10% of all birth defects are caused by a prenatal exposure or teratogen. These exposures include, but are not limited to, medication or drug exposures, maternal infections and diseases, and environmental and occupational exposures. Teratogen-caused birth defects are potentially preventable. Studies have shown that nearly 50% of pregnant women have been exposed to at least one medication during gestation. An additional study found that of 200 individuals referred for genetic counseling for a teratogenic exposure, 52% were exposed to more than one potential teratogen. # Teratogenic agents A wide range of different chemicals and environmental factors are suspected or are known to be teratogenic in humans and in animals. A selected few include: - Ionizing radiation: atomic weapons, radioiodine, radiation therapy - Infections: cytomegalovirus, herpes virus, parvovirus B-19, rubella virus (German measles), syphilis, toxoplasmosis, Venezuelan equine encephalitis virus - Metabolic imbalance: alcoholism, endemic cretinism, diabetes, folic acid deficiency, hyperthermia, phenylketonuria, rheumatic disease and congenital heart block, virilizing tumors - Drugs and environmental chemicals: 13-cis-retinoic acid, isotretinoin (Accutane), temazepam (Restoril; Normisson), nitrazepam (Mogadon), nimetazepam (Ermin), aminopterin, androgenic hormones, busulfan, captopril, enalapril, chlorobiphenyls (PCBs), Dioxin, coumarin, cyclophosphamide, diethylstilbestrol, diphenylhydantoin (Phenytoin, Dilantin, Epanutin), ethanol, ethidium bromide, etretinate, lithium (Ebstein Anomalies), methimazole, organic mercury, penicillamine, tetracyclines, thalidomide, trimethadione, uranium, methoxyethyl ethers, Valganciclovir hydrochloride and valproic acid. The status of some of the above substances (e.g. diphenylhydantoin) is subject to debate, and many other compounds are under varying degrees of suspicion. These include Agent Orange, nicotine, aspirin and other NSAIDs. Other compounds are known as severe teratogens based on veterinary work and animal studies, but aren't listed above because they have not been studied in humans, e.g. cyclopamine. Teratogenic effects also help to determine the pregnancy category assigned by regulatory authorities; in the United States, a pregnancy category of X, D, or C may be assigned if teratogenic effects (or other risks in pregnancy) are documented or cannot be excluded. Isotretinoin (13-cis-retinoic-acid; brand name Accutane), which is often used to treat severe acne, is such a strong teratogen that just a single dose taken by a pregnant woman may result in serious birth defects. Because of this effect, most countries have systems in place to ensure that it is not given to pregnant women, and that the patient is aware of how important it is to prevent pregnancy during and at least one month after treatment. Medical guidelines also suggest that pregnant women should limit vitamin A intake to about 700 μg/day, as it has teratogenic potential when consumed in excess. # Teratogenic outcomes Exposure to teratogens can result in a wide range of structural abnormalities such as cleft lip, cleft palate, dysmelia, anencephaly, ventricular septal defect. In most cases, specific agents produce a specific teratogenic response. # Related Chapters - Summa izbu - a set of Mesopotamian omen texts about Teratology. - Congenital abnormalities - Carcinogen - Mutagen # Resources - Society of Teratology - European Teratology Society - Organization of Teratology Information Specialists - March of Dimes Foundation - A Telling of Wonders: Teratology in Western Medicine through 1800 (New York Academy of Medicine Historical Collections)	Teratology Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background Teratology (from the Greek Template:Polytonic (genitive Template:Polytonic), meaning monster, or marvel and Template:Polytonic, meaning word, speech) In contemporary usage, the term teratology generally refers to disfiguring birth defects or malformations. Another term for this is dysmorphology, meaning "the study of abnormal form." # Etymology Teratology as early as 17th century referred to a discourse on prodigies and marvels, of anything so extraordinary as to seem abnormal. In 19th century, it acquired a meaning closer related to biological deformities, mostly in the field of botany. Currently, its most instrumental meaning is that of the medical study of teratogenesis, congenital malformations or grossly deformed individuals. Monster is a pejorative term for a grossly deformed individual, although it is interesting to note that, etymologically, this word is related to demonstration, and used to simply mean something worth looking at, for being unusual, without necessarily being pejorative. Teratology as a medical term was popularized in the 1960s by Dr. David W. Smith of the University of Washington Medical School, one of the researchers who became known in 1973 for the discovery of Fetal alcohol syndrome.[citation needed] With greater understanding of the origins of birth defects, the field of teratology now overlaps with other fields of basic science, including developmental biology, embryology, and genetics. # Teratogenesis and teratology Birth defects are known to occur in 3-5% of all newborns.[1] They are the leading cause of infant mortality in the United States, accounting for more than 20% of all infant deaths. Seven to ten percent of all children will require extensive medical care to diagnose or treat a birth defect.[2] Although significant progress has been made in identifying etiologic causes of some birth defects, approximately 65% have no known or identifiable cause.[3] It was previously believed that the mammalian embryo developed in the impervious uterus of the mother, protected from all extrinsic factors. However, after the thalidomide disaster of the 1960's, it became apparent and more accepted that the developing embryo could be highly vulnerable to certain environmental agents that have negligible or non-toxic effects to adult individuals. ## Wilson's 6 principles Along with this new awareness of the in utero vulnerability of the developing mammalian embryo came the development and refinement of The Six Principles of Teratology which are still applied today. These principles of teratology were put forth by Jim Wilson in 1959 and in his monograph Environment and Birth Defects.[4] These principles guide the study and understanding of teratogenic agents and their effects on developing organisms - Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors. - Susceptibility to teratogenesis varies with the developmental stage at the time of exposure to an adverse influence. There are critical periods of susceptibility to agents and organ systems affected by these agents. - Teratogenic agents act in specific ways on developing cells and tissues to initiate sequences of abnormal developmental events. - The access of adverse influences to developing tissues depends on the nature of the influence. Several factors affect the ability of a teratogen to contact a developing conceptus, such as the nature of the agent itself, route and degree of maternal exposure, rate of placental transfer and systemic absorption, and composition of the maternal and embryonic/fetal genotypes. - There are four manifestations of deviant development (Death, Malformation, Growth Retardation and Functional Defect). - Manifestations of deviant development increase in frequency and degree as dosage increases from the No Observable Adverse Effect Level (NOAEL) to a dose producing 100% Lethality (LD100). Studies designed to test the teratogenic potential of environmental agents use animal model systems (e.g., rat, mouse, rabbit, dog, and monkey). Early teratologists exposed pregnant animals to environmental agents and observed the fetuses for gross visceral and skeletal abnormalities. While this is still part of the teratological evaluation procedures today, the field of Teratology is moving to a more molecular level, seeking the mechanism(s) of action by which these agents act. Genetically modified mice are commonly used for this purpose. In addition, pregnancy registries are large, prospective studies that monitor exposures women receive during their pregnancies and record the outcome of their births. These studies provide information about possible risks of medications or other exposures in human pregnancies. Understanding how a teratogen causes its effect is not only important in preventing congenital abnormalities but also has the potential for developing new therapeutic drugs safe for use with pregnant women. # Teratology education It is estimated that 10% of all birth defects are caused by a prenatal exposure or teratogen.[3] These exposures include, but are not limited to, medication or drug exposures, maternal infections and diseases, and environmental and occupational exposures. Teratogen-caused birth defects are potentially preventable. Studies have shown that nearly 50% of pregnant women have been exposed to at least one medication during gestation.[5] An additional study found that of 200 individuals referred for genetic counseling for a teratogenic exposure, 52% were exposed to more than one potential teratogen.[6] # Teratogenic agents A wide range of different chemicals and environmental factors are suspected or are known to be teratogenic in humans and in animals. A selected few include: - Ionizing radiation: atomic weapons, radioiodine, radiation therapy - Infections: cytomegalovirus, herpes virus, parvovirus B-19, rubella virus (German measles), syphilis, toxoplasmosis, Venezuelan equine encephalitis virus - Metabolic imbalance: alcoholism, endemic cretinism, diabetes, folic acid deficiency, hyperthermia, phenylketonuria, rheumatic disease and congenital heart block, virilizing tumors - Drugs and environmental chemicals: 13-cis-retinoic acid, isotretinoin (Accutane), temazepam (Restoril; Normisson), nitrazepam (Mogadon), nimetazepam (Ermin), aminopterin, androgenic hormones, busulfan, captopril, enalapril, chlorobiphenyls (PCBs), Dioxin, coumarin, cyclophosphamide, diethylstilbestrol, diphenylhydantoin (Phenytoin, Dilantin, Epanutin), ethanol, ethidium bromide, etretinate, lithium (Ebstein Anomalies), methimazole, organic mercury, penicillamine, tetracyclines, thalidomide, trimethadione, uranium, methoxyethyl ethers, Valganciclovir hydrochloride and valproic acid. The status of some of the above substances (e.g. diphenylhydantoin) is subject to debate, and many other compounds are under varying degrees of suspicion. These include Agent Orange,[7] nicotine,[8] aspirin and other NSAIDs. Other compounds are known as severe teratogens based on veterinary work and animal studies, but aren't listed above because they have not been studied in humans, e.g. cyclopamine. Teratogenic effects also help to determine the pregnancy category assigned by regulatory authorities; in the United States, a pregnancy category of X, D, or C may be assigned if teratogenic effects (or other risks in pregnancy) are documented or cannot be excluded. Isotretinoin (13-cis-retinoic-acid; brand name Accutane), which is often used to treat severe acne, is such a strong teratogen that just a single dose taken by a pregnant woman may result in serious birth defects. Because of this effect, most countries have systems in place to ensure that it is not given to pregnant women, and that the patient is aware of how important it is to prevent pregnancy during and at least one month after treatment. Medical guidelines also suggest that pregnant women should limit vitamin A intake to about 700 μg/day, as it has teratogenic potential when consumed in excess.[9][10] # Teratogenic outcomes Exposure to teratogens can result in a wide range of structural abnormalities such as cleft lip, cleft palate, dysmelia, anencephaly, ventricular septal defect. In most cases, specific agents produce a specific teratogenic response. # Related Chapters - Summa izbu - a set of Mesopotamian omen texts about Teratology. - Congenital abnormalities - Carcinogen - Mutagen # Resources - Society of Teratology - European Teratology Society - Organization of Teratology Information Specialists - March of Dimes Foundation - A Telling of Wonders: Teratology in Western Medicine through 1800 (New York Academy of Medicine Historical Collections)	https://www.wikidoc.org/index.php/Teratogen
e0e0ce1a3d2c72c53bd43ba4399af9a11c05b70b	wikidoc	Tetrazepam	Tetrazepam # Overview Tetrazepam (is marketed under the following brand names, Clinoxan, Epsipam, Myolastan, Musaril, Relaxam and Spasmorelax) is a benzodiazepine derivative with anticonvulsant, anxiolytic, hypnotic and muscle relaxant properties. It was formerly used mainly in Austria, France, Belgium, Germany and Spain to treat muscle spasm, anxiety disorders such as panic attacks, or more rarely to treat depression, premenstrual syndrome or agoraphobia. Tetrazepam has relatively little sedative effect at low doses while still producing useful muscle relaxation and anxiety relief. The Co-ordination Group for Mutual Recognition and Decentralised Procedures-Human (CMD(h)) endorsed the Pharmacovigilance Risk Assessment Committee (PRAC) recommendation to suspend the marketing authorisations of tetrazepam-containing medicines across the European Union (EU) in April 2013. The European Commission has confirmed the suspension of the marketing authorisations for Tetrazepam in Europe because of cutaneous toxicity, effective from the 1 August 2013. Delayed type 4 allergic hypersensitivity reactions including aculopapular exanthema, erythematous rash, urticarial eruption, erythema multiforme, photodermatitis, eczema and Stevens–Johnson syndrome can occasionally occur as a result of tetrazepam exposure. These hypersensitivity reactions to tetrazepam share no cross-reactivity with other benzodiazepines. # Indications Tetrazepam is used therapeutically as a muscle relaxant. # Availability The indicated adult dose for muscle spasm is 25 mg to 150 mg per day, increased if necessary to a maximum of 300 mg per day, in divided doses. Tetrazepam is not generally recommended for use in children, except on the advice of a specialist. Tetrazepam is only available in one strength and formulation, 50 mg tablets. The benzodiazepine equivalent of tetrazepam is approximately 100mg of tetrazepam = 10 mg of diazepam. # Adverse effects Allergic reactions to tetrazepam occasionally occur involving the skin. Allergic reactions can develop to tetrazepam and it is considered to be a potential allergen. Drug rash and drug-induced eosinophilia with systemic symptoms is a known complication of tetrazepam exposure. These hypersensitive allergic reactions can be of the delayed type. Toxic epidermal necrolysis has occurred from the use of tetrazepam including at least one reported death. Stevens–Johnson syndrome and erythema multiforme has been reported from use of tetrazepam. Cross-reactivity with other benzodiazepines does not typically occur in such patients. Exanthema and eczema may occur. The lack of cross-reactivity with other benzodiazepines is believed to be due to the molecular structure of tetrazepam. Photodermatitis and phototoxicity have also been reported. Occupational contact allergy can also develop from regularly handling tetrazepam. Airborne contact dermatitis can also occur as an allergy which can develop from occupational exposure. Patch testing has been used successfully to demonstrate tetrazepam allergy. Oral testing can also be used. Skin prick tests are not always accurate and may produce false negatives. Drowsiness is a common side effect of tetrazepam. A reduction in muscle force can occur. Myasthenia gravis, a condition characterised by severe muscle weakness is another potential adverse effect from tetrazepam. Cardiovascular and respiratory adverse effects can occur with tetrazepam similar to other benzodiazepines. ## Tolerance, dependence and withdrawal Prolonged use, as with all benzodiazepines, should be avoided, as tolerance occurs and there is a risk of benzodiazepine dependence and a benzodiazepine withdrawal syndrome after stopping or reducing dosage. # Overdose Tetrazepam, like other benzodiazepines is a drug which is very frequently present in cases of overdose. These overdoses are often mixed overdoses, i.e. a mixture of other benzodiazepines or other drug classes with tetrazepam. # Contraindications and special caution Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders. # Pharmacology Tetrazepam is an unusual benzodiazepine in its molecular structure as it has cyclohexenyl group which has substituted the typical 5-phenyl moiety seen in other benzodiazepines. Tetrazepam, is rapidly absorbed after oral administration, within 45 mins and reaches peak plasma levels in less than 2 hours. It is classed as an intermediate acting benzodiazepine with an elimination half-life of approximately 15 hours. It is primarily metabolised to the inactive metabolites 3-hydroxy-tetrazepam and norhydroxytetrazepam. The pharmacological effects of tetrazepam are significantly less potent when compared against diazepam, in animal studies. Tetrazepam is a benzodiazepine site agonist and binds unselectively to type 1 and type 2 benzodiazepine site types as well as to peripheral benzodiazepine receptors. The muscle relaxant properties of tetrazepam are most likely due to a reduction of calcium influx. Small amounts of diazepam as well as the active metabolites of diazepam are produced from metabolism of tetrazepam. The metabolism of tetrazepam has led to false accusations of prisoners prescribed tetrazepam of taking illicit diazepam; this can lead to increased prison sentences for prisoners. # Abuse Tetrazepam as with other benzodiazepines is sometimes abused. It is sometimes abused to incapacitate a victim in order to carry out a drug-facilitated crime. or abused in order to achieve a state of intoxication. Tetrazepam's abuse for to carry out drug facilitated crimes may be less however, than other benzodiazepines due to its reduced hypnotic properties.	Tetrazepam Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Tetrazepam[1] (is marketed under the following brand names, Clinoxan, Epsipam, Myolastan, Musaril, Relaxam and Spasmorelax) is a benzodiazepine derivative with anticonvulsant, anxiolytic, hypnotic and muscle relaxant properties. It was formerly used mainly in Austria, France, Belgium, Germany and Spain to treat muscle spasm, anxiety disorders such as panic attacks, or more rarely to treat depression, premenstrual syndrome or agoraphobia. Tetrazepam has relatively little sedative effect at low doses while still producing useful muscle relaxation and anxiety relief. The Co-ordination Group for Mutual Recognition and Decentralised Procedures-Human (CMD(h)) endorsed the Pharmacovigilance Risk Assessment Committee (PRAC) recommendation to suspend the marketing authorisations of tetrazepam-containing medicines across the European Union (EU) in April 2013.[2] The European Commission has confirmed the suspension of the marketing authorisations for Tetrazepam in Europe because of cutaneous toxicity, effective from the 1 August 2013.[3] Delayed type 4 allergic hypersensitivity reactions including aculopapular exanthema, erythematous rash, urticarial eruption, erythema multiforme, photodermatitis, eczema and Stevens–Johnson syndrome can occasionally occur as a result of tetrazepam exposure. These hypersensitivity reactions to tetrazepam share no cross-reactivity with other benzodiazepines.[4] # Indications Tetrazepam is used therapeutically as a muscle relaxant.[5][6] # Availability The indicated adult dose for muscle spasm is 25 mg to 150 mg per day, increased if necessary to a maximum of 300 mg per day, in divided doses. Tetrazepam is not generally recommended for use in children, except on the advice of a specialist. Tetrazepam is only available in one strength and formulation, 50 mg tablets. The benzodiazepine equivalent of tetrazepam is approximately 100mg of tetrazepam = 10 mg of diazepam.[7] # Adverse effects Allergic reactions to tetrazepam occasionally occur involving the skin.[4] Allergic reactions can develop to tetrazepam[8][9] and it is considered to be a potential allergen.[10][11] Drug rash and drug-induced eosinophilia with systemic symptoms is a known complication of tetrazepam exposure.[12][13] These hypersensitive allergic reactions can be of the delayed type.[14][15][16] Toxic epidermal necrolysis has occurred from the use of tetrazepam[17][18] including at least one reported death.[19] Stevens–Johnson syndrome and erythema multiforme has been reported from use of tetrazepam. Cross-reactivity with other benzodiazepines does not typically occur in such patients.[20][21][22] Exanthema[23] and eczema may occur.[24] The lack of cross-reactivity with other benzodiazepines is believed to be due to the molecular structure of tetrazepam.[25][26] Photodermatitis[27] and phototoxicity have also been reported.[28] Occupational contact allergy can also develop from regularly handling tetrazepam.[29][30] Airborne contact dermatitis can also occur as an allergy which can develop from occupational exposure.[31] Patch testing has been used successfully to demonstrate tetrazepam allergy.[32][33] Oral testing can also be used. Skin prick tests are not always accurate and may produce false negatives.[34] Drowsiness is a common side effect of tetrazepam.[35] A reduction in muscle force can occur.[36] Myasthenia gravis, a condition characterised by severe muscle weakness is another potential adverse effect from tetrazepam.[37] Cardiovascular and respiratory adverse effects can occur with tetrazepam similar to other benzodiazepines.[26] ## Tolerance, dependence and withdrawal Prolonged use, as with all benzodiazepines, should be avoided, as tolerance occurs and there is a risk of benzodiazepine dependence and a benzodiazepine withdrawal syndrome after stopping or reducing dosage.[26] # Overdose Tetrazepam, like other benzodiazepines is a drug which is very frequently present in cases of overdose. These overdoses are often mixed overdoses, i.e. a mixture of other benzodiazepines or other drug classes with tetrazepam.[38][39] # Contraindications and special caution Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.[40] # Pharmacology Tetrazepam is an unusual benzodiazepine in its molecular structure as it has cyclohexenyl group which has substituted the typical 5-phenyl moiety seen in other benzodiazepines.[41] Tetrazepam, is rapidly absorbed after oral administration, within 45 mins and reaches peak plasma levels in less than 2 hours. It is classed as an intermediate acting benzodiazepine with an elimination half-life of approximately 15 hours. It is primarily metabolised to the inactive metabolites 3-hydroxy-tetrazepam and norhydroxytetrazepam.[41][42] The pharmacological effects of tetrazepam are significantly less potent when compared against diazepam, in animal studies.[43] Tetrazepam is a benzodiazepine site agonist and binds unselectively to type 1 and type 2 benzodiazepine site types as well as to peripheral benzodiazepine receptors.[44] The muscle relaxant properties of tetrazepam are most likely due to a reduction of calcium influx.[45] Small amounts of diazepam as well as the active metabolites of diazepam are produced from metabolism of tetrazepam.[46][47] The metabolism of tetrazepam has led to false accusations of prisoners prescribed tetrazepam of taking illicit diazepam; this can lead to increased prison sentences for prisoners.[41] # Abuse Tetrazepam as with other benzodiazepines is sometimes abused. It is sometimes abused to incapacitate a victim in order to carry out a drug-facilitated crime.[48] or abused in order to achieve a state of intoxication.[49] Tetrazepam's abuse for to carry out drug facilitated crimes may be less however, than other benzodiazepines due to its reduced hypnotic properties.[50]	https://www.wikidoc.org/index.php/Tetrazepam
e7100d9a334bedf0b850b5deaeabecfaf61639e0	wikidoc	The Lancet	The Lancet # Overview The Lancet is one of the oldest peer-reviewed medical journals in the world, published weekly by Elsevier, part of Reed Elsevier. It was founded in 1823 by Thomas Wakley, who named it after the surgical instrument called a lancet, as well as an arched window ("to let in light"). The present editor-in-chief is Richard Horton. The Lancet takes a stand on several important medical issues - recent examples include criticism of the World Health Organization, rejecting the efficacy of homeopathy as a therapeutic option and its disapproval of Reed Elsevier's links with the arms industry. # Impact The Lancet has a significant readership throughout the world with a high impact factor. It publishes original research articles, review articles ("seminars" and "reviews"), editorials, book reviews, correspondences, amidst other regulars such as news features and case reports. The Lancet is considered to be one of the "core" general medical journals, the others being the New England Journal of Medicine, the Journal of the American Medical Association, and the British Medical Journal. The Lancet's impact factor is currently ranked #2 among general medical journals (click here for impact factor rankings). # Journals family The Lancet has now given birth to a few sub-speciality journals, all bearing the parent title - The Lancet Neurology (neurology), The Lancet Oncology (oncology) and The Lancet Infectious Diseases (infectious diseases). All of them have established significant reputations as medical journals, though most started out publishing only review articles. # Volume renumbering Prior to 1990, Lancet had volume numbering that reset every year. Issues in January to June were in volume i, with the rest in volume ii. In 1990, Lancet moved to a sequential volume numbering scheme, with two volumes per year. Volumes were retro-actively assigned to the years prior to 1990, with the first issue of 1990 being assigned volume 335, and the last issue of 1989 assigned volume 334. The table of contents listing on Science Direct uses this new numbering scheme. # Controversial articles The Lancet was severely criticized after it published a paper in 1998, in which the authors linked the MMR vaccine with autism. In February 2004 The Lancet published a partial retraction of the paper (Lancet 2004;363:750). Dr Horton went on the record to say the paper had "fatal conflicts of interest" because one of the authors had a serious conflict of interest that he had not declared to The Lancet . The Lancet published a controversial estimate of the Iraq war's Iraqi death toll--around one hundred thousand--in 2004. In 2006 a followup study by the same team suggested that the violent death rate in Iraq was not only consistent with the earlier estimate, but had increased considerably in the intervening period (Lancet surveys of mortality before and after the 2003 invasion of Iraq). The second survey estimated that there had been 654,965 excess Iraqi deaths as a consequence of the war. The 95% confidence interval was 392,979 to 942,636. 1849 households that contained 12,801 people were surveyed. In January 2006, it was revealed that data had been fabricated in an article by the Norwegian cancer researcher Jon Sudbø and 13 co-authors published in The Lancet in October 2005 . The fabricated article was entitled "Non-steroidal anti-inflammatory drugs and the risk of oral cancer: a nested case-control study". . Within a week after this scandal surfaced in the news, the high-impact New England Journal of Medicine published an expression of editorial concern regarding another research paper published on a similar topic in the journal.	The Lancet Template:Infobox Journal # Overview The Lancet is one of the oldest peer-reviewed medical journals in the world, published weekly by Elsevier, part of Reed Elsevier. It was founded in 1823 by Thomas Wakley, who named it after the surgical instrument called a lancet, as well as an arched window ("to let in light"). The present editor-in-chief is Richard Horton. The Lancet takes a stand on several important medical issues - recent examples include criticism of the World Health Organization, rejecting the efficacy of homeopathy as a therapeutic option and its disapproval of Reed Elsevier's links with the arms industry. # Impact The Lancet has a significant readership throughout the world with a high impact factor. It publishes original research articles, review articles ("seminars" and "reviews"), editorials, book reviews, correspondences, amidst other regulars such as news features and case reports. The Lancet is considered to be one of the "core" general medical journals, the others being the New England Journal of Medicine, the Journal of the American Medical Association, and the British Medical Journal. The Lancet's impact factor is currently ranked #2 among general medical journals (click here for impact factor rankings). # Journals family The Lancet has now given birth to a few sub-speciality journals, all bearing the parent title - The Lancet Neurology (neurology), The Lancet Oncology (oncology) and The Lancet Infectious Diseases (infectious diseases). All of them have established significant reputations as medical journals, though most started out publishing only review articles. # Volume renumbering Prior to 1990, Lancet had volume numbering that reset every year. Issues in January to June were in volume i, with the rest in volume ii. In 1990, Lancet moved to a sequential volume numbering scheme, with two volumes per year. Volumes were retro-actively assigned to the years prior to 1990, with the first issue of 1990 being assigned volume 335, and the last issue of 1989 assigned volume 334. The table of contents listing on Science Direct uses this new numbering scheme. # Controversial articles The Lancet was severely criticized after it published a paper in 1998, in which the authors linked the MMR vaccine with autism. In February 2004 The Lancet published a partial retraction of the paper (Lancet 2004;363:750). Dr Horton went on the record to say the paper had "fatal conflicts of interest" because one of the authors had a serious conflict of interest that he had not declared to The Lancet [1]. The Lancet published a controversial estimate of the Iraq war's Iraqi death toll--around one hundred thousand--in 2004. In 2006 a followup study by the same team suggested that the violent death rate in Iraq was not only consistent with the earlier estimate, but had increased considerably in the intervening period (Lancet surveys of mortality before and after the 2003 invasion of Iraq). The second survey estimated that there had been 654,965 excess Iraqi deaths as a consequence of the war. The 95% confidence interval was 392,979 to 942,636. 1849 households that contained 12,801 people were surveyed.[2] In January 2006, it was revealed that data had been fabricated in an article by the Norwegian cancer researcher Jon Sudbø and 13 co-authors published in The Lancet in October 2005 [3]. The fabricated article was entitled "Non-steroidal anti-inflammatory drugs and the risk of oral cancer: a nested case-control study". [4]. Within a week after this scandal surfaced in the news, the high-impact New England Journal of Medicine published an expression of editorial concern regarding another research paper published on a similar topic in the journal.	https://www.wikidoc.org/index.php/The_Lancet
a95dadddfdc26c529faa29daa4ea70bb4b278302	wikidoc	The U Wave	The U Wave # Overview U waves were described by Einthoven in 1903 and normally have same polarity as T waves # Pathophysiology There are three hypotheses regarding the origin of the U wave: - Late repolarization of Purkinje fibers, - Late repolarization of some other portions of left ventricle, - Alteration in the normal action potential shape by after potentials. # Appearance - Ordinarily the U wave has the same polarity as the T wave and is 5 to 25% of the T wave amplitude. - Tallest in leads V2 and V3, usually not greater than 1.0 mm. - Considered abnormally large if the U wave is greater than 1.5 mm in any lead. # Causes of Abnormal U wave Prominence - Bradycardia - CNS disease - Drugs such as: - amiodarone - digitalis - disopyramide - epinephrine - phenothiazines - procainamide - quinidine - Electrolyte imbalance - Hypokalemia - Hypomagnesemia - Hypercalcemia - Hyperthyroidism - Left ventricular hypertrophy - Long QT syndrome - Mitral valve prolapse # Causes of U Wave Inversion - Left ventricular hypertrophy (in I, V5, V6) - Right ventricular hypertrophy (in II, III) - Ischemic heart disease - May occur during anginal episode - U wave inversion during an exercise tolerance test is considered indicative of ischemia by some	The U Wave Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] # Overview U waves were described by Einthoven in 1903 and normally have same polarity as T waves[1] # Pathophysiology There are three hypotheses regarding the origin of the U wave[2]: - Late repolarization of Purkinje fibers, - Late repolarization of some other portions of left ventricle, - Alteration in the normal action potential shape by after potentials. # Appearance - Ordinarily the U wave has the same polarity as the T wave and is 5 to 25% of the T wave amplitude. - Tallest in leads V2 and V3, usually not greater than 1.0 mm. - Considered abnormally large if the U wave is greater than 1.5 mm in any lead.[3] # Causes of Abnormal U wave Prominence - Bradycardia - CNS disease - Drugs such as: - amiodarone - digitalis - disopyramide - epinephrine - phenothiazines - procainamide - quinidine - Electrolyte imbalance - Hypokalemia - Hypomagnesemia - Hypercalcemia - Hyperthyroidism - Left ventricular hypertrophy - Long QT syndrome - Mitral valve prolapse # Causes of U Wave Inversion - Left ventricular hypertrophy (in I, V5, V6) - Right ventricular hypertrophy (in II, III) - Ischemic heart disease - May occur during anginal episode - U wave inversion during an exercise tolerance test is considered indicative of ischemia by some	https://www.wikidoc.org/index.php/The_U_Wave
577ad6c5146c1565330213c7af6fbc80d3e79348	wikidoc	Theaflavin	Theaflavin Theaflavin and its derivatives, known collectively as theaflavins, are polyphenols that are formed from catechins such as in tea leaves during the enzymatic oxidation (called fermentation by the tea trade) of tea leaves, such as in black tea. Several tea polyphenols, especially those with galloyl moiety, can inhibit HIV-1 replication with multiple mechanisms of action. It is showed that the theaflavin derivatives had more potent anti-HIV-1 activity than catechin derivatives. - Theaflavin-3'-monogallate (TF-2) causes apoptosis in colon cancer cells. - Theaflavin-3,3'-digallate (TF3) binds to gp41 of HIV as well as inhibit 3CLPro of severe acute respiratory syndrome (SARS). - 3-Isotheaflavin-3-gallate (TF2B) inhibits 3CLPro of SARS. Epigallocatechin gallate (EGCG), a catechin in green tea, binds to gp120, which works in conjunction with gp41 of HIV to enter into healthy human immune cells. Like EGCG, Theaflavins and Thearubigins compounds found in black teas penetrate the blood brain barrier, and have been shown to be effective against age and AIDS related dementia in vitro. Since modern anti-retroviral meds do not reach the brain, HIV can maintain reservoirs for reinfection. Theaflavins were also found to reduce blood cholesterol levels.	Theaflavin Template:Chembox new Theaflavin and its derivatives, known collectively as theaflavins, are polyphenols that are formed from catechins such as in tea leaves during the enzymatic oxidation (called fermentation by the tea trade) of tea leaves, such as in black tea. Several tea polyphenols, especially those with galloyl moiety, can inhibit HIV-1 replication with multiple mechanisms of action. It is showed that the theaflavin derivatives had more potent anti-HIV-1 activity than catechin derivatives.[1] - Theaflavin-3'-monogallate (TF-2) causes apoptosis in colon cancer cells.[2] - Theaflavin-3,3'-digallate (TF3) binds to gp41 of HIV as well as inhibit 3CLPro of severe acute respiratory syndrome (SARS).[3] - 3-Isotheaflavin-3-gallate (TF2B) inhibits 3CLPro of SARS.[3] Epigallocatechin gallate (EGCG), a catechin in green tea, binds to gp120, which works in conjunction with gp41 of HIV to enter into healthy human immune cells. Like EGCG, Theaflavins and Thearubigins compounds found in black teas penetrate the blood brain barrier, and have been shown to be effective against age and AIDS related dementia in vitro. Since modern anti-retroviral meds do not reach the brain, HIV can maintain reservoirs for reinfection. Theaflavins were also found to reduce blood cholesterol levels.[4]	https://www.wikidoc.org/index.php/Theaflavin
62d9e4884b48af29b0069f688669a0c466acaf19	wikidoc	Theobromos	Theobromos Theobromos is the scientific name for chocolate as used in The Company series of science fiction novels by Kage Baker. Theobromos' effects on immortals are unique from theobromine effects on humans. In the novels, Theobromos induces mood elevation and other emotional effects in immortals. Overindulgence causes inebriation similar to the effects of alcohol, including disorientation, loss of balance, and emotional effusiveness. Overindulgence also results in a morning-after hangover, characterized by an intense headache, skin irritation, and ravenous hunger. Theobromos is typically ingested orally in the form of chocolate or hot chocolate. Powdered cocoa can also be nasally insufflated, just as one would snort cocaine.	Theobromos Theobromos is the scientific name for chocolate as used in The Company series of science fiction novels by Kage Baker. Theobromos' effects on immortals are unique from theobromine effects on humans. In the novels, Theobromos induces mood elevation and other emotional effects in immortals. Overindulgence causes inebriation similar to the effects of alcohol, including disorientation, loss of balance, and emotional effusiveness. Overindulgence also results in a morning-after hangover, characterized by an intense headache, skin irritation, and ravenous hunger. Theobromos is typically ingested orally in the form of chocolate or hot chocolate. Powdered cocoa can also be nasally insufflated, just as one would snort cocaine. Template:Food-stub Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Theobromos
0c5a9b303cc7e0987b4c52c34df0d62932f6789a	wikidoc	Theta wave	Theta wave # Overview Theta rhythms are one of several characteristic electroencephalogram waveforms associated with various sleep and wakefulness states. When seen in this fashion, they are between 4 and 8 Hz, and involve many neurons firing synchronously, probably in the hippocampus and through the cortex. Theta rhythms are observed in awake children under the age of 13 years. Theta activity can be observed in adults during some sleep states, and in states of quiet focus, for example meditation (e.g. Aftanas & Golosheykin, 2005). These rhythms are associated with spacial navigation and some forms of memory and learning, especially in the temporal lobes. They can equally be seen in cases of focal or generalized subcortical brain damage and epilepsy. Theta-frequency EEG activity is also manifested during some short term memory tasks (reviewed in Vertes 2005). Some suggest that they reflect the "on-line" state of the hippocampus; one of readiness to process incoming signals (Buzsáki, 2002). Conversely, theta oscillations have been correlated to various voluntary behaviors (exploration, spatial navigation, etc.) and alert states (piloerection, etc.) in the rat (Vanderwolf, 1969), suggesting that it may reflect the integration of sensory information with motor output (for review, see Bland & Oddie, 2001). A large body of evidence indicates that theta rhythm is likely involved in spatial learning and navigation (e.g. Buzsáki 2005). Theta rhythms are very strong in rodent hippocampi and entorhinal cortex during learning and memory retrieval, and are believed to be vital to the induction of long-term potentiation, a potential cellular mechanism of learning and memory. A putative functional role of the theta rhythm has been put forth by Dr. Michael Hasselmo in a series of papers (Hasselmo et al. 2002, Hasselmo and Eichenbaum 2005). Based on evidence from electrophysiological studies showing that both synaptic plasticity and strength of inputs to hippocampal region CA1 vary systematically with ongoing theta oscillations (Hyman et al. 2003, Brankack et al. 1993, Pavlides et al. 1988), it has been suggested that the theta rhythm functions to separate periods of encoding of current sensory stimuli and retrieval of episodic memory cued by current stimuli so as to avoid interference that would occur if encoding and retrieval were simultaneous. Underlying large-scale synchronization which results in rhythmic slow activity of field EEG are theta-frequency membrane potential oscillations, typically sodium-dependent voltage-sensitive oscillations in membrane potential at near-action potential voltages (Alonso & Llinas, 1989; Chapman & Lacaille, 1999). Specifically, it appears that in neurons of the CA1 and dentate gyrus, these oscillations result from an interplay of dendritic excitation via a persistent sodium current (INaP) with perisomatic inhibition (Buzsáki, 2002). Electrophysiological or pharmacological stimulation of the medial septum and the diagonal band of Broca projecting to hippocampus also induces theta-like rhythms (Manseau et al. 2005). It is likely that human sources of theta rhythm are similar to those found in other mammals, and thus it is likely that cholinergic projections from the basal forebrain drive the theta rhythm seen in human EEG patterns. Similarly, humans show hippocampal theta rhythms that are probably mediated by inputs from the ascending brainstem synchronizing system via the medial septum (see ).	Theta wave Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] # Overview Theta rhythms are one of several characteristic electroencephalogram waveforms associated with various sleep and wakefulness states. When seen in this fashion, they are between 4 and 8 Hz, and involve many neurons firing synchronously, probably in the hippocampus and through the cortex. Theta rhythms are observed in awake children under the age of 13 years. Theta activity can be observed in adults during some sleep states, and in states of quiet focus, for example meditation (e.g. Aftanas & Golosheykin, 2005). These rhythms are associated with spacial navigation and some forms of memory and learning, especially in the temporal lobes. They can equally be seen in cases of focal or generalized subcortical brain damage and epilepsy. Theta-frequency EEG activity is also manifested during some short term memory tasks (reviewed in Vertes 2005). Some suggest that they reflect the "on-line" state of the hippocampus; one of readiness to process incoming signals (Buzsáki, 2002). Conversely, theta oscillations have been correlated to various voluntary behaviors (exploration, spatial navigation, etc.) and alert states (piloerection, etc.) in the rat (Vanderwolf, 1969), suggesting that it may reflect the integration of sensory information with motor output (for review, see Bland & Oddie, 2001). A large body of evidence indicates that theta rhythm is likely involved in spatial learning and navigation (e.g. Buzsáki 2005). Theta rhythms are very strong in rodent hippocampi and entorhinal cortex during learning and memory retrieval, and are believed to be vital to the induction of long-term potentiation, a potential cellular mechanism of learning and memory. A putative functional role of the theta rhythm has been put forth by Dr. Michael Hasselmo in a series of papers (Hasselmo et al. 2002, Hasselmo and Eichenbaum 2005). Based on evidence from electrophysiological studies showing that both synaptic plasticity and strength of inputs to hippocampal region CA1 vary systematically with ongoing theta oscillations (Hyman et al. 2003, Brankack et al. 1993, Pavlides et al. 1988), it has been suggested that the theta rhythm functions to separate periods of encoding of current sensory stimuli and retrieval of episodic memory cued by current stimuli so as to avoid interference that would occur if encoding and retrieval were simultaneous. Underlying large-scale synchronization which results in rhythmic slow activity of field EEG are theta-frequency membrane potential oscillations, typically sodium-dependent voltage-sensitive oscillations in membrane potential at near-action potential voltages (Alonso & Llinas, 1989; Chapman & Lacaille, 1999). Specifically, it appears that in neurons of the CA1 and dentate gyrus, these oscillations result from an interplay of dendritic excitation via a persistent sodium current (INaP) with perisomatic inhibition (Buzsáki, 2002). Electrophysiological or pharmacological stimulation of the medial septum and the diagonal band of Broca projecting to hippocampus also induces theta-like rhythms (Manseau et al. 2005). It is likely that human sources of theta rhythm are similar to those found in other mammals, and thus it is likely that cholinergic projections from the basal forebrain drive the theta rhythm seen in human EEG patterns. Similarly, humans show hippocampal theta rhythms that are probably mediated by inputs from the ascending brainstem synchronizing system via the medial septum (see [3]).	https://www.wikidoc.org/index.php/Theta_wave
d1f39abee53376ed63f7305d5cab4e568fa415cc	wikidoc	Thixotropy	Thixotropy Thixotropy is the property of some non-Newtonian pseudoplastic fluids to show a time-dependent change in viscosity; the longer the fluid undergoes shear stress, the lower its viscosity. A thixotropic fluid is a fluid which takes a finite amount of time to attain equilibrium viscosity when introduced to a step change in shear rate. However, this is not a universal definition; the term is sometimes applied to pseudoplastic fluids without a viscosity/time component. Many gels and colloids are thixotropic materials, exhibiting a stable form at rest but becoming fluid when agitated. It is important to note the distinction between a thixotropic fluid and a shear thinning fluid. The former displays a decrease in viscosity over time at a constant shear rate, while the latter displays decreasing viscosity with increasing shear rate. Fluids which exhibit the opposite property, in which constant shear stress for a time, such as shaking or mixing, causes an increase in viscosity or even solidification, are called rheopectic, sometimes called anti-thixotropic, and are much less common. # Natural examples Some clays are thixotropic, with their behavior of great importance in structural and geotechnical engineering. In earthquake zones, clay-like ground can exhibit characteristics of liquefaction under the shaking of a tremor, greatly affecting earth structures and buildings. Landslides, such as those common in the cliffs around Lyme Regis, Dorset and in the Aberfan slag heap disaster in Wales are evidence of this phenomenon. Similarly, a lahar is a mass of earth liquefied by a volcanic event, which rapidly solidifies once coming to a rest. Drilling muds used in geotechnical applications can be thixotropic. Honey from honey bees may also exhibit this property under certain conditions. Another example of a thixotropic fluid is the synovial fluid found in joints between some bones. The ground substance in the human body is thixotropic. Some clay deposits found in the process of exploring caves exhibit thixotropism: an initially solid-seeming mudbank will turn soupy and yield up moisture when dug into or otherwise disturbed. These clays were deposited in the past by low-velocity streams which tend to deposit fine-grained sediment. # Applications Examples of applications for thixotropic fluids are the thickening of food stuffs and medical products. Toothpaste is thixotropic, which allows it to be squeezed out of the tube, yet retain a solid shape on the brush. The ink developed for the Fisher space pen is thixotropic so that the ink flows only when the roller ball is pressed on paper. Ketchup is frequently thixotropic. Modern alkyd and latex paint varieties are often thixotropic and will not run off the painter's brush, but will still spread easily and evenly, since the gel-like paint "liquefies" when brushed out. Many clutch-type automatic transmissions use fluids with thixotropic properties, to engage the different clutch plates inside the transmission housing at specific pressures, which then changes the gearset. # Etymology The word comes from Greek thixis, touch (from thinganein, to touch) + -tropy, -tropous, from Greek -tropos, of turning, from tropos, changeable, from trepein, to turn.	Thixotropy Thixotropy is the property of some non-Newtonian pseudoplastic fluids to show a time-dependent change in viscosity; the longer the fluid undergoes shear stress, the lower its viscosity. A thixotropic fluid is a fluid which takes a finite amount of time to attain equilibrium viscosity when introduced to a step change in shear rate. However, this is not a universal definition; the term is sometimes applied to pseudoplastic fluids without a viscosity/time component. Many gels and colloids are thixotropic materials, exhibiting a stable form at rest but becoming fluid when agitated. It is important to note the distinction between a thixotropic fluid and a shear thinning fluid. The former displays a decrease in viscosity over time at a constant shear rate, while the latter displays decreasing viscosity with increasing shear rate. Fluids which exhibit the opposite property, in which constant shear stress for a time, such as shaking or mixing, causes an increase in viscosity or even solidification, are called rheopectic, sometimes called anti-thixotropic, and are much less common. # Natural examples Some clays are thixotropic, with their behavior of great importance in structural and geotechnical engineering. In earthquake zones, clay-like ground can exhibit characteristics of liquefaction under the shaking of a tremor, greatly affecting earth structures and buildings. Landslides, such as those common in the cliffs around Lyme Regis, Dorset and in the Aberfan slag heap disaster in Wales are evidence of this phenomenon. Similarly, a lahar is a mass of earth liquefied by a volcanic event, which rapidly solidifies once coming to a rest. Drilling muds used in geotechnical applications can be thixotropic. Honey from honey bees may also exhibit this property under certain conditions. Another example of a thixotropic fluid is the synovial fluid found in joints between some bones. The ground substance in the human body is thixotropic. [1] Some clay deposits found in the process of exploring caves exhibit thixotropism: an initially solid-seeming mudbank will turn soupy and yield up moisture when dug into or otherwise disturbed. These clays were deposited in the past by low-velocity streams which tend to deposit fine-grained sediment. # Applications Examples of applications for thixotropic fluids are the thickening of food stuffs and medical products. Toothpaste is thixotropic, which allows it to be squeezed out of the tube, yet retain a solid shape on the brush. The ink developed for the Fisher space pen is thixotropic so that the ink flows only when the roller ball is pressed on paper.[2] Ketchup is frequently thixotropic. Modern alkyd and latex paint varieties are often thixotropic and will not run off the painter's brush, but will still spread easily and evenly, since the gel-like paint "liquefies" when brushed out. Many clutch-type automatic transmissions use fluids with thixotropic properties, to engage the different clutch plates inside the transmission housing at specific pressures, which then changes the gearset. # Etymology The word comes from Greek thixis, touch (from thinganein, to touch) + -tropy, -tropous, from Greek -tropos, of turning, from tropos, changeable, from trepein, to turn.	https://www.wikidoc.org/index.php/Thixotropic
61b16a36f45b89b79821e31a872cb65a2df8d026	wikidoc	Thorianite	Thorianite Thorianite is a rare mineral, originally discovered by Ananda Coomaraswamy in 1904 as uraninite, but recognized as a new species by W. R. Dunston. It was so named on account of its high percentage of thorium (about 70% ThO2); it also contains the oxides of uranium, lanthanum, cerium and didymium. Helium is present, and the mineral is slightly less radioactive than pitchblende but harder to shield due its high energy gamma rays. It is relatively more common in the alluvial gem-gravels of Sri Lanka, where it occurs mostly as water worn, small, heavy, black, cubic crystals. The largest crystals (sizes usually up to around 1.5 cm; very rare are sizes greater than 2.5 cm; largest is 6 cm and 2.2 kilos) came from Madagascar. # Chemistry Based on color, specific gravity and composition three types of thorianite are distinguished: - α - thorianite - β - thorianite - γ - thorianite Thorianite and uraninite form a complete solid solution series in synthetic and natural material. The division between the two species is at Th:U = 1:1 with U up to 46.50% and Th 45.3% to 87.9%. Rare earths, chiefly Ce, substitute for Th in amounts up to 8% by weight. Ce is probably present as Ce4+. Complete series is known in synthetic material between CeO2 - PrO2 - ThO2 - UO2. Small amounts of Fe3+ and Zr also may be isomorphous with Th. Pb present is probably radiogenic. # Varieties - Aldanite - a variety of thorianite containing 14.9% to 29.0% UO2 and 11.2% to 12.5% PbO. - Uranothorianite - Thorianite Cerian - Thorianite La bearing # Occurrence Usually found in alluvial deposits, beach sands heavy mineral placers and pegmatites. - Sri Lanka - In stream gravels, Galle district, Southern Province; Balangonda district; near Kodrugala, S'abaragamuwa Province; and from a pegmatite in Bambarabotuwa area. - India - Reported from beach sands of Travancore (Kerala). - Madagascar - Found in alluvial deposits of Betroka and Andolobe. Also as very large crystals from Tôlanaro (Fort Dauphin); at Andranondambo and other localities. - Russia - In black sands of a gold placer on Boshogoch River, Transbaikalia, Siberia; in the Kovdor massif, Kola Peninsula; in the Yenisei Range, Siberia. - United States - reported from Easton, Pennsylvania; black sands in Missouri River, near Helena, Montana; Scott River, Siskiyou County, California; black sands in Nixon Fork and Wiseman districts, Alaska. - Canada - Reported with uraninite in a pegmatite on Charlebois Lake, east of Lake Athabasca; Uranon variety reported from pegmatite and metesomatized zones in crystalline limestones from many locations in Quebec and Ontario. - South Africa - Occurs with baddeleyite as an accessory in carbonatite at Phalaborwa, Eastern Transvaal. - Belgian Congo	Thorianite Template:Infobox mineral Thorianite is a rare mineral,[1] originally discovered by Ananda Coomaraswamy in 1904 as uraninite,[2] but recognized as a new species by W. R. Dunston.[3] It was so named on account of its high percentage of thorium (about 70% ThO2); it also contains the oxides of uranium, lanthanum, cerium and didymium. Helium is present, and the mineral is slightly less radioactive than pitchblende but harder to shield due its high energy gamma rays. It is relatively more common in the alluvial gem-gravels of Sri Lanka, where it occurs mostly as water worn, small, heavy, black, cubic crystals. The largest crystals (sizes usually up to around 1.5 cm; very rare are sizes greater than 2.5 cm; largest is 6 cm and 2.2 kilos) came from Madagascar. # Chemistry Based on color, specific gravity and composition three types of thorianite are distinguished:[4] - α - thorianite - β - thorianite - γ - thorianite Thorianite and uraninite form a complete solid solution series in synthetic and natural material.[5] The division between the two species is at Th:U = 1:1 with U up to 46.50% and Th 45.3% to 87.9%.[6] Rare earths, chiefly Ce, substitute for Th in amounts up to 8% by weight. [7][8] Ce is probably present as Ce4+. Complete series is known in synthetic material between CeO2 - PrO2 - ThO2 - UO2. Small amounts of Fe3+ and Zr also may be isomorphous with Th. Pb present is probably radiogenic. # Varieties - Aldanite - a variety of thorianite containing 14.9% to 29.0% UO2 and 11.2% to 12.5% PbO.[9] - Uranothorianite[10] - Thorianite Cerian[11][12] - Thorianite La bearing[11] # Occurrence Usually found in alluvial deposits, beach sands heavy mineral placers and pegmatites. - Sri Lanka - In stream gravels, Galle district, Southern Province; Balangonda district; near Kodrugala, S'abaragamuwa Province; and from a pegmatite in Bambarabotuwa area. - India - Reported from beach sands of Travancore (Kerala).[13] - Madagascar - Found in alluvial deposits of Betroka and Andolobe.[14] Also as very large crystals from Tôlanaro (Fort Dauphin); at Andranondambo and other localities. - Russia - In black sands of a gold placer on Boshogoch River, Transbaikalia, Siberia; in the Kovdor massif, Kola Peninsula; in the Yenisei Range, Siberia. - United States - reported from Easton, Pennsylvania; black sands in Missouri River, near Helena, Montana; Scott River, Siskiyou County, California;[15] black sands in Nixon Fork and Wiseman districts, Alaska.[16][17] - Canada - Reported with uraninite in a pegmatite on Charlebois Lake, east of Lake Athabasca;[18] Uranon variety reported from pegmatite and metesomatized zones in crystalline limestones from many locations in Quebec and Ontario.[19] - South Africa - Occurs with baddeleyite as an accessory in carbonatite at Phalaborwa, Eastern Transvaal.[20] - Belgian Congo[21]	https://www.wikidoc.org/index.php/Thorianite
3d48f302df660b3a1cf21b571e3cb02d72a0a49e	wikidoc	Thorotrast	Thorotrast # Overview Thorotrast is a suspension containing particles of the radioactive compound thorium dioxide, ThO2, used as a contrast medium in X-ray diagnostics in the 1930s and 40s (use in some countries, such as the U.S., continued into the 1950s). The naturally abundant thorium nuclide 232Th is slightly unstable and decays through the emission of an alpha particle. Thorium compounds produce excellent images because of thorium's high opacity to X-rays (it has a high cross section for absorption). Because the suspension offered high image quality and had virtually no immediate side-effects compared to the alternatives available at the time, Thorotrast became widely used after its introduction in 1931. 2-10 million patients worldwide have been treated with Thorotrast. Even at the time of introduction, there was concern about the safety of Thorotrast. Following injection, the drug is distributed to the liver, spleen, lymph nodes, and bone,where it is absorbed. After this initial absorption, redistribution takes place at a very slow pace. Specifically, the biological half-life is estimated to be 22 years. This means that the organs of patients who have been given Thorotrast will be exposed to the alpha-radiation it emits for much of the rest of their lives. The significance of this exposure was not fully understood in 1931. Unfortunately, Thorotrast turned out to be extremely carcinogenic, because of these alpha particles. There is a high over-incidence of various cancers in patients who have been treated with Thorotrast. The cancers occur several (usually 20-30) years after injection of Thorotrast. The risk of getting liver cancer in former Thorotrast patients has been measured to be well above 100 times the risk of the rest of the population. The risk of leukemia appears to be 20 times higher in Thorotrast patients. These observations have led some to characterize Thorotrast as the most potent human carcinogen known. The Danish director Nils Malmros's movie, Facing the Truth (original Danish title At Kende Sandheden) from 2002, portrays the dilemma that faced Malmros's father, Richard Malmros, when treating his patients in the 1940s. Richard Malmros was deeply concerned about the persistence of Thorotrast in the body but was forced to use Thorotrast, because the only available alternative (per-abrodil) had serious immediate side-effects, suffered from image quality problems and was difficult to obtain during the Second World War. The use of Thorotrast in Denmark ended in 1947 when safer alternatives became available. Today, barium sulfate is the most commonly-used X-ray contrast medium. Thorotrast has also been used in research to stain neural tissue samples for examination by historadiography.	Thorotrast # Overview Thorotrast is a suspension containing particles of the radioactive compound thorium dioxide, ThO2, used as a contrast medium in X-ray diagnostics in the 1930s and 40s (use in some countries, such as the U.S., continued into the 1950s[1]). The naturally abundant thorium nuclide 232Th is slightly unstable and decays through the emission of an alpha particle. Thorium compounds produce excellent images because of thorium's high opacity to X-rays (it has a high cross section for absorption). Because the suspension offered high image quality and had virtually no immediate side-effects compared to the alternatives available at the time, Thorotrast became widely used after its introduction in 1931. 2-10 million patients worldwide have been treated with Thorotrast. Even at the time of introduction, there was concern about the safety of Thorotrast. Following injection, the drug is distributed to the liver, spleen, lymph nodes, and bone,where it is absorbed. After this initial absorption, redistribution takes place at a very slow pace. Specifically, the biological half-life is estimated to be 22 years. [1] This means that the organs of patients who have been given Thorotrast will be exposed to the alpha-radiation it emits for much of the rest of their lives. The significance of this exposure was not fully understood in 1931. Unfortunately, Thorotrast turned out to be extremely carcinogenic, because of these alpha particles. There is a high over-incidence of various cancers in patients who have been treated with Thorotrast. The cancers occur several (usually 20-30) years after injection of Thorotrast. The risk of getting liver cancer in former Thorotrast patients has been measured to be well above 100 times the risk of the rest of the population. The risk of leukemia appears to be 20 times higher in Thorotrast patients. These observations have led some to characterize Thorotrast as the most potent human carcinogen known. The Danish director Nils Malmros's movie, Facing the Truth (original Danish title At Kende Sandheden) from 2002, portrays the dilemma that faced Malmros's father, Richard Malmros, when treating his patients in the 1940s. Richard Malmros was deeply concerned about the persistence of Thorotrast in the body but was forced to use Thorotrast, because the only available alternative (per-abrodil) had serious immediate side-effects, suffered from image quality problems and was difficult to obtain during the Second World War. The use of Thorotrast in Denmark ended in 1947 when safer alternatives became available. Today, barium sulfate is the most commonly-used X-ray contrast medium. Thorotrast has also been used in research to stain neural tissue samples for examination by historadiography.[2]	https://www.wikidoc.org/index.php/Thorotrast
207dfc07aa2c2eeb0b1b262a89e8ec665fca5e6d	wikidoc	Thymectomy	Thymectomy A thymectomy is an operation to remove the thymus gland. It usually results in remission of myasthenia gravis with the help of medication including steroids. However, this remission may not be permanent. A thymectomy is mainly carried out in an adult. This is because the thymus loses most of its functional capacity after adolescence, but does retain a small portion of its function during adulthood. This is shown in the decreasing size of the thymus with increasing age after adolescence. The role of the thymus prior to adolescence is to educate T-cells to a specific response where they then populate the lymphoid organs, for storage until needed. Removal of the thymus as an adult has little immediate effect on the immune system as its role has been completed. Thymic hypoplasia as may be seen in DiGeorge Syndrome results in no T-cell education, and therefore a severe compromise in T cell mediated and humoral responses. ca:Timectomia	Thymectomy Template:Interventions infobox A thymectomy is an operation to remove the thymus gland. It usually results in remission of myasthenia gravis with the help of medication including steroids. However, this remission may not be permanent. A thymectomy is mainly carried out in an adult. This is because the thymus loses most of its functional capacity after adolescence, but does retain a small portion of its function during adulthood. This is shown in the decreasing size of the thymus with increasing age after adolescence. The role of the thymus prior to adolescence is to educate T-cells to a specific response where they then populate the lymphoid organs, for storage until needed. Removal of the thymus as an adult has little immediate effect on the immune system as its role has been completed. Thymic hypoplasia as may be seen in DiGeorge Syndrome results in no T-cell education, and therefore a severe compromise in T cell mediated and humoral responses. Template:Endocrine system intervention Template:WikiDoc Sources ca:Timectomia	https://www.wikidoc.org/index.php/Thymectomy
c1f26fed5cb62bebcb115a684365500673b83267	wikidoc	Tiletamine	Tiletamine Tiletamine is a dissociative anesthetic and pharmacologically classified as an NMDA receptor antagonist. It is related chemically and pharmacologically to other anesthetics in this family such as ketamine and phencyclidine...The appearance when in its raw form is a salt like crystal with a odourless smell . It is used in veterinary medicine in the compound product Telazol® (tiletamine/zolazepam, 50mg/ml of each in 5ml vial) as an injectable anesthetic. It is sometimes used in combination with xylazine (Rompun®) to tranquilize large mammals such as bears and horses. Telazol is the only commercially available tiletamine product in the USA. CONTRAINDICATED in patients of an ASA statues of III or greater and in animals with CNS signs, hyperthyroidism, cardiac disease, pancreatic or renal disease, pregnancy, glaucoma, or penetrating eye injuries. Tiletamine/zolazepam products are classified as Schedule III controlled substances in the United States.	Tiletamine Tiletamine is a dissociative anesthetic and pharmacologically classified as an NMDA receptor antagonist. It is related chemically and pharmacologically to other anesthetics in this family such as ketamine and phencyclidine...The appearance when in its raw form is a salt like crystal with a odourless smell . It is used in veterinary medicine in the compound product Telazol® (tiletamine/zolazepam, 50mg/ml of each in 5ml vial) as an injectable anesthetic. It is sometimes used in combination with xylazine (Rompun®) to tranquilize large mammals such as bears and horses. Telazol is the only commercially available tiletamine product in the USA. CONTRAINDICATED in patients of an ASA statues of III or greater and in animals with CNS signs, hyperthyroidism, cardiac disease, pancreatic or renal disease, pregnancy, glaucoma, or penetrating eye injuries. Tiletamine/zolazepam products are classified as Schedule III controlled substances in the United States. Template:Pharma-stub Template:Dissociative hallucinogens Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Tiletamine
cb21da39b5192cf3b6360036126506591f70adc4	wikidoc	Tilia tree	Tilia tree # Overview Tilia is a genus of about 30 species of trees native throughout most of the temperate Northern Hemisphere. They are generally called lime in Britain and linden or basswood in North America. The greatest species diversity is found in Asia, and the genus also occurs in Europe and eastern North America, but not western North America. Under the Cronquist classification system, this genus was placed in the family Tiliaceae, but genetic research by the Angiosperm Phylogeny Group has resulted in the incorporation of this family into the Malvaceae. Tilia species are large deciduous trees, reaching typically 20 to 40 m tall, with oblique-cordate leaves 6 to 20 cm across. The exact number of species is subject to considerable uncertainty, as many or most of the species will hybridise readily, both in the wild and in cultivation. # Name "Lime" is an altered form of Middle English lind, in the 16th century also line, from Old English feminine lind or linde, Proto-Germanic lendā, cognate to Latin lentus "flexible" and Sanskrit latā "liana". Within Germanic languages, English "lithe", German lind "lenient, yielding" are from the same root. "Linden" was originally the adjective, "made from lime-wood" (equivalent to "wooden"); from the late 16th century, "linden" was also used as a noun, probably influenced by translations of German romance, as an adoption of Linden, the plural of German Linde. Neither the name nor the tree is related to the citrus fruit called "lime" (Citrus aurantifolia, family Rutaceae). Another common name used in North America is basswood, derived from bast, the name for the inner bark (see Uses, below). In the US, the name "lime" is used only for the citrus tree. Teil is an old name for the lime tree. Latin tilia is cognate to Greek πτελέᾱ, ptelea, "elm tree", τιλίαι, tiliai, "black poplar" (Hes.), ultimately from a Proto-Indo-European word ptel-ei̯ā with a meaning of "broad" (feminine); perhaps "broad-leaved" or similar. # Description The Tilia's sturdy trunk stands like a pillar and the branches divide and subdivide into numerous ramifications on which the twigs are fine and thick. In summer, these are profusely clothed with large leaves and the result is a dense head of abundant foliage. The leaves of all the Tilia species are heart-shaped and most are asymmetrical, and the tiny fruit, looking like peas, always hang attached to a ribbon-like, greenish-yellow bract, whose use seems to be to launch the ripened seed-clusters just a little beyond the parent tree. The flowers of the European and American Tilia species are similar, except the American bears a petal-like scale among its stamens and the European varieties are devoid of these appendages. All of the Tilia species may be propagated by cuttings and grafting, as well as by seed. They grow rapidly in rich soil, but are subject to the attack of many insects. In particular, aphids are attracted by the rich supply of sap, and are in turn often "farmed" by ants for the production of the sap which the ants collect for their own use, and the result can often be a dripping of excess sap onto the lower branches and leaves, and anything else below. Cars left under the trees can quickly become coated with a film of the syrup ("honeydew") thus dropped from higher up. The ant/aphid "farming" process does not appear to cause any serious damage to the trees. # History In Europe, linden trees are known to have reached ages measured in centuries, if not longer. A coppice of T. cordata in Westonbirt Arboretum in Gloucestershire, for example, is estimated to be 2,000 years old. In the courtyard of the Imperial Castle at Nuremberg is a Tilia which tradition says was planted by the Empress Cunigunde, the wife of Henry II of Germany. This would make the tree about 900 years old in 1900 when it was described. It looks ancient and infirm, but in 1900 was sending forth a few leaves on its two or three remaining branches and was, of course, cared for tenderly. The Tilia of Neuenstadt am Kocher in Baden-Württemberg, Germany, was computed to be 1000 years old when it fell. The Alte Linde tree of Naters, Switzerland, is mentioned in a document in 1357 and described by the writer at that time as already magnam (huge). A plaque at its foot mentions that in 1155 a linden tree was already on this spot. - The excellence of the honey of far-famed Hyblaean Mountains was due to the linden trees that covered its sides and crowned its summit. - The name of Linnaeus, the great botanist, was derived from a lime tree. - Lime fossils have been found in the Tertiary formations of Grinnell Land, Canada, at 82° N latitude, and in Spitzbergen, Norway. Sapporta believed he had found there the common ancestor of the Tilia species of Europe and America. # Uses The linden is recommended as an ornamental tree when a mass of foliage or a deep shade is desired. The tree produces fragrant and nectar-producing flowers, the medicinal herb lime blossom. They are very important honey plants for beekeepers, producing a very pale but richly flavoured monofloral honey. The flowers are also used for herbal tea and tinctures; this kind of use is particularly popular in Europe and also used in North American herbal medicine practices. ## Wood The timber of linden trees is soft and easily worked; it has very little grain and a density of 560 kg per cubic metre. During the Viking era, it was often used for constructing shields. It is a popular wood for model building and intricate carving. Especially in Germany, it was the classic wood for sculpture from the Middle Ages onwards, and is the material for the elaborate altarpieces of Veit Stoss, Tilman Riemenschneider, and many others. In England, it was the favoured medium of Grinling Gibbons. Ease of working and good acoustic properties also make it popular for electric guitar and bass bodies and wind instruments such as recorders. In the past, it was typically used (along with Agathis) for less-expensive models. However, due to its better resonance at middle and high frequencies, and better sustain than alder, it is now more commonly used in the "superstrat" type of guitar. It can also be used for the neck because of its excellent material integrity when bent and ability to produce consistent tone without any dead spots, according to Parker Guitars. In the percussion industry, Tilia is sometimes used as a material for drum shells, both to enhance their sound and their aesthetics. Lime wood is known in the aquarium industry for its use as an air diffuser inside protein skimmers. Air pumped through the grain of the wood turns into consistently very fine bubbles (0.5-1.0 mm), difficult to achieve with any other natural or man-made medium. However, the wood decomposes underwater much faster than ceramic air stones and must be replaced more frequently for maximum efficiency. It is also the wood of choice for window blinds and shutters. Real wood blinds are often made from this lightweight but strong and stable wood, which is well suited to natural and stained finishes. ## Bark It is known in the trade as basswood, particularly in North America. This name originates from the inner fibrous bark of the tree, known as bast. A very strong fibre is obtained from this, by peeling off the bark and soaking it in water for a month, after which the inner fibres can be easily separated. Bast obtained from the inside of the bark of the Tilia tree, it has been used by the Ainu people of Japan to weave their traditional clothing, the attus. Similar fibres obtained from other plants are also called bast, named after those from the Tilia: see Bast fibre. ## Herbalism Tilia cordata is the preferred species for medical use, having a high concentration of active compounds.Template:Vague It is said to be a nervine, used by herbalists in treating restlessness, hysteria, and headaches. Usually, the double-flowered species are used to make perfumes. The leaf buds and young leaves are also edible raw. Tilia species are used as food plants by the larvae of some Lepidoptera species; see List of Lepidoptera that feed on Tilia. Most medicinal research has focused on Tilia cordata, although other species are also used medicinally and somewhat interchangeably. The dried flowers are mildly sweet and sticky, and the fruit is somewhat sweet and mucilaginous. Limeflower tea has a pleasing taste, due to the aromatic volatile oil found in the flowers. The flowers, leaves, wood, and charcoal (obtained from the wood) are used for medicinal purposes. Active ingredients in the Tilia flowers include flavonoids (which act as antioxidants), volatile oils, and mucilaginous constituents (which soothe and reduce inflammation). The plant also contains tannins that can act as an astringent. Linden flowers are used in herbalism for colds, cough, fever, infections, inflammation, high blood pressure, headache (particularly migraine), and as a diuretic (increases urine production), antispasmodic (reduces smooth muscle spasm along the digestive tract), and sedative. New evidence shows that the flowers may be hepatoprotective. The flowers were added to baths to quell hysteria, and steeped as a tea to relieve anxiety-related indigestion, irregular heartbeat, and vomiting. The leaves are used to promote sweating to reduce fevers. The wood is used for liver and gallbladder disorders and cellulitis (inflammation of the skin and surrounding soft tissue). That wood burned to charcoal is ingested to treat intestinal disorders and used topically to treat edema or infection such as cellulitis or ulcers of the lower leg. # Classification The following list comprises those most widely accepted as species, hybrids, and cultivars. ## Species - Tilia americana L. – Basswood, American Linden - Tilia amurensis – Amur Lime, Amur Linden - Tilia argentea – Silver Lime - Tilia caroliniana – Carolina Basswood - Tilia chinensis - Tilia chingiana Hu & W.C.Cheng - Tilia cordata Mill. – Small-leaved Lime, Little-leaf Linden or Greenspire Linden - Tilia dasystyla Steven - Tilia euchlora – Caucasian Lime - Tilia henryana Szyszyl. – Henry's Lime, Henry's Linden - Tilia heterophylla Vent. – White Basswood - Tilia hupehensis – Hubei Lime - Tilia insularis - Tilia intonsa - Tilia japonica – Japanese Lime, Shina (When used as a laminate) - †Tilia johnsoni Wolfe & Wehr Eocene; Washington and British Columbia - Tilia kiusiana - Tilia mandshurica – Manchurian Lime - Tilia maximowicziana - Tilia mexicana (T. americana var. mexicana) - Tilia miqueliana - Tilia mongolica – Mongolian Lime, Mongolian Linden - Tilia nasczokinii – Nasczokin's Lime, Nasczokin's Linden - Tilia nobilis - Tilia occidentalis – West lime - Tilia oliveri – Oliver's Lime - Tilia paucicostata - Tilia platyphyllos Scop. – Large-leaved Lime - Tilia rubra – Red Stem Lime (syn. T. platyphyllos var. rubra) - Tilia tomentosa Moench – Silver Lime, Silver Linden - Tilia tuan ## Hybrids and cultivars - Tilia × euchlora (T. dasystyla × T. cordata) - Tilia × europaea – Common Lime (T. cordata × T. platyphyllos; syn. T. × vulgaris) - Tilia × petiolaris (T. tomentosa × T. ?) - Tilia 'Flavescens' – Glenleven Linden (T. americana × T. cordata) - Tilia 'Moltkei' (hybrid, unknown origin) - Tilia 'Orbicularis' (hybrid, unknown origin) - Tilia 'Spectabilis' (hybrid, unknown origin) # Cultural significance ## Slavic mythology In old Slavic mythology, the linden (lipa, as called in all Slavic languages) was considered a sacred tree. Particularly in Poland, many villages have a name "Święta Lipka" (or similar), which literally means "Holy Lime". To this day, the tree is a national emblem of Slovakia, Slovenia, the Czech Republic, and the Sorbs. Lipa gave name to the traditional Slavic name for the month of June (Croatian, lipanj) or July (Polish, lipiec). It is also the root for the German city of Leipzig, taken from the Sorbian name lipsk. The Croatian currency, kuna, consists of 100 lipa (Tilia). "Lipa" was also a proposed name for Slovenian currency in 1990, however the name "tolar" ultimately prevailed. In the Slavic Orthodox Christian world, limewood was the preferred wood for panel icon painting. The icons by the hand of Andrei Rublev, including the Holy Trinity (Hospitality of Abraham), and The Savior, now in the State Tretyakov Gallery in Moscow, are painted on linden wood. Its wood was chosen for its ability to be sanded very smooth and for its resistance to warping once seasoned. ## Germanic mythology The linden was also a highly symbolic and hallowed tree to the Germanic peoples in their native pre-Christian Germanic mythology. Originally, local communities assembled not only to celebrate and dance under a linden tree, but to hold their judicial thing meetings there in order to restore justice and peace. It was believed that the tree would help unearth the truth. Thus the tree became associated with jurisprudence even after Christianization, such as in the case of the Gerichtslinde, and verdicts in rural Germany were frequently returned sub tilia (under the linden) until the Age of Enlightenment. In the Nibelungenlied, a medieval German work ultimately based on oral tradition recounting events amongst the Germanic tribes in the 5th and 6th centuries, Siegfried gains his invulnerability by bathing in the blood of a dragon. While he did so, a single linden leaf sticks to him, leaving a spot on his body untouched by the blood and he thus has a single point of vulnerability. The most notable street in Berlin, Germany is called Unter den Linden, named after the trees lining the avenue. In German folklore, the linden tree is the "tree of lovers." Hohenlinden (translated as "High linden") is a community in the upper Barvarian district of Ebersberg in which the Battle of Hohenlinden took place; Thomas Campbell wrote the poem Hohenlinden about said battle. ## Greek mythology Homer, Horace, Virgil, and Pliny mention the linden tree and its virtues. As Ovid tells the old story of Baucis and Philemon, she was changed into a linden and he into an oak when the time came for them both to die. Herodotus says: The Scythian diviners take also the leaf of the linden tree, which, dividing into three parts, they twine round their fingers; they then unbind it and exercise the art to which they pretend. ## Romantic symbol A mediaeval love poem by Walther von der Vogelweide (c. 1170–c. 1230) starts with a reference to the tree: Linden trees play a significant motif in a number of poems written by Romanian poet Mihai Eminescu. An excerpt from his poem Mai am un singur dor (One Wish Alone Have I): In 1979, linden trees were featured in the song Gelato al Cioccolato on the album of the same name by Italian singer-songwriter Enzo Ghinazzi, also known as Pupo. In 2003, linden trees were featured in the popular song "Dragostea Din Tei" ("Love from linden Trees") by the Moldovan band O-Zone. The tree also has cultural and spiritual significance in Hungary, where it is called hárs (fa). ### Literary references - A play called "The Linden Tree" (1947) was written by Bradford-born English novelist, playwright and broadcaster J.B. Priestley. - Samuel Taylor Coleridge features linden trees as an important symbol in his poem "This Lime-Tree Bower My Prison" (written 1797; first published 1800). - The short poems (Fraszki) of Polish poet Jan Kochanowski commonly feature linden trees, especially "Na Lipę" (To The Tilia Tree), published in 1584. Kochanowski was heavily influenced by the Czarnolas, or the Polish Black Forest, where it is the dominant tree species. - The lined tree is featured as a symbol of supernatural dread in Hannah Crafts' The Bondwoman's Narrative. - A poem from Wilhelm Müller's Winterreise cycle of poems is called "Der Lindenbaum" (The Linden Tree). The cycle was later set to music by Franz Schubert. - Goethe's The Sorrows of Young Werther features a linden tree throughout the novel, and the protagonist, Werther, is buried under the tree after his suicide. - In Swann's Way, the first book of Proust's In Search of Lost Time, the narrator dips a petite madeleine into a cup of Tilia blossom tea. The aroma and taste of cake and tea triggers his first conscious involuntary memory. - The band Bright Eyes has a song called "Lime Tree" on the album Cassadaga: "Under the eaves of that old Lime Tree I stood examining the fruit." - Prominently featured throughout Nobel Laureate Orhan Pamuk's The Museum of Innocence. - Tilia trees are a recurring theme in Romanian author Mihai Eminescu's poems. Upon his wish he was interred under one's shade. - A Tilia tree is prominent in the setting of Anton Chekhov's play The Seagull (Act II). - The song "Dragostea din tei" by Moldovan band O-zone features several references to linden trees. - A short story written by Herman Hesse, "The Three Linden Trees" - A song written by Joan Baez, "For Sasha", mentions the linden tree; from the album Honest Lullaby - A poem from Thomas Pynchon's Gravity's Rainbow, sung by the German witch Geli Tripping, mentions a linden tree: "Though it’s another year, Though it’s another me, Under the rose is a drying tear, Under my linden tree… Love never goes away, Not if it’s really true, It can return by night, by day, Tender and green and new As the leaves from a linden tree, love, That I left with you." - In "Inkdeath", the third book of Cornelia Funke's Inkheart trilogy, fish scales are described as "as large as linden leaves" # Gallery - Tilia foliage in autumn colors from Ekoparken in Stockholm. Tilia foliage in autumn colors from Ekoparken in Stockholm. - New growth following a devastating late spring storm. New growth following a devastating late spring storm. - Decomposing lime bark. Decomposing lime bark. - Edward VII Limes, in Parkend, Gloucestershire. Edward VII Limes, in Parkend, Gloucestershire.	Tilia tree Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Tilia is a genus of about 30 species of trees native throughout most of the temperate Northern Hemisphere. They are generally called lime in Britain and linden or basswood in North America. The greatest species diversity is found in Asia, and the genus also occurs in Europe and eastern North America, but not western North America. Under the Cronquist classification system, this genus was placed in the family Tiliaceae, but genetic research by the Angiosperm Phylogeny Group has resulted in the incorporation of this family into the Malvaceae. Tilia species are large deciduous trees, reaching typically 20 to 40 m tall, with oblique-cordate leaves 6 to 20 cm across. The exact number of species is subject to considerable uncertainty, as many or most of the species will hybridise readily, both in the wild and in cultivation. # Name "Lime" is an altered form of Middle English lind, in the 16th century also line, from Old English feminine lind or linde, Proto-Germanic lendā, cognate to Latin lentus "flexible" and Sanskrit latā "liana". Within Germanic languages, English "lithe", German lind "lenient, yielding" are from the same root. "Linden" was originally the adjective, "made from lime-wood" (equivalent to "wooden"); from the late 16th century, "linden" was also used as a noun, probably influenced by translations of German romance, as an adoption of Linden, the plural of German Linde.[1] Neither the name nor the tree is related to the citrus fruit called "lime" (Citrus aurantifolia, family Rutaceae). Another common name used in North America is basswood, derived from bast, the name for the inner bark (see Uses, below). In the US, the name "lime" is used only for the citrus tree. Teil is an old name for the lime tree. Latin tilia is cognate to Greek πτελέᾱ, ptelea, "elm tree", τιλίαι, tiliai, "black poplar" (Hes.), ultimately from a Proto-Indo-European word ptel-ei̯ā with a meaning of "broad" (feminine); perhaps "broad-leaved" or similar.[2] # Description The Tilia's sturdy trunk stands like a pillar and the branches divide and subdivide into numerous ramifications on which the twigs are fine and thick. In summer, these are profusely clothed with large leaves and the result is a dense head of abundant foliage. The leaves of all the Tilia species are heart-shaped and most are asymmetrical, and the tiny fruit, looking like peas, always hang attached to a ribbon-like, greenish-yellow bract, whose use seems to be to launch the ripened seed-clusters just a little beyond the parent tree. The flowers of the European and American Tilia species are similar, except the American bears a petal-like scale among its stamens and the European varieties are devoid of these appendages. All of the Tilia species may be propagated by cuttings and grafting, as well as by seed. They grow rapidly in rich soil, but are subject to the attack of many insects. In particular, aphids are attracted by the rich supply of sap, and are in turn often "farmed" by ants for the production of the sap which the ants collect for their own use, and the result can often be a dripping of excess sap onto the lower branches and leaves, and anything else below. Cars left under the trees can quickly become coated with a film of the syrup ("honeydew") thus dropped from higher up. The ant/aphid "farming" process does not appear to cause any serious damage to the trees. # History In Europe, linden trees are known to have reached ages measured in centuries, if not longer. A coppice of T. cordata in Westonbirt Arboretum in Gloucestershire, for example, is estimated to be 2,000 years old.[2] In the courtyard of the Imperial Castle at Nuremberg is a Tilia which tradition says was planted by the Empress Cunigunde, the wife of Henry II of Germany. This would make the tree about 900 years old in 1900 when it was described. It looks ancient and infirm, but in 1900 was sending forth a few leaves on its two or three remaining branches and was, of course, cared for tenderly. The Tilia of Neuenstadt am Kocher in Baden-Württemberg, Germany, was computed to be 1000 years old when it fell.[3] The Alte Linde tree of Naters, Switzerland, is mentioned in a document in 1357 and described by the writer at that time as already magnam (huge). A plaque at its foot mentions that in 1155 a linden tree was already on this spot. - The excellence of the honey of far-famed Hyblaean Mountains[4] was due to the linden trees that covered its sides and crowned its summit. - The name of Linnaeus, the great botanist, was derived from a lime tree. - Lime fossils have been found in the Tertiary formations of Grinnell Land, Canada, at 82° N latitude, and in Spitzbergen, Norway. Sapporta believed he had found there the common ancestor of the Tilia species of Europe and America.[3] # Uses The linden is recommended as an ornamental tree when a mass of foliage or a deep shade is desired.[3] The tree produces fragrant and nectar-producing flowers, the medicinal herb lime blossom. They are very important honey plants for beekeepers, producing a very pale but richly flavoured monofloral honey. The flowers are also used for herbal tea and tinctures; this kind of use is particularly popular in Europe and also used in North American herbal medicine practices. ## Wood The timber of linden trees is soft and easily worked; it has very little grain and a density of 560 kg per cubic metre.[5] During the Viking era, it was often used for constructing shields. It is a popular wood for model building and intricate carving. Especially in Germany, it was the classic wood for sculpture from the Middle Ages onwards, and is the material for the elaborate altarpieces of Veit Stoss, Tilman Riemenschneider, and many others. In England, it was the favoured medium of Grinling Gibbons.[6] Ease of working and good acoustic properties also make it popular for electric guitar and bass bodies and wind instruments such as recorders. In the past, it was typically used (along with Agathis) for less-expensive models. However, due to its better resonance at middle and high frequencies, and better sustain than alder, it is now more commonly used in the "superstrat" type of guitar. It can also be used for the neck because of its excellent material integrity when bent and ability to produce consistent tone without any dead spots, according to Parker Guitars. In the percussion industry, Tilia is sometimes used as a material for drum shells, both to enhance their sound and their aesthetics. Lime wood is known in the aquarium industry for its use as an air diffuser inside protein skimmers. Air pumped through the grain of the wood turns into consistently very fine bubbles (0.5-1.0 mm), difficult to achieve with any other natural or man-made medium. However, the wood decomposes underwater much faster than ceramic air stones and must be replaced more frequently for maximum efficiency. It is also the wood of choice for window blinds and shutters. Real wood blinds are often made from this lightweight but strong and stable wood, which is well suited to natural and stained finishes. ## Bark It is known in the trade as basswood, particularly in North America. This name originates from the inner fibrous bark of the tree, known as bast. A very strong fibre is obtained from this, by peeling off the bark and soaking it in water for a month, after which the inner fibres can be easily separated. Bast obtained from the inside of the bark of the Tilia tree, it has been used by the Ainu people of Japan to weave their traditional clothing, the attus. Similar fibres obtained from other plants are also called bast, named after those from the Tilia: see Bast fibre. ## Herbalism Tilia cordata is the preferred species for medical use, having a high concentration of active compounds.Template:Vague It is said to be a nervine, used by herbalists in treating restlessness, hysteria, and headaches.[citation needed] Usually, the double-flowered species are used to make perfumes. The leaf buds and young leaves are also edible raw. Tilia species are used as food plants by the larvae of some Lepidoptera species; see List of Lepidoptera that feed on Tilia. Most medicinal research has focused on Tilia cordata, although other species are also used medicinally and somewhat interchangeably. The dried flowers are mildly sweet and sticky, and the fruit is somewhat sweet and mucilaginous. Limeflower tea has a pleasing taste, due to the aromatic volatile oil found in the flowers. The flowers, leaves, wood, and charcoal (obtained from the wood) are used for medicinal purposes. Active ingredients in the Tilia flowers include flavonoids (which act as antioxidants), volatile oils, and mucilaginous constituents (which soothe and reduce inflammation).[citation needed] The plant also contains tannins that can act as an astringent.[7] Linden flowers are used in herbalism for colds, cough, fever, infections, inflammation, high blood pressure, headache (particularly migraine), and as a diuretic (increases urine production), antispasmodic (reduces smooth muscle spasm along the digestive tract), and sedative.[8] New evidence shows that the flowers may be hepatoprotective.[9] The flowers were added to baths to quell hysteria, and steeped as a tea to relieve anxiety-related indigestion, irregular heartbeat, and vomiting.[citation needed] The leaves are used to promote sweating to reduce fevers. The wood is used for liver and gallbladder disorders and cellulitis (inflammation of the skin and surrounding soft tissue). That wood burned to charcoal is ingested to treat intestinal disorders and used topically to treat edema or infection such as cellulitis or ulcers of the lower leg.[7] # Classification The following list comprises those most widely accepted as species, hybrids, and cultivars. ## Species - Tilia americana L. – Basswood, American Linden - Tilia amurensis – Amur Lime, Amur Linden - Tilia argentea – Silver Lime - Tilia caroliniana – Carolina Basswood - Tilia chinensis - Tilia chingiana Hu & W.C.Cheng - Tilia cordata Mill. – Small-leaved Lime, Little-leaf Linden or Greenspire Linden - Tilia dasystyla Steven - Tilia euchlora – Caucasian Lime - Tilia henryana Szyszyl. – Henry's Lime, Henry's Linden - Tilia heterophylla Vent. – White Basswood - Tilia hupehensis – Hubei Lime - Tilia insularis - Tilia intonsa - Tilia japonica – Japanese Lime, Shina (When used as a laminate) - †Tilia johnsoni Wolfe & Wehr Eocene; Washington and British Columbia - Tilia kiusiana - Tilia mandshurica – Manchurian Lime - Tilia maximowicziana - Tilia mexicana (T. americana var. mexicana) - Tilia miqueliana - Tilia mongolica – Mongolian Lime, Mongolian Linden - Tilia nasczokinii – Nasczokin's Lime, Nasczokin's Linden - Tilia nobilis - Tilia occidentalis – West lime - Tilia oliveri – Oliver's Lime - Tilia paucicostata - Tilia platyphyllos Scop. – Large-leaved Lime - Tilia rubra – Red Stem Lime (syn. T. platyphyllos var. rubra) - Tilia tomentosa Moench – Silver Lime, Silver Linden - Tilia tuan ## Hybrids and cultivars - Tilia × euchlora (T. dasystyla × T. cordata) - Tilia × europaea – Common Lime (T. cordata × T. platyphyllos; syn. T. × vulgaris) - Tilia × petiolaris (T. tomentosa × T. ?) - Tilia 'Flavescens' – Glenleven Linden (T. americana × T. cordata) - Tilia 'Moltkei' (hybrid, unknown origin) - Tilia 'Orbicularis' (hybrid, unknown origin) - Tilia 'Spectabilis' (hybrid, unknown origin) # Cultural significance ## Slavic mythology In old Slavic mythology, the linden (lipa, as called in all Slavic languages) was considered a sacred tree.[10] Particularly in Poland, many villages have a name "Święta Lipka" (or similar), which literally means "Holy Lime". To this day, the tree is a national emblem of Slovakia, Slovenia, the Czech Republic, and the Sorbs.[citation needed] Lipa gave name to the traditional Slavic name for the month of June (Croatian, lipanj) or July (Polish, lipiec). It is also the root for the German city of Leipzig, taken from the Sorbian name lipsk.[11] The Croatian currency, kuna, consists of 100 lipa (Tilia). "Lipa" was also a proposed name for Slovenian currency in 1990, however the name "tolar" ultimately prevailed.[12] In the Slavic Orthodox Christian world, limewood was the preferred wood for panel icon painting. The icons by the hand of Andrei Rublev, including the Holy Trinity (Hospitality of Abraham), and The Savior, now in the State Tretyakov Gallery in Moscow, are painted on linden wood. Its wood was chosen for its ability to be sanded very smooth and for its resistance to warping once seasoned. ## Germanic mythology The linden was also a highly symbolic and hallowed tree to the Germanic peoples in their native pre-Christian Germanic mythology. Originally, local communities assembled not only to celebrate and dance under a linden tree, but to hold their judicial thing meetings there in order to restore justice and peace. It was believed that the tree would help unearth the truth. Thus the tree became associated with jurisprudence even after Christianization, such as in the case of the Gerichtslinde, and verdicts in rural Germany were frequently returned sub tilia (under the linden) until the Age of Enlightenment. In the Nibelungenlied, a medieval German work ultimately based on oral tradition recounting events amongst the Germanic tribes in the 5th and 6th centuries, Siegfried gains his invulnerability by bathing in the blood of a dragon. While he did so, a single linden leaf sticks to him, leaving a spot on his body untouched by the blood and he thus has a single point of vulnerability. The most notable street in Berlin, Germany is called Unter den Linden, named after the trees lining the avenue. In German folklore, the linden tree is the "tree of lovers." Hohenlinden (translated as "High linden") is a community in the upper Barvarian district of Ebersberg in which the Battle of Hohenlinden took place; Thomas Campbell wrote the poem Hohenlinden about said battle. ## Greek mythology Homer, Horace, Virgil, and Pliny mention the linden tree and its virtues. As Ovid tells the old story of Baucis and Philemon, she was changed into a linden and he into an oak when the time came for them both to die. Herodotus says:[3] The Scythian diviners take also the leaf of the linden tree, which, dividing into three parts, they twine round their fingers; they then unbind it and exercise the art to which they pretend. ## Romantic symbol A mediaeval love poem by Walther von der Vogelweide (c. 1170–c. 1230) starts with a reference to the tree: Linden trees play a significant motif in a number of poems written by Romanian poet Mihai Eminescu. An excerpt from his poem Mai am un singur dor (One Wish Alone Have I): In 1979, linden trees were featured in the song Gelato al Cioccolato on the album of the same name by Italian singer-songwriter Enzo Ghinazzi, also known as Pupo. In 2003, linden trees were featured in the popular song "Dragostea Din Tei" ("Love from linden Trees") by the Moldovan band O-Zone. The tree also has cultural and spiritual significance in Hungary, where it is called hárs (fa). ### Literary references - A play called "The Linden Tree" (1947) was written by Bradford-born English novelist, playwright and broadcaster J.B. Priestley. - Samuel Taylor Coleridge features linden trees as an important symbol in his poem "This Lime-Tree Bower My Prison" (written 1797; first published 1800). - The short poems (Fraszki) of Polish poet Jan Kochanowski commonly feature linden trees, especially "Na Lipę" (To The Tilia Tree), published in 1584. Kochanowski was heavily influenced by the Czarnolas, or the Polish Black Forest, where it is the dominant tree species. - The lined tree is featured as a symbol of supernatural dread in Hannah Crafts' The Bondwoman's Narrative. - A poem from Wilhelm Müller's Winterreise cycle of poems is called "Der Lindenbaum" (The Linden Tree). The cycle was later set to music by Franz Schubert. - Goethe's The Sorrows of Young Werther features a linden tree throughout the novel, and the protagonist, Werther, is buried under the tree after his suicide. - In Swann's Way, the first book of Proust's In Search of Lost Time, the narrator dips a petite madeleine into a cup of Tilia blossom tea. The aroma and taste of cake and tea triggers his first conscious involuntary memory. - The band Bright Eyes has a song called "Lime Tree" on the album Cassadaga: "Under the eaves of that old Lime Tree I stood examining the fruit." - Prominently featured throughout Nobel Laureate Orhan Pamuk's The Museum of Innocence. - Tilia trees are a recurring theme in Romanian author Mihai Eminescu's poems. Upon his wish he was interred under one's shade. - A Tilia tree is prominent in the setting of Anton Chekhov's play The Seagull (Act II). - The song "Dragostea din tei" by Moldovan band O-zone features several references to linden trees. - A short story written by Herman Hesse, "The Three Linden Trees" - A song written by Joan Baez, "For Sasha", mentions the linden tree; from the album Honest Lullaby - A poem from Thomas Pynchon's Gravity's Rainbow, sung by the German witch Geli Tripping, mentions a linden tree: "Though it’s another year, Though it’s another me, Under the rose is a drying tear, Under my linden tree… Love never goes away, Not if it’s really true, It can return by night, by day, Tender and green and new As the leaves from a linden tree, love, That I left with you." - In "Inkdeath", the third book of Cornelia Funke's Inkheart trilogy, fish scales are described as "as large as linden leaves" # Gallery - Tilia foliage in autumn colors from Ekoparken in Stockholm. Tilia foliage in autumn colors from Ekoparken in Stockholm. - New growth following a devastating late spring storm. New growth following a devastating late spring storm. - Decomposing lime bark. Decomposing lime bark. - Edward VII Limes, in Parkend, Gloucestershire. Edward VII Limes, in Parkend, Gloucestershire.	https://www.wikidoc.org/index.php/Tilia_tree
5a2cc244d16006f31b18fee558d236f3f8263885	wikidoc	Tiocarlide	Tiocarlide # Overview Thiocarlide (or tiocarlide or isoxyl) is a thiourea drug used in the treatment of tuberculosis, inhibiting synthesis of oleic acid and tuberculostearic acid. Thiocarlide has considerable antimycobacterial activity in vitro and is effective against multi-drug resistant strains of Mycobacterium tuberculosis. Isoxyl inhibits M. bovis with six hours of exposure, which is similar to isoniazid and ethionamide, two other prominent anti-TB drugs. Unlike these two drugs, however, isoxyl also partially inhibits the synthesis of fatty acids. Thiocarlide was developed by a Belgian company, Continental Pharma S.A. Belgo-Canadienne in Brussels, Belgium. The head researcher was Professor N. P. Buu-Hoi, head of Continental Pharma's Research Division.	Tiocarlide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Thiocarlide (or tiocarlide or isoxyl) is a thiourea drug used in the treatment of tuberculosis, inhibiting synthesis of oleic acid and tuberculostearic acid.[1] Thiocarlide has considerable antimycobacterial activity in vitro and is effective against multi-drug resistant strains of Mycobacterium tuberculosis.[2] Isoxyl inhibits M. bovis with six hours of exposure, which is similar to isoniazid and ethionamide, two other prominent anti-TB drugs. Unlike these two drugs, however, isoxyl also partially inhibits the synthesis of fatty acids. Thiocarlide was developed by a Belgian company, Continental Pharma S.A. Belgo-Canadienne in Brussels, Belgium. The head researcher was Professor N. P. Buu-Hoi, head of Continental Pharma's Research Division.	https://www.wikidoc.org/index.php/Tiocarlide
f05875b29cf60f7b895ecff2780e751a08f5977a	wikidoc	Tipepidine	Tipepidine # Overview Tipepidine (INN) (brand names Asverin, Antupex, Asvelik, Asvex, Bitiodin, Cofdenin A, Hustel, Nodal, Sotal), also known as tipepidine hibenzate (JAN), is a synthetic, non-opioid antitussive and expectorant of the thiambutene class. It acts as an inhibitor of G protein-coupled inwardly-rectifying potassium channels (GIRKs). The drug was discovered in the 1950s, and was developed in Japan in 1959. It is used as the hibenzate and citrate salts. The usual dose is 20 mg every 4–6 hours. Possible side effects of tipepidine, especially in overdose, may include drowsiness, vertigo, delirium, disorientation, loss of consciousness, and confusion. Tipepidine has recently garnered interest as a potential psychiatric drug. It is being investigated in depression, obsessive-compulsive disorder, and attention-deficit hyperactivity disorder (ADHD). Through inhibition of GIRK channels, tipepidine increases dopamine levels in the nucleus accumbens, but without increasing locomotor activity or producing methamphetamine-like behavioral sensitization, and this action appears to be at least partly responsible for its antidepressant-like effects in rodents.	Tipepidine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Tipepidine (INN) (brand names Asverin, Antupex, Asvelik, Asvex, Bitiodin, Cofdenin A, Hustel, Nodal, Sotal), also known as tipepidine hibenzate (JAN), is a synthetic, non-opioid antitussive and expectorant of the thiambutene class.[1][2] It acts as an inhibitor of G protein-coupled inwardly-rectifying potassium channels (GIRKs).[3] The drug was discovered in the 1950s,[4] and was developed in Japan in 1959.[5] It is used as the hibenzate and citrate salts.[1][5] The usual dose is 20 mg every 4–6 hours.[citation needed] Possible side effects of tipepidine, especially in overdose, may include drowsiness, vertigo, delirium, disorientation, loss of consciousness, and confusion.[5] Tipepidine has recently garnered interest as a potential psychiatric drug. It is being investigated in depression,[3][6][7] obsessive-compulsive disorder,[8] and attention-deficit hyperactivity disorder (ADHD).[9][10] Through inhibition of GIRK channels, tipepidine increases dopamine levels in the nucleus accumbens, but without increasing locomotor activity or producing methamphetamine-like behavioral sensitization, and this action appears to be at least partly responsible for its antidepressant-like effects in rodents.[11][12]	https://www.wikidoc.org/index.php/Tipepidine
10c80f14f2d8eeca417674c41bc861cf1bcb3dcc	wikidoc	Tipranavir	Tipranavir # 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 Tipranavir is a protease inhibitor, co-administered with ritonavir that is FDA approved for the treatment of HIV-1 infected patients who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - APTIVUS must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions. - The recommended adult dose of APTIVUS is 500 mg (two 250 mg capsules or 5 mL oral solution) co-administered with 200 mg of ritonavir, twice daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tipranavir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tipranavir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Healthcare professionals should pay special attention to accurate calculation of the dose of APTIVUS, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose. - Prescribers should calculate the appropriate dose of APTIVUS for each individual child based on body weight (kg) or body surface area (BSA, m2) and should not exceed the recommended adult dose. - Before prescribing APTIVUS 250 mg capsules, children should be assessed for the ability to swallow capsules. If a child is unable to reliably swallow an APTIVUS capsule, the APTIVUS oral solution formulation should be prescribed. - The recommended pediatric dose of APTIVUS is 14 mg/kg with 6 mg/kg ritonavir (or 375 mg/m2 co-administered with ritonavir 150 mg/m2) taken twice daily not to exceed a maximum dose of APTIVUS 500 mg co-administered with ritonavir 200 mg twice daily. For children who develop intolerance or toxicity and cannot continue with APTIVUS 14 mg/kg with 6 mg/kg ritonavir, physicians may consider decreasing the dose to APTIVUS 12 mg/kg with 5 mg/kg ritonavir (or APTIVUS 290 mg/m2 co-administered with 115 mg/m2 ritonavir) taken twice daily provided their virus is not resistant to multiple protease inhibitors. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tipranavir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tipranavir in pediatric patients. # Contraindications - Hepatic Impairment - APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment. - Drug Interactions - Co-administration of APTIVUS/ritonavir with drugs that are highly dependent on CYP 3A for clearance or are potent CYP 3A inducers are contraindicated (see Table 1). These recommendations are based on either drug interaction studies or they are predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. For information regarding clinical recommendations. # Warnings ### Precautions - Hepatic Impairment and Toxicity - Clinical hepatitis and hepatic decompensation, including some fatalities, were reported with APTIVUS co-administered with 200 mg of ritonavir. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications. A causal relationship to APTIVUS/ritonavir could not be established. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. - All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with APTIVUS/ritonavir, and frequently throughout the duration of treatment. - If asymptomatic elevations in AST or ALT greater than 10 times the upper limit of normal occur, APTIVUS/ritonavir therapy should be discontinued. If asymptomatic elevations in AST or ALT between 5 – 10 times the upper limit of normal and increases in total bilirubin greater than 2.5 times the upper limit of normal occur, APTIVUS/ritonavir therapy should be discontinued. - Treatment-experienced patients with chronic hepatitis B or hepatitis C co-infection or elevated transaminases are at approximately 2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation. In two large, randomized, open-label, controlled clinical trials with an active comparator (1182.12 and 1182.48) of treatment-experienced patients, Grade 3 and 4 increases in hepatic transaminases were observed in 10.3% (10.9/100 PEY) receiving APTIVUS/ritonavir through week 48. In a study of treatment-naïve patients, 20.3% (21/100 PEY) experienced Grade 3 or 4 hepatic transaminase elevations while receiving APTIVUS/ritonavir 500 mg/200 mg through week 48. - Tipranavir is principally metabolized by the liver. Caution should be exercised when administering APTIVUS/ritonavir to patients with mild hepatic impairment (Child-Pugh Class A) because tipranavir concentrations may be increased. - Intracranial Hemorrhage - APTIVUS, co-administered with 200 mg of ritonavir, has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH). Many of these patients had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events. No pattern of abnormal coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on APTIVUS. - Drug Interactions - See Table 1 for a listing of contraindicated drugs with APTIVUS/ritonavir due to potentially life-threatening adverse events, significant drug interactions, or due to loss of virologic activity. See Table 4 for a listing of established and other potentially significant drug interactions with APTIVUS/ritonavir. - Effects on Platelet Aggregation and Coagulation - APTIVUS/ritonavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants, or who are taking supplemental high doses of vitamin E. - In rats, tipranavir treatment alone induced dose-dependent changes in coagulation parameters, bleeding events and death. Co-administration with vitamin E significantly increased these effects. However, analyses of stored plasma from adult patients treated with APTIVUS capsules and pediatric patients treated with APTIVUS oral solution (which contains a vitamin E derivative) showed no effect of APTIVUS/ritonavir on vitamin K-dependent coagulation factors (Factor II and Factor VII), Factor V, or on prothrombin or activated partial thromboplastin times. - In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving APTIVUS/ritonavir. - Vitamin E Intake - Patients taking APTIVUS oral solution should be advised not to take supplemental vitamin E greater than a standard multivitamin as APTIVUS oral solution contains 116 IU/mL of vitamin E which is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU). - Rash - Rash, including urticarial rash, maculopapular rash, and possible photosensitivity, has been reported in subjects receiving APTIVUS/ritonavir. In some cases rash was accompanied by joint pain or stiffness, throat tightness, or generalized pruritus. In controlled adult clinical trials, rash (all grades, all causality) was observed in 10% of females and in 8% of males receiving APTIVUS/ritonavir through 48 weeks of treatment. The median time to onset of rash was 53 days and the median duration of rash was 22 days. The discontinuation rate for rash in clinical trials was 0.5%. In an uncontrolled compassionate use program (n=3920), cases of rash, some of which were severe, accompanied by myalgia, fever, erythema, desquamation, and mucosal erosions were reported. In the pediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was 21%. Overall, most of the pediatric patients had mild rash and 5 (5%) had moderate rash. Overall 3% of pediatric patients interrupted APTIVUS treatment due to rash and the discontinuation rate for rash in pediatric patients was 0.9%. Discontinue and initiate appropriate treatment if severe skin rash develops. - Sulfa Allergy - APTIVUS should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and APTIVUS is unknown. - Diabetes Mellitus/Hyperglycemia - New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. - Immune Reconstitution Syndrome - Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including APTIVUS. 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, tuberculosis, or reactivation of herpes simplex and herpes zoster), 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. - 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. - Elevated Lipids - Treatment with APTIVUS co-administered with 200 mg of ritonavir has resulted in large increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating APTIVUS/ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate; taking into account any potential drug-drug interactions. - Patients with Hemophilia - There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship between protease inhibitors and these events has not been established. - Resistance/Cross Resistance - Because the potential for HIV-1 cross-resistance among protease inhibitors has not been fully explored in APTIVUS/ritonavir treated patients, it is unknown what effect therapy with APTIVUS will have on the activity of subsequently administered protease inhibitors. # Adverse Reactions ## Clinical Trials Experience - APTIVUS, co-administered with ritonavir, has been studied in a total of 6308 HIV-1 positive adults as combination therapy in clinical studies. Of these, 1299 treatment-experienced patients received the dose of 500/200 mg BID. Nine hundred nine (909) adults, including 541 in the 1182.12 and 1182.48 controlled clinical trials, have been treated for at least 48 weeks. - In 1182.12 and 1182.48 in the APTIVUS/ritonavir arm, the most frequent adverse reactions were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain. The 48-Week Kaplan-Meier rates of adverse reactions leading to discontinuation were 13.3% for APTIVUS/ritonavir-treated patients and 10.8% for the comparator arm patients. - Adverse reactions reported in the controlled clinical trials 1182.12 and 1182.48, based on treatment-emergent clinical adverse reactions of moderate to severe intensity (Grades 2 - 4) in at least 2% of treatment-experienced subjects in either treatment group are summarized in Table 2 below. - Less Common Adverse Reactions - Other adverse reactions reported in <2% of adult patients (n=1474) treated with APTIVUS/ritonavir 500/200 mg in Phase 2 and 3 clinical trials are listed below by body system: Thrombocytopenia Abdominal distension, dyspepsia, flatulence, gastroesophageal reflux disease, pancreatitis Influenza-like illness, malaise Hepatitis, hepatic failure, hyperbilirubinemia, cytolytic hepatitis, toxic hepatitis, hepatic steatosis Hypersensitivity Hepatic enzymes increased, liver function test abnormal, lipase increased Anorexia, decreased appetite, diabetes mellitus, facial wasting, hyperamylasemia, hypercholesterolemia, hyperglycemia, mitochondrial toxicity Muscle cramp Dizziness, intracranial hemorrhage, somnolence Sleep disorder Renal insufficiency Exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy, pruritus - Treatment-emergent laboratory abnormalities reported at 48 weeks in the controlled clinical trials 1182.12 and 1182.48 in adults are summarized in Table 3 below. - APTIVUS, co-administered with ritonavir, has been studied in a total of 135 HIV-1 infected pediatric patients age 2 through 18 years as combination therapy. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment-naïve patients), with baseline HIV-1 RNA of at least 1500 copies/mL. One hundred and ten (110) patients were enrolled in a randomized, open-label 48-week clinical trial (Study 1182.14) and 25 patients were enrolled in other clinical studies including Expanded Access and Emergency Use Programs. - The adverse reactions profile seen in Study 1182.14 was similar to adults. Pyrexia (6.4%), vomiting (5.5%), cough (5.5%), rash (5.5%), nausea (4.5%), and diarrhea (3.6%) were the most frequently reported adverse reactions (Grade 2-4, all causes) in pediatric patients. Rash was reported more frequently in pediatric patients than in adults. - The most common Grade 3-4 laboratory abnormalities were increases in CPK (11%), ALT (6.5%), and amylase (7.5%). - Due to previous reports of both fatal and non-fatal intracranial hemorrhage (ICH), an analysis of bleeding events was performed. At 48 weeks of treatment, the frequency of pediatric patients with any bleeding adverse reactions was 7.5%. No drug related serious bleeding adverse reaction was reported. The most frequent bleeding adverse reaction was epistaxis (3.7%). No other bleeding adverse reaction was reported in frequency of >1%. Additional trial follow-up through 100 weeks showed a cumulative 12% frequency of any bleeding adverse reaction. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Tipranavir in the drug label. # Drug Interactions - Potential for APTIVUS/ritonavir to Affect Other Drugs - APTIVUS co-administered with ritonavir at the recommended dose is a net inhibitor of CYP 3A and may increase plasma concentrations of agents that are primarily metabolized by CYP 3A. Thus, co-administration of APTIVUS/ritonavir with drugs highly dependent on CYP 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring. - Clinically significant drug-drug interactions of APTIVUS co-administered with ritonavir are summarized in Table 4 below. - A phenotypic cocktail study was conducted with 16 healthy volunteers to quantify the influence of 10 days of APTIVUS/ritonavir capsule administration on the activity of hepatic CYP 1A2 (caffeine), 2C9 (warfarin), 2C19 (omeprazole), 2D6 (dextromethorphan) and the activity of intestinal and hepatic CYP 3A4/5 (midazolam) and P-glycoprotein (P-gp) (digoxin). This study determined the first-dose and steady-state effects of 500 mg of APTIVUS co-administered with 200 mg of ritonavir twice daily in capsule form. APTIVUS oral solution co-administered with ritonavir capsules demonstrated similar effects as APTIVUS capsules co-administrated with ritonavir. - There was no net effect on CYP 2C9 or hepatic P-gp at first dose or steady state. There was no net effect after first dose on CYP 1A2, but there was moderate induction at steady state. There was modest inhibition of CYP 2C19 at the first dose, but there was marked induction at steady state. Potent inhibition of CYP 2D6 and both hepatic and intestinal CYP 3A4/5 activities were observed after first dose and steady state. - Intestinal and hepatic P-gp activity was assessed by administering oral and intravenous digoxin, respectively. The digoxin results indicate P-gp was inhibited after the first dose of APTIVUS/ritonavir followed by induction of P-gp over time. Thus, it is difficult to predict the net effect of APTIVUS administered with ritonavir on oral bioavailability and plasma concentrations of drugs that are dual substrates of CYP 3A and P-gp. The net effect will vary depending on the relative affinity of the co-administered drugs for CYP 3A and P-gp, and the extent of intestinal first-pass metabolism/efflux. An in vitro induction study in human hepatocytes showed an increase in UGT1A1 by tipranavir similar to that evoked by rifampin. The clinical consequences of this finding have not been established. - Potential for Other Drugs to Affect Tipranavir - Tipranavir is a CYP 3A substrate and a P-gp substrate. Co-administration of APTIVUS/ritonavir and drugs that induce CYP 3A and/or P-gp may decrease tipranavir plasma concentrations. Co-administration of APTIVUS/ritonavir and drugs that inhibit P-gp may increase tipranavir plasma concentrations. Co-administration of APTIVUS/ritonavir with drugs that inhibit CYP 3A may not further increase tipranavir plasma concentrations, because the level of metabolites is low following steady-state administration of APTIVUS/ritonavir 500/200 mg twice daily. - Clinically significant drug-drug interactions of APTIVUS co-administered with ritonavir are summarized in Table 4 below. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Investigation of fertility and early embryonic development with tipranavir disodium was performed in rats, teratogenicity studies were performed in rats and rabbits, and pre- and post-natal development were explored in rats. - No teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits up to dose levels of 1000 mg/kg/day and 150 mg/kg/day tipranavir, respectively, at exposure levels approximately 1.1-fold and 0.1-fold human exposure. At 400 mg/kg/day and above in rats, fetal toxicity (decreased sternebrae ossification and body weights) was observed, corresponding to an AUC of 1310 μM·h or approximately 0.8-fold human exposure at the recommended dose. In rats and rabbits, fetal toxicity was not noted at 40 mg/kg/day and 150 mg/kg/day, respectively, corresponding accordingly to Cmax/AUC0-24h levels of 30.4 μM/340 μM·h and 8.4 μM/120 μM·h. These exposure levels (AUC) are approximately 0.2-fold and 0.1-fold the exposure in humans at the recommended dose. - In pre- and post-development studies in rats, tipranavir showed no adverse effects at 40 mg/kg/day (~0.2-fold human exposure), but caused growth inhibition in pups and maternal toxicity at dose levels of 400 mg/kg/day (~0.8-fold human exposure). No post-weaning functions were affected at any dose level. - There are no adequate and well-controlled studies in pregnant women for the treatment of HIV-1 infection. APTIVUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tipranavir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tipranavir during labor and delivery. ### Nursing Mothers - The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Because of both the potential for HIV-1 transmission and any possible adverse effects of APTIVUS, mothers should be instructed not to breast-feed if they are receiving APTIVUS. ### Pediatric Use - The safety, pharmacokinetic profile, and virologic and immunologic responses of APTIVUS oral solution and capsules were evaluated in HIV-1 infected pediatric patients age 2 to 18 years. - The most frequent adverse reactions (grades 2-4) were similar to those described in adults. However, rash was reported more frequently in pediatric patients than in adults. - The risk-benefit has not been established in pediatric patients <2 years of age. ### Geriatic Use - Clinical studies of APTIVUS/ritonavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, caution should be exercised in the administration and monitoring of APTIVUS 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 Tipranavir with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tipranavir with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tipranavir in patients with renal impairment. ### Hepatic Impairment - Tipranavir is principally metabolized by the liver. Caution should be exercised when administering APTIVUS/ritonavir to patients with mild (Child-Pugh Class A) hepatic impairment because tipranavir concentrations may be increased. APTIVUS/ritonavir is contraindicated in patients with moderate or severe (Child-Pugh Class B or Child-Pugh Class C) hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tipranavir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tipranavir in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Tipranavir in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tipranavir in the drug label. # Overdosage ## Acute Overdose - There is no known antidote for APTIVUS overdose. Treatment of overdose should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. If indicated, elimination of unabsorbed tipranavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since tipranavir is highly protein bound, dialysis is unlikely to provide significant removal of the drug. ## Chronic Overdose There is limited information regarding Chronic Overdose of Tipranavir in the drug label. # Pharmacology ## Mechanism of Action - Tipranavir (TPV) is an HIV-1 protease inhibitor that inhibits the virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. - Antiviral Activity - Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% effective concentrations (EC50) ranging from 0.03 to 0.07 μM (18-42 ng/mL). Tipranavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility in cell culture to tipranavir with EC50 values ranging from 0.164 -1 μM and 0.233-0.522 μM, respectively. When used with other antiretroviral agents in cell culture, the combination of tipranavir was additive to antagonistic with other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and generally additive with the NNRTIs (delavirdine, efavirenz, and nevirapine) and the NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine). Tipranavir was synergistic with the HIV-1 fusion inhibitor enfuvirtide. There was no antagonism of the cell culture combinations of tipranavir with either adefovir or ribavirin, used in the treatment of viral hepatitis. ## Structure - APTIVUS is a protease inhibitor of HIV-1 belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrone sulfonamides. - The chemical name of tipranavir is 2-Pyridinesulfonamide, N-propyl]phenyl]-5-(trifluoromethyl). It has a molecular formula of C31H33F3N2O5S and a molecular weight of 602.7. Tipranavir has the following structural formula and is a single stereoisomer with the 1R, 6R configuration. - Tipranavir is a white to off-white to slightly yellow solid. It is freely soluble in dehydrated alcohol and propylene glycol, and insoluble in aqueous buffer at pH 7.5. - APTIVUS soft gelatin capsules are for oral administration. Each capsule contains 250 mg tipranavir. The major inactive ingredients in the capsule are dehydrated alcohol (7% w/w or 0.1 g per capsule), polyoxyl 35 castor oil, propylene glycol, mono/diglycerides of caprylic/capric acid and gelatin. - APTIVUS oral solution is available in a strength of 100 mg/mL of tipranavir. APTIVUS oral solution is a yellow, viscous clear liquid with a buttermint-butter toffee flavor. The major inactive ingredients in the oral solution are polyethylene glycol 400, vitamin E polyethylene glycol succinate (TPGS), purified water, and propylene glycol. Each milliliter of APTIVUS oral solution contains 116 IU of vitamin E, and when taken at the recommended maximum dose of 500 mg/200 mg tipranavir/ritonavir BID results in a daily dose of 1160 IU. ## Pharmacodynamics - ECG Evaluation - The effect of APTIVUS/ritonavir on the QTcF interval was measured in a study in which 81 healthy subjects received the following treatments twice daily for 2.5 days: APTIVUS/ritonavir (500/200 mg), APTIVUS/ritonavir at a supra-therapeutic dose (750/200 mg), and placebo/ritonavir (-/200 mg). After baseline and placebo adjustment, the maximum mean QTcF change was 3.2 ms (1-sided 95% Upper CI: 5.6 ms) for the 500/200 mg dose and 8.3 ms (1-sided 95% Upper CI: 10.9 ms) for the supra-therapeutic 750/200 mg dose. - Antiviral Activity in vivo - The median Inhibitory Quotient (IQ) determined from 264 treatment-experienced adult patients was about 80 (inter-quartile range: 31-226), from the controlled clinical trials 1182.12 and 1182.48. The IQ is defined as the tipranavir trough concentration divided by the viral EC50 value, corrected for protein binding. There was a relationship between the proportion of patients with a ≥1 log10 reduction of viral load from baseline at week 48 and their IQ value. Among the 198 patients receiving APTIVUS/ritonavir with no new enfuvirtide use (e.g., new enfuvirtide, defined as initiation of enfuvirtide for the first time), the response rate was 23% in those with an IQ value <80 and 59% in those with an IQ value ≥80. Among the 66 patients receiving APTIVUS/ritonavir with new enfuvirtide, the response rates in patients with an IQ value <80 versus those with an IQ value ≥80 were 55% and 71%, respectively. These IQ groups are derived from a select population and are not meant to represent clinical breakpoints. ## Pharmacokinetics - In order to achieve effective tipranavir plasma concentrations and a twice-daily dosing regimen, co-administration of APTIVUS with ritonavir is essential . Ritonavir inhibits hepatic cytochrome P450 3A (CYP 3A), the intestinal P-gp efflux pump and possibly intestinal CYP 3A. In a dose-ranging evaluation in 113 HIV-1 negative male and female volunteers, there was a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations of tipranavir following APTIVUS co-administered with low-dose ritonavir (500/200 mg twice daily) compared to APTIVUS 500 mg twice daily without ritonavir. In adults the mean systemic ritonavir concentration when 200 mg of ritonavir was given with 500 mg of APTIVUS was similar to the concentrations observed when 100 mg was given with the other protease inhibitors. - Figure 1 displays mean plasma concentrations of tipranavir and ritonavir at steady state for 30 HIV-1 infected adult patients dosed with 500/200 mg tipranavir/ritonavir for 14 days. - Absorption and Bioavailability - Absorption of tipranavir in humans is limited, although no absolute quantification of absorption is available. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer as well. In vivo data suggest that tipranavir/ritonavir, at the dose of 500/200 mg, is a P-gp inhibitor after the first dose and induction of P-gp occurs over time. Tipranavir trough concentrations at steady-state are about 70% lower than those on Day 1, presumably due to intestinal P-gp induction. Steady state is attained in most subjects after 7-10 days of dosing. - Dosing APTIVUS 500 mg with 200 mg ritonavir capsules twice daily for greater than 2 weeks and without meal restriction produced the pharmacokinetic parameters for male and female HIV-1 positive patients presented in Table 5. - Effects of Food on Oral Absorption - For APTIVUS capsules or oral solution co-administered with ritonavir capsules at steady-state, no clinically significant changes in tipranavir Cmax, Cp12h, and AUC were observed under fed conditions (500-682 Kcal, 23-25% calories from fat) compared to fasted conditions . The effect of food on tipranavir exposure when APTIVUS capsules or oral solution is co-administered with ritonavir tablets has not been evaluated . For information on the effect of food on the bioavailability of ritonavir tablets, please refer to the ritonavir tablet prescribing information. - Distribution - Tipranavir is extensively bound to plasma proteins (>99.9%). It binds to both human serum albumin and α-1-acid glycoprotein. The mean fraction of tipranavir (dosed without ritonavir) unbound in plasma was similar in clinical samples from healthy volunteers and HIV-1 positive patients. Total plasma tipranavir concentrations for these samples ranged from 9 to 82 μM. The unbound fraction of tipranavir appeared to be independent of total drug concentration over this concentration range. - No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal fluid or semen. - Metabolism - In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism. - The oral clearance of tipranavir decreased after the addition of ritonavir, which may represent diminished first-pass clearance of the drug at the gastrointestinal tract as well as the liver. - The metabolism of tipranavir in the presence of 200 mg ritonavir is minimal. Administration of 14C-tipranavir to subjects that received APTIVUS/ritonavir 500/200 mg dosed to steady-state demonstrated that unchanged tipranavir accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or 12 hours after dosing. Only a few metabolites were found in plasma, and all were at trace levels (0.2% or less of the plasma radioactivity). In feces, unchanged tipranavir represented the majority of fecal radioactivity (79.9% of fecal radioactivity). The most abundant fecal metabolite, at 4.9% of fecal radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir was found in trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at 11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir. - Elimination - Administration of 14C-tipranavir to subjects (n=8) that received APTIVUS/ritonavir 500/200 mg dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in feces, while only a median of 4.4% of the radioactive dose administered was recovered in urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The effective mean elimination half-life of tipranavir/ritonavir in healthy volunteers (n=67) and HIV-1 infected adult patients (n=120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500/200 mg twice daily with a light meal. - Special Populations - Renal Impairment - APTIVUS pharmacokinetics have not been studied in patients with renal dysfunction. However, since the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency. - Hepatic Impairment - In a study comparing 9 HIV-1 negative patients with mild (Child-Pugh Class A) hepatic impairment to 9 HIV-1 negative controls, the single and multiple dose plasma concentrations of tipranavir and ritonavir were increased in patients with hepatic impairment, but were within the range observed in clinical trials. No dosing adjustment is required in patients with mild hepatic impairment. - The influence of moderate hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh Class C) on the multiple-dose pharmacokinetics of tipranavir administered with ritonavir has not been evaluated . - Gender - Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that females generally had higher tipranavir concentrations than males. After 4 weeks of APTIVUS/ritonavir 500/200 mg BID, the median plasma trough concentration of tipranavir was 43.9 μM for females and 31.1 μM for males. The difference in concentrations does not warrant a dose adjustment. - Race - Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that white males generally had more variability in tipranavir concentrations than black males, but the median concentration and the range making up the majority of the data are comparable between the races. - Geriatric Patients - Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that there was no change in median trough tipranavir concentrations as age increased for either gender through 65 years of age. There were an insufficient number of women greater than age 65 years in the two trials to evaluate the elderly. - Pediatric Patients - Among pediatric patients in clinical trial 1182.14, steady-state plasma tipranavir trough concentrations were obtained 10 to 14 hours following study drug administration. Pharmacokinetic parameters by age group are presented in Table 6. - Drug Interactions - Drug interaction studies were performed with APTIVUS capsules co-administered with ritonavir, and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of APTIVUS with 200 mg ritonavir on the AUC, Cmax, and Cmin of tipranavir or the co-administered drug, are summarized in Tables 7 and 8, respectively. For information regarding clinical recommendations see Drug Interactions (7.2). ## Nonclinical Toxicology - Long-term carcinogenicity studies in mice and rats have been conducted with tipranavir. Mice were administered 30, 150 or 300 mg/kg/day tipranavir, 150/40 mg/kg/day tipranavir/ritonavir in combination, or 40 mg/kg/day ritonavir. The incidences of benign hepatocellular adenomas and combined adenomas/carcinomas were increased in females of all groups except the low dose of tipranavir. These tumors were also increased in male mice at the high-dose of tipranavir and the tipranavir/ritonavir combination group. Hepatocellular carcinoma incidence was increased in female mice given the high dose of tipranavir and both sexes receiving tipranavir/ritonavir. The combination of tipranavir and ritonavir caused an exposure-related increase in this same tumor type in both sexes. The clinical relevance of the carcinogenic findings in mice is unknown. Systemic exposures in mice (based on AUC or Cmax) at all dose levels tested were below those in humans receiving the recommended dose level. Rats were administered 30, 100 or 300 mg/kg/day tipranavir, 100/26.7 mg/kg/day tipranavir/ritonavir in combination, or 10 mg/kg/day ritonavir. No drug-related findings in male rats were observed. At the highest dose of tipranavir, an increased incidence of benign follicular cell adenomas of the thyroid gland was observed in female rats. Based on AUC measurements, exposure to tipranavir at this dose level in rats is approximately equivalent to exposure in humans at the recommended therapeutic dose. This finding is probably not relevant to humans, because thyroid follicular cell adenomas are considered a rodent-specific effect secondary to enzyme induction. - Tipranavir showed no evidence of mutagenicity or clastogenicity in a battery of five in vitro and in vivo tests including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, unscheduled DNA synthesis in rat hepatocytes, induction of gene mutation in Chinese hamster ovary cells, a chromosome aberration assay in human peripheral lymphocytes, and a micronucleus assay in mice. - Tipranavir had no effect on fertility or early embryonic development in rats at dose levels up to 1000 mg/kg/day, equivalent to a Cmax of 258 μM in females. Based on Cmax levels in these rats, as well as an exposure (AUC) of 1670 μM·h in pregnant rats from another study, this exposure was approximately equivalent to the anticipated exposure in humans at the recommended dose level of 500/200 mg APTIVUS/ritonavir BID. # Clinical Studies - The following clinical data is derived from analyses of 48-week data from ongoing studies measuring effects on plasma HIV-1 RNA levels and CD4+ cell counts. At present there are no results from controlled studies evaluating the effect of APTIVUS/ritonavir on clinical progression of HIV-1. - APTIVUS/ritonavir 500/200 mg BID + optimized background regimen (OBR) vs. Comparator Protease Inhibitor/ritonavir BID + OBR - The two clinical trials 1182.12 and 1182.48 (RESIST 1 and RESIST 2) are ongoing, randomized, controlled, open-label, multicenter studies in HIV-1 positive, triple antiretroviral class experienced patients. All patients were required to have previously received at least two protease inhibitor-based antiretroviral regimens and were failing a protease inhibitor-based regimen at the time of study entry with baseline HIV-1 RNA at least 1000 copies/mL and any CD4+ cell count. At least one primary protease gene mutation from among 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than two mutations at codons 33, 82, 84 or 90. - These studies evaluated treatment response at 48 weeks in a total of 1483 patients receiving either APTIVUS co-administered with 200 mg of ritonavir plus OBR versus a control group receiving a ritonavir-boosted protease inhibitor (lopinavir, amprenavir, saquinavir or indinavir) plus OBR. Prior to randomization, OBR was individually defined for each patient based on genotypic resistance testing and patient history. The investigator had to declare OBR, comparator protease inhibitor, and use of new enfuvirtide prior to randomization. Randomization was stratified by choice of comparator protease inhibitor and use of new enfuvirtide. - After Week 8, patients in the control group who met the protocol defined criteria of initial lack of virologic response or confirmed virologic failure had the option of discontinuing treatment and switching to APTIVUS/ritonavir in a separate roll-over study. - Demographics and baseline characteristics were balanced between the APTIVUS/ritonavir arm and control arm. In both studies combined, the 1483 patients had a median age of 43 years (range 17-80), and were 86.3% male, 75.6% white, 12.9% black, and 0.9% Asian. The median baseline plasma HIV-1 RNA for both treatment groups was 4.8 (range 2.0 to 6.8) log10 copies/mL and median baseline CD4+ cell count was 162 (range 1 to 1894) cells/mm3. Overall, 38.4% of patients had a baseline HIV-1 RNA of >100,000 copies/mL, 58.6% had a baseline CD4+ cell count ≤200 cells/mm3, and 57.8% had experienced an AIDS defining Class C event at baseline. - Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. A total of 10.1% of patients had previously used enfuvirtide. In baseline patient samples (n=454), 97% of the HIV-1 isolates were resistant to at least one protease inhibitor, 95% of the isolates were resistant to at least one NRTI, and >75% of the isolates were resistant to at least one NNRTI. - The individually pre-selected protease inhibitor based on genotypic testing and the patient’s medical history was lopinavir in 48.7%, amprenavir in 26.4%, saquinavir in 21.8% and indinavir in 3.1% of patients. A total of 85.1% were possibly resistant or resistant to the pre-selected comparator protease inhibitors. Approximately 21% of patients used enfuvirtide during the study of which 16.6% in the APTIVUS/ritonavir arm and 13.2% in the comparator/ritonavir arm represented first time use of enfuvirtide (new enfuvirtide). - Treatment response and efficacy outcomes of randomized treatment through Week 48 of studies 1182.12 and 1182.48 are shown in Table 12. - Through 48 weeks of treatment, the proportion of patients in the APTIVUS/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA <400 copies/mL was 30.3% and 13.6% respectively, and with HIV-1 RNA <50 copies/mL was 22.7% and 10.2% respectively. Among all randomized and treated patients, the median change from baseline in HIV-1 RNA at the last measurement up to Week 48 was -0.64 log10 copies/mL in patients receiving APTIVUS/ritonavir versus -0.22 log10 copies/mL in the comparator PI/ritonavir arm. - Among all randomized and treated patients, the median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +23 cells/mm3 in patients receiving APTIVUS/ritonavir (N=740) versus +4 cells/mm3 in the comparator PI/ritonavir (N=727) arm. - Patients in the APTIVUS/ritonavir arm achieved a significantly better virologic outcome when APTIVUS/ritonavir was combined with enfuvirtide. Among patients with new enfuvirtide use, the proportion of patients in the APTIVUS/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA <400 copies/mL was 52.4% and 19.6% respectively, and with HIV-1 RNA <50 copies/mL was 37.3% and 14.4% respectively . The median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +89 cells/mm3 in patients receiving APTIVUS/ritonavir in combination with newly introduced enfuvirtide (N=124) and +18 cells/mm3 in the comparator PI/ritonavir (N=96) arm. - The pharmacokinetic profile, safety and activity of APTIVUS/ritonavir was evaluated in a randomized, open-label, multicenter study. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment-naïve patients), with baseline HIV-1 RNA of at least 1500 copies/mL. The age ranged from 2 through 18 years and patients were stratified by age (2 to <6 years, 6 to <12 years and 12 to 18 years). One hundred and ten (110) patients were randomized to receive one of two APTIVUS/ritonavir dose regimens: 375 mg/m2/150 mg/m2 dose (N=55) or 290 mg/m2/115 mg/m2 dose (N=55), plus background therapy of at least two non-protease inhibitor antiretroviral drugs, optimized using baseline genotypic resistance testing. All patients initially received APTIVUS oral solution. Pediatric patients who were 12 years or older and received the maximum dose of 500/200 mg BID could subsequently change to APTIVUS capsules at day 28 . - Demographics and baseline characteristics were balanced between the APTIVUS/ritonavir dose groups. The 110 randomized pediatric patients had a median age of 11.7 years (range 2 to 18), and were 57.2% male, 68.1% white, 30% black, and 1.8% Asian. The median baseline plasma HIV-1 RNA was 4.7 (range 3.0 to 6.8) log10 copies/mL and median baseline CD4+ cell count was 379 (range 2 to 2578) cells/mm3. Overall, 37.4% of patients had a baseline HIV-1 RNA of >100,000 copies/mL; 28.7% had a baseline CD4+ cell count ≤200 cells/mm3, and 48% had experienced a prior AIDS defining Class C event at baseline. Patients had prior exposure to a median of 4 NRTIs, 1 NNRTI, and 2 PIs. - Eighty three (75%) completed the 48 week period while 25% discontinued prematurely. Of the patients who discontinued prematurely, 9 (8%) discontinued due to virologic failure, and 9 (8%) discontinued due to adverse reactions. - At 48 weeks, 40% of patients had viral load <400 copies/mL. The proportion of patients with viral load <400 copies/mL tended to be greater (70%) in the youngest group of patients, who had less baseline viral resistance, compared to the older groups (37% and 31%). The HIV-1 RNA results are presented in Table 13. - The dose selection for all age groups was based on the following: - A greater proportion of patients receiving APTIVUS/ritonavir 375 mg/m2/150 mg/m2 compared to 290 mg/m2/115 mg/m2 achieved HIV-1 RNA <400 and <50 copies/mL. - A greater proportion of patients 6 to 18 years of age with multiple baseline protease inhibitor resistance-associated substitutions receiving APTIVUS/ritonavir 375 mg/m2/150 mg/m2 achieved HIV-1 RNA <400 copies/mL at 48 weeks compared to patients receiving APTIVUS/ritonavir 290 mg/m2/115 mg/m2. - No clinically significant increase in adverse event rates observed with 375 mg/m2/150 mg/m2 compared to 290 mg/m2/115 mg/m2. - Overall, 6 (5%) patients ages 6 to 18 had AIDS defining illness during the treatment period and all received the 290 mg/m2/115 mg/m2 dose. - The guidance for possible dose reduction for patients who develop intolerance or toxicity and cannot continue with APTIVUS/ritonavir 14 mg/kg/6 mg/kg (or 375 mg/m2/150 mg/m2) is based on the following: - The 290 mg/m2/115 mg/m2 twice daily regimen provided tipranavir plasma concentrations similar to those obtained in adults receiving 500/200 mg twice daily. The 375 mg/m2/150 mg/m2 twice daily regimen provided tipranavir plasma concentrations 37% higher than those obtained in adults receiving 500/200 mg twice daily. - The observed response rates for APTIVUS/ritonavir dose of 290 mg/m2/115 mg/m2 as shown in Table 13. - Dose reduction is not appropriate for patients whose virus is resistant to more than one protease inhibitor. - When body surface area (BSA) dosing is converted to mg/kg dosing, the APTIVUS/ritonavir 375 mg/m2/150 mg/m2 twice daily regimen is similar to 14 mg/kg/6 mg/kg and APTIVUS/ritonavir 290 mg/m2/115 mg/m2 twice daily regimen is similar to 12 mg/kg/5 mg/kg twice daily. # How Supplied - APTIVUS capsules 250 mg are pink, oblong soft gelatin capsules imprinted in black with "TPV 250". They are packaged in HDPE unit-of-use bottles with a child resistant closure and 120 capsules. (NDC 0597-0003-02) - APTIVUS oral solution is a clear yellow viscous buttermint-butter toffee flavored liquid containing 100 mg tipranavir in each mL. The solution is supplied in a unit-of-use amber glass bottle providing 95 mL of solution with a child resistant closure. A 5 mL plastic oral dispensing syringe is also provided. (NDC 0597-0002-01). - Storage - APTIVUS capsules should be stored in a refrigerator 2°-8°C (36°-46°F) prior to opening the bottle. After opening the bottle, the capsules may be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) and must be used within 60 days after first opening the bottle. - APTIVUS oral solution should be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Do not refrigerate or freeze. The solution must be used within 60 days after first opening the bottle. - Store in a safe place out of the reach of children. ## Storage There is limited information regarding Tipranavir Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Hepatic Impairment and Toxicity - Inform patients that APTIVUS co-administered with 200 mg of ritonavir, has been associated with severe liver disease, including some deaths. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. Symptoms of hepatitis include fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Extra vigilance is needed for patients with chronic hepatitis B or C co-infection, as these patients have an increased risk of developing hepatotoxicity. - Liver function tests should be performed prior to initiating therapy with APTIVUS and 200 mg of ritonavir, and frequently throughout the duration of treatment. Patients with chronic hepatitis B or C co-infection or elevations in liver enzymes prior to treatment are at increased risk (approximately 2-fold) for developing further liver enzyme elevations or severe liver disease. Caution should be exercised when administering APTIVUS/ritonavir to patients with liver enzyme abnormalities or history of chronic liver disease. Increased liver function testing is warranted in these patients. APTIVUS should not be given to patients with moderate to severe hepatic impairment. - Intracranial Hemorrhage - Inform patients that APTIVUS co-administered with 200 mg of ritonavir has been associated with reports of both fatal and non-fatal intracranial hemorrhage. Patients should report any unusual or unexplained bleeding to their physician. - Drug Interactions - APTIVUS may interact with some drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medications or herbal products, particularly St. John’s wort. - Use of Vitamin E - Advise patients taking APTIVUS oral solution not to take supplemental vitamin E greater than a standard multivitamin as APTIVUS oral solution contains 116 IU/mL of vitamin E and when taken at the recommended maximum dose of 500 mg/200 mg tipranavir/ritonavir BID, results in a daily dose of 1160 IU. This intake is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU). - Rash - Rash, including flat or raised rashes or sensitivity to the sun, have been reported in approximately 10% of subjects receiving APTIVUS. Some patients who developed rash also had one or more of the following symptoms: joint pain or stiffness, throat tightness, generalized itching, muscle aches, fever, redness, blisters, or peeling of the skin. Women taking birth control pills may get a skin rash. Tell patients to discontinue use of APTIVUS and call their physician right away if any of these symptoms develop. - Sulfa Allergy - Tell patients to report any history of sulfonamide allergy to the physician. - Contraceptives - Women receiving estrogen-based hormonal contraceptives should be instructed that additional or alternative contraceptive measures should be used during therapy with APTIVUS/ritonavir. There may be an increased risk of rash when APTIVUS is given with hormonal contraceptives. - Fat Redistribution - Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. - Administration - Inform patients that APTIVUS must be co-administered with ritonavir to ensure its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that may be insufficient to achieve the desired antiviral effect. - APTIVUS co-administered with ritonavir capsules or solution can be taken with or without meals - APTIVUS co-administered with ritonavir tablets must only be taken with meals - Tell patients that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using APTIVUS. Advise patients to take APTIVUS and other concomitant antiretroviral therapy every day as prescribed. APTIVUS, co-administered with ritonavir, must be given in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their healthcare professional. If a dose of APTIVUS is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose. - APTIVUS 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 APTIVUS. - 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. It is not known if APTIVUS 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. # Precautions with Alcohol - Alcohol-Tipranavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - APTIVUS® # Look-Alike Drug Names There is limited information regarding Tipranavir Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Tipranavir 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 Tipranavir is a protease inhibitor, co-administered with ritonavir that is FDA approved for the treatment of HIV-1 infected patients who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - APTIVUS must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions. - The recommended adult dose of APTIVUS is 500 mg (two 250 mg capsules or 5 mL oral solution) co-administered with 200 mg of ritonavir, twice daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tipranavir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tipranavir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Healthcare professionals should pay special attention to accurate calculation of the dose of APTIVUS, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose. - Prescribers should calculate the appropriate dose of APTIVUS for each individual child based on body weight (kg) or body surface area (BSA, m2) and should not exceed the recommended adult dose. - Before prescribing APTIVUS 250 mg capsules, children should be assessed for the ability to swallow capsules. If a child is unable to reliably swallow an APTIVUS capsule, the APTIVUS oral solution formulation should be prescribed. - The recommended pediatric dose of APTIVUS is 14 mg/kg with 6 mg/kg ritonavir (or 375 mg/m2 co-administered with ritonavir 150 mg/m2) taken twice daily not to exceed a maximum dose of APTIVUS 500 mg co-administered with ritonavir 200 mg twice daily. For children who develop intolerance or toxicity and cannot continue with APTIVUS 14 mg/kg with 6 mg/kg ritonavir, physicians may consider decreasing the dose to APTIVUS 12 mg/kg with 5 mg/kg ritonavir (or APTIVUS 290 mg/m2 co-administered with 115 mg/m2 ritonavir) taken twice daily provided their virus is not resistant to multiple protease inhibitors. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tipranavir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tipranavir in pediatric patients. # Contraindications - Hepatic Impairment - APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment. - Drug Interactions - Co-administration of APTIVUS/ritonavir with drugs that are highly dependent on CYP 3A for clearance or are potent CYP 3A inducers are contraindicated (see Table 1). These recommendations are based on either drug interaction studies or they are predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. For information regarding clinical recommendations. # Warnings ### Precautions - Hepatic Impairment and Toxicity - Clinical hepatitis and hepatic decompensation, including some fatalities, were reported with APTIVUS co-administered with 200 mg of ritonavir. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications. A causal relationship to APTIVUS/ritonavir could not be established. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. - All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with APTIVUS/ritonavir, and frequently throughout the duration of treatment. - If asymptomatic elevations in AST or ALT greater than 10 times the upper limit of normal occur, APTIVUS/ritonavir therapy should be discontinued. If asymptomatic elevations in AST or ALT between 5 – 10 times the upper limit of normal and increases in total bilirubin greater than 2.5 times the upper limit of normal occur, APTIVUS/ritonavir therapy should be discontinued. - Treatment-experienced patients with chronic hepatitis B or hepatitis C co-infection or elevated transaminases are at approximately 2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation. In two large, randomized, open-label, controlled clinical trials with an active comparator (1182.12 and 1182.48) of treatment-experienced patients, Grade 3 and 4 increases in hepatic transaminases were observed in 10.3% (10.9/100 PEY) receiving APTIVUS/ritonavir through week 48. In a study of treatment-naïve patients, 20.3% (21/100 PEY) experienced Grade 3 or 4 hepatic transaminase elevations while receiving APTIVUS/ritonavir 500 mg/200 mg through week 48. - Tipranavir is principally metabolized by the liver. Caution should be exercised when administering APTIVUS/ritonavir to patients with mild hepatic impairment (Child-Pugh Class A) because tipranavir concentrations may be increased. - Intracranial Hemorrhage - APTIVUS, co-administered with 200 mg of ritonavir, has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH). Many of these patients had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events. No pattern of abnormal coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on APTIVUS. - Drug Interactions - See Table 1 for a listing of contraindicated drugs with APTIVUS/ritonavir due to potentially life-threatening adverse events, significant drug interactions, or due to loss of virologic activity. See Table 4 for a listing of established and other potentially significant drug interactions with APTIVUS/ritonavir. - Effects on Platelet Aggregation and Coagulation - APTIVUS/ritonavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants, or who are taking supplemental high doses of vitamin E. - In rats, tipranavir treatment alone induced dose-dependent changes in coagulation parameters, bleeding events and death. Co-administration with vitamin E significantly increased these effects. However, analyses of stored plasma from adult patients treated with APTIVUS capsules and pediatric patients treated with APTIVUS oral solution (which contains a vitamin E derivative) showed no effect of APTIVUS/ritonavir on vitamin K-dependent coagulation factors (Factor II and Factor VII), Factor V, or on prothrombin or activated partial thromboplastin times. - In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving APTIVUS/ritonavir. - Vitamin E Intake - Patients taking APTIVUS oral solution should be advised not to take supplemental vitamin E greater than a standard multivitamin as APTIVUS oral solution contains 116 IU/mL of vitamin E which is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU). - Rash - Rash, including urticarial rash, maculopapular rash, and possible photosensitivity, has been reported in subjects receiving APTIVUS/ritonavir. In some cases rash was accompanied by joint pain or stiffness, throat tightness, or generalized pruritus. In controlled adult clinical trials, rash (all grades, all causality) was observed in 10% of females and in 8% of males receiving APTIVUS/ritonavir through 48 weeks of treatment. The median time to onset of rash was 53 days and the median duration of rash was 22 days. The discontinuation rate for rash in clinical trials was 0.5%. In an uncontrolled compassionate use program (n=3920), cases of rash, some of which were severe, accompanied by myalgia, fever, erythema, desquamation, and mucosal erosions were reported. In the pediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was 21%. Overall, most of the pediatric patients had mild rash and 5 (5%) had moderate rash. Overall 3% of pediatric patients interrupted APTIVUS treatment due to rash and the discontinuation rate for rash in pediatric patients was 0.9%. Discontinue and initiate appropriate treatment if severe skin rash develops. - Sulfa Allergy - APTIVUS should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and APTIVUS is unknown. - Diabetes Mellitus/Hyperglycemia - New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. - Immune Reconstitution Syndrome - Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including APTIVUS. 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, tuberculosis, or reactivation of herpes simplex and herpes zoster), 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. - 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. - Elevated Lipids - Treatment with APTIVUS co-administered with 200 mg of ritonavir has resulted in large increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating APTIVUS/ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate; taking into account any potential drug-drug interactions. - Patients with Hemophilia - There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship between protease inhibitors and these events has not been established. - Resistance/Cross Resistance - Because the potential for HIV-1 cross-resistance among protease inhibitors has not been fully explored in APTIVUS/ritonavir treated patients, it is unknown what effect therapy with APTIVUS will have on the activity of subsequently administered protease inhibitors. # Adverse Reactions ## Clinical Trials Experience - APTIVUS, co-administered with ritonavir, has been studied in a total of 6308 HIV-1 positive adults as combination therapy in clinical studies. Of these, 1299 treatment-experienced patients received the dose of 500/200 mg BID. Nine hundred nine (909) adults, including 541 in the 1182.12 and 1182.48 controlled clinical trials, have been treated for at least 48 weeks. - In 1182.12 and 1182.48 in the APTIVUS/ritonavir arm, the most frequent adverse reactions were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain. The 48-Week Kaplan-Meier rates of adverse reactions leading to discontinuation were 13.3% for APTIVUS/ritonavir-treated patients and 10.8% for the comparator arm patients. - Adverse reactions reported in the controlled clinical trials 1182.12 and 1182.48, based on treatment-emergent clinical adverse reactions of moderate to severe intensity (Grades 2 - 4) in at least 2% of treatment-experienced subjects in either treatment group are summarized in Table 2 below. - Less Common Adverse Reactions - Other adverse reactions reported in <2% of adult patients (n=1474) treated with APTIVUS/ritonavir 500/200 mg in Phase 2 and 3 clinical trials are listed below by body system: Thrombocytopenia Abdominal distension, dyspepsia, flatulence, gastroesophageal reflux disease, pancreatitis Influenza-like illness, malaise Hepatitis, hepatic failure, hyperbilirubinemia, cytolytic hepatitis, toxic hepatitis, hepatic steatosis Hypersensitivity Hepatic enzymes increased, liver function test abnormal, lipase increased Anorexia, decreased appetite, diabetes mellitus, facial wasting, hyperamylasemia, hypercholesterolemia, hyperglycemia, mitochondrial toxicity Muscle cramp Dizziness, intracranial hemorrhage, somnolence Sleep disorder Renal insufficiency Exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy, pruritus - Treatment-emergent laboratory abnormalities reported at 48 weeks in the controlled clinical trials 1182.12 and 1182.48 in adults are summarized in Table 3 below. - APTIVUS, co-administered with ritonavir, has been studied in a total of 135 HIV-1 infected pediatric patients age 2 through 18 years as combination therapy. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment-naïve patients), with baseline HIV-1 RNA of at least 1500 copies/mL. One hundred and ten (110) patients were enrolled in a randomized, open-label 48-week clinical trial (Study 1182.14) and 25 patients were enrolled in other clinical studies including Expanded Access and Emergency Use Programs. - The adverse reactions profile seen in Study 1182.14 was similar to adults. Pyrexia (6.4%), vomiting (5.5%), cough (5.5%), rash (5.5%), nausea (4.5%), and diarrhea (3.6%) were the most frequently reported adverse reactions (Grade 2-4, all causes) in pediatric patients. Rash was reported more frequently in pediatric patients than in adults. - The most common Grade 3-4 laboratory abnormalities were increases in CPK (11%), ALT (6.5%), and amylase (7.5%). - Due to previous reports of both fatal and non-fatal intracranial hemorrhage (ICH), an analysis of bleeding events was performed. At 48 weeks of treatment, the frequency of pediatric patients with any bleeding adverse reactions was 7.5%. No drug related serious bleeding adverse reaction was reported. The most frequent bleeding adverse reaction was epistaxis (3.7%). No other bleeding adverse reaction was reported in frequency of >1%. Additional trial follow-up through 100 weeks showed a cumulative 12% frequency of any bleeding adverse reaction. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Tipranavir in the drug label. # Drug Interactions - Potential for APTIVUS/ritonavir to Affect Other Drugs - APTIVUS co-administered with ritonavir at the recommended dose is a net inhibitor of CYP 3A and may increase plasma concentrations of agents that are primarily metabolized by CYP 3A. Thus, co-administration of APTIVUS/ritonavir with drugs highly dependent on CYP 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring. - Clinically significant drug-drug interactions of APTIVUS co-administered with ritonavir are summarized in Table 4 below. - A phenotypic cocktail study was conducted with 16 healthy volunteers to quantify the influence of 10 days of APTIVUS/ritonavir capsule administration on the activity of hepatic CYP 1A2 (caffeine), 2C9 (warfarin), 2C19 (omeprazole), 2D6 (dextromethorphan) and the activity of intestinal and hepatic CYP 3A4/5 (midazolam) and P-glycoprotein (P-gp) (digoxin). This study determined the first-dose and steady-state effects of 500 mg of APTIVUS co-administered with 200 mg of ritonavir twice daily in capsule form. APTIVUS oral solution co-administered with ritonavir capsules demonstrated similar effects as APTIVUS capsules co-administrated with ritonavir. - There was no net effect on CYP 2C9 or hepatic P-gp at first dose or steady state. There was no net effect after first dose on CYP 1A2, but there was moderate induction at steady state. There was modest inhibition of CYP 2C19 at the first dose, but there was marked induction at steady state. Potent inhibition of CYP 2D6 and both hepatic and intestinal CYP 3A4/5 activities were observed after first dose and steady state. - Intestinal and hepatic P-gp activity was assessed by administering oral and intravenous digoxin, respectively. The digoxin results indicate P-gp was inhibited after the first dose of APTIVUS/ritonavir followed by induction of P-gp over time. Thus, it is difficult to predict the net effect of APTIVUS administered with ritonavir on oral bioavailability and plasma concentrations of drugs that are dual substrates of CYP 3A and P-gp. The net effect will vary depending on the relative affinity of the co-administered drugs for CYP 3A and P-gp, and the extent of intestinal first-pass metabolism/efflux. An in vitro induction study in human hepatocytes showed an increase in UGT1A1 by tipranavir similar to that evoked by rifampin. The clinical consequences of this finding have not been established. - Potential for Other Drugs to Affect Tipranavir - Tipranavir is a CYP 3A substrate and a P-gp substrate. Co-administration of APTIVUS/ritonavir and drugs that induce CYP 3A and/or P-gp may decrease tipranavir plasma concentrations. Co-administration of APTIVUS/ritonavir and drugs that inhibit P-gp may increase tipranavir plasma concentrations. Co-administration of APTIVUS/ritonavir with drugs that inhibit CYP 3A may not further increase tipranavir plasma concentrations, because the level of metabolites is low following steady-state administration of APTIVUS/ritonavir 500/200 mg twice daily. - Clinically significant drug-drug interactions of APTIVUS co-administered with ritonavir are summarized in Table 4 below. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Investigation of fertility and early embryonic development with tipranavir disodium was performed in rats, teratogenicity studies were performed in rats and rabbits, and pre- and post-natal development were explored in rats. - No teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits up to dose levels of 1000 mg/kg/day and 150 mg/kg/day tipranavir, respectively, at exposure levels approximately 1.1-fold and 0.1-fold human exposure. At 400 mg/kg/day and above in rats, fetal toxicity (decreased sternebrae ossification and body weights) was observed, corresponding to an AUC of 1310 μM·h or approximately 0.8-fold human exposure at the recommended dose. In rats and rabbits, fetal toxicity was not noted at 40 mg/kg/day and 150 mg/kg/day, respectively, corresponding accordingly to Cmax/AUC0-24h levels of 30.4 μM/340 μM·h and 8.4 μM/120 μM·h. These exposure levels (AUC) are approximately 0.2-fold and 0.1-fold the exposure in humans at the recommended dose. - In pre- and post-development studies in rats, tipranavir showed no adverse effects at 40 mg/kg/day (~0.2-fold human exposure), but caused growth inhibition in pups and maternal toxicity at dose levels of 400 mg/kg/day (~0.8-fold human exposure). No post-weaning functions were affected at any dose level. - There are no adequate and well-controlled studies in pregnant women for the treatment of HIV-1 infection. APTIVUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tipranavir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tipranavir during labor and delivery. ### Nursing Mothers - The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Because of both the potential for HIV-1 transmission and any possible adverse effects of APTIVUS, mothers should be instructed not to breast-feed if they are receiving APTIVUS. ### Pediatric Use - The safety, pharmacokinetic profile, and virologic and immunologic responses of APTIVUS oral solution and capsules were evaluated in HIV-1 infected pediatric patients age 2 to 18 years. - The most frequent adverse reactions (grades 2-4) were similar to those described in adults. However, rash was reported more frequently in pediatric patients than in adults. - The risk-benefit has not been established in pediatric patients <2 years of age. ### Geriatic Use - Clinical studies of APTIVUS/ritonavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, caution should be exercised in the administration and monitoring of APTIVUS 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 Tipranavir with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tipranavir with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tipranavir in patients with renal impairment. ### Hepatic Impairment - Tipranavir is principally metabolized by the liver. Caution should be exercised when administering APTIVUS/ritonavir to patients with mild (Child-Pugh Class A) hepatic impairment because tipranavir concentrations may be increased. APTIVUS/ritonavir is contraindicated in patients with moderate or severe (Child-Pugh Class B or Child-Pugh Class C) hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tipranavir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tipranavir in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Tipranavir in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tipranavir in the drug label. # Overdosage ## Acute Overdose - There is no known antidote for APTIVUS overdose. Treatment of overdose should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. If indicated, elimination of unabsorbed tipranavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since tipranavir is highly protein bound, dialysis is unlikely to provide significant removal of the drug. ## Chronic Overdose There is limited information regarding Chronic Overdose of Tipranavir in the drug label. # Pharmacology ## Mechanism of Action - Tipranavir (TPV) is an HIV-1 protease inhibitor that inhibits the virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. - Antiviral Activity - Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% effective concentrations (EC50) ranging from 0.03 to 0.07 μM (18-42 ng/mL). Tipranavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility in cell culture to tipranavir with EC50 values ranging from 0.164 -1 μM and 0.233-0.522 μM, respectively. When used with other antiretroviral agents in cell culture, the combination of tipranavir was additive to antagonistic with other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and generally additive with the NNRTIs (delavirdine, efavirenz, and nevirapine) and the NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine). Tipranavir was synergistic with the HIV-1 fusion inhibitor enfuvirtide. There was no antagonism of the cell culture combinations of tipranavir with either adefovir or ribavirin, used in the treatment of viral hepatitis. ## Structure - APTIVUS is a protease inhibitor of HIV-1 belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrone sulfonamides. - The chemical name of tipranavir is 2-Pyridinesulfonamide, N-[3-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl). It has a molecular formula of C31H33F3N2O5S and a molecular weight of 602.7. Tipranavir has the following structural formula and is a single stereoisomer with the 1R, 6R configuration. - Tipranavir is a white to off-white to slightly yellow solid. It is freely soluble in dehydrated alcohol and propylene glycol, and insoluble in aqueous buffer at pH 7.5. - APTIVUS soft gelatin capsules are for oral administration. Each capsule contains 250 mg tipranavir. The major inactive ingredients in the capsule are dehydrated alcohol (7% w/w or 0.1 g per capsule), polyoxyl 35 castor oil, propylene glycol, mono/diglycerides of caprylic/capric acid and gelatin. - APTIVUS oral solution is available in a strength of 100 mg/mL of tipranavir. APTIVUS oral solution is a yellow, viscous clear liquid with a buttermint-butter toffee flavor. The major inactive ingredients in the oral solution are polyethylene glycol 400, vitamin E polyethylene glycol succinate (TPGS), purified water, and propylene glycol. Each milliliter of APTIVUS oral solution contains 116 IU of vitamin E, and when taken at the recommended maximum dose of 500 mg/200 mg tipranavir/ritonavir BID results in a daily dose of 1160 IU. ## Pharmacodynamics - ECG Evaluation - The effect of APTIVUS/ritonavir on the QTcF interval was measured in a study in which 81 healthy subjects received the following treatments twice daily for 2.5 days: APTIVUS/ritonavir (500/200 mg), APTIVUS/ritonavir at a supra-therapeutic dose (750/200 mg), and placebo/ritonavir (-/200 mg). After baseline and placebo adjustment, the maximum mean QTcF change was 3.2 ms (1-sided 95% Upper CI: 5.6 ms) for the 500/200 mg dose and 8.3 ms (1-sided 95% Upper CI: 10.9 ms) for the supra-therapeutic 750/200 mg dose. - Antiviral Activity in vivo - The median Inhibitory Quotient (IQ) determined from 264 treatment-experienced adult patients was about 80 (inter-quartile range: 31-226), from the controlled clinical trials 1182.12 and 1182.48. The IQ is defined as the tipranavir trough concentration divided by the viral EC50 value, corrected for protein binding. There was a relationship between the proportion of patients with a ≥1 log10 reduction of viral load from baseline at week 48 and their IQ value. Among the 198 patients receiving APTIVUS/ritonavir with no new enfuvirtide use (e.g., new enfuvirtide, defined as initiation of enfuvirtide for the first time), the response rate was 23% in those with an IQ value <80 and 59% in those with an IQ value ≥80. Among the 66 patients receiving APTIVUS/ritonavir with new enfuvirtide, the response rates in patients with an IQ value <80 versus those with an IQ value ≥80 were 55% and 71%, respectively. These IQ groups are derived from a select population and are not meant to represent clinical breakpoints. ## Pharmacokinetics - In order to achieve effective tipranavir plasma concentrations and a twice-daily dosing regimen, co-administration of APTIVUS with ritonavir is essential [see Dosage and Administration (2)]. Ritonavir inhibits hepatic cytochrome P450 3A (CYP 3A), the intestinal P-gp efflux pump and possibly intestinal CYP 3A. In a dose-ranging evaluation in 113 HIV-1 negative male and female volunteers, there was a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations of tipranavir following APTIVUS co-administered with low-dose ritonavir (500/200 mg twice daily) compared to APTIVUS 500 mg twice daily without ritonavir. In adults the mean systemic ritonavir concentration when 200 mg of ritonavir was given with 500 mg of APTIVUS was similar to the concentrations observed when 100 mg was given with the other protease inhibitors. - Figure 1 displays mean plasma concentrations of tipranavir and ritonavir at steady state for 30 HIV-1 infected adult patients dosed with 500/200 mg tipranavir/ritonavir for 14 days. - Absorption and Bioavailability - Absorption of tipranavir in humans is limited, although no absolute quantification of absorption is available. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer as well. In vivo data suggest that tipranavir/ritonavir, at the dose of 500/200 mg, is a P-gp inhibitor after the first dose and induction of P-gp occurs over time. Tipranavir trough concentrations at steady-state are about 70% lower than those on Day 1, presumably due to intestinal P-gp induction. Steady state is attained in most subjects after 7-10 days of dosing. - Dosing APTIVUS 500 mg with 200 mg ritonavir capsules twice daily for greater than 2 weeks and without meal restriction produced the pharmacokinetic parameters for male and female HIV-1 positive patients presented in Table 5. - Effects of Food on Oral Absorption - For APTIVUS capsules or oral solution co-administered with ritonavir capsules at steady-state, no clinically significant changes in tipranavir Cmax, Cp12h, and AUC were observed under fed conditions (500-682 Kcal, 23-25% calories from fat) compared to fasted conditions [see Dosage and Administration (2)]. The effect of food on tipranavir exposure when APTIVUS capsules or oral solution is co-administered with ritonavir tablets has not been evaluated [see Dosage and Administration (2)]. For information on the effect of food on the bioavailability of ritonavir tablets, please refer to the ritonavir tablet prescribing information. - Distribution - Tipranavir is extensively bound to plasma proteins (>99.9%). It binds to both human serum albumin and α-1-acid glycoprotein. The mean fraction of tipranavir (dosed without ritonavir) unbound in plasma was similar in clinical samples from healthy volunteers and HIV-1 positive patients. Total plasma tipranavir concentrations for these samples ranged from 9 to 82 μM. The unbound fraction of tipranavir appeared to be independent of total drug concentration over this concentration range. - No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal fluid or semen. - Metabolism - In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism. - The oral clearance of tipranavir decreased after the addition of ritonavir, which may represent diminished first-pass clearance of the drug at the gastrointestinal tract as well as the liver. - The metabolism of tipranavir in the presence of 200 mg ritonavir is minimal. Administration of 14C-tipranavir to subjects that received APTIVUS/ritonavir 500/200 mg dosed to steady-state demonstrated that unchanged tipranavir accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or 12 hours after dosing. Only a few metabolites were found in plasma, and all were at trace levels (0.2% or less of the plasma radioactivity). In feces, unchanged tipranavir represented the majority of fecal radioactivity (79.9% of fecal radioactivity). The most abundant fecal metabolite, at 4.9% of fecal radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir was found in trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at 11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir. - Elimination - Administration of 14C-tipranavir to subjects (n=8) that received APTIVUS/ritonavir 500/200 mg dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in feces, while only a median of 4.4% of the radioactive dose administered was recovered in urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The effective mean elimination half-life of tipranavir/ritonavir in healthy volunteers (n=67) and HIV-1 infected adult patients (n=120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500/200 mg twice daily with a light meal. - Special Populations - Renal Impairment - APTIVUS pharmacokinetics have not been studied in patients with renal dysfunction. However, since the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency. - Hepatic Impairment - In a study comparing 9 HIV-1 negative patients with mild (Child-Pugh Class A) hepatic impairment to 9 HIV-1 negative controls, the single and multiple dose plasma concentrations of tipranavir and ritonavir were increased in patients with hepatic impairment, but were within the range observed in clinical trials. No dosing adjustment is required in patients with mild hepatic impairment. - The influence of moderate hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh Class C) on the multiple-dose pharmacokinetics of tipranavir administered with ritonavir has not been evaluated [see Dosage and Administration (2), Contraindications (4.1), and Warnings and Precautions (5.1)]. - Gender - Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that females generally had higher tipranavir concentrations than males. After 4 weeks of APTIVUS/ritonavir 500/200 mg BID, the median plasma trough concentration of tipranavir was 43.9 μM for females and 31.1 μM for males. The difference in concentrations does not warrant a dose adjustment. - Race - Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that white males generally had more variability in tipranavir concentrations than black males, but the median concentration and the range making up the majority of the data are comparable between the races. - Geriatric Patients - Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that there was no change in median trough tipranavir concentrations as age increased for either gender through 65 years of age. There were an insufficient number of women greater than age 65 years in the two trials to evaluate the elderly. - Pediatric Patients - Among pediatric patients in clinical trial 1182.14, steady-state plasma tipranavir trough concentrations were obtained 10 to 14 hours following study drug administration. Pharmacokinetic parameters by age group are presented in Table 6. - Drug Interactions - Drug interaction studies were performed with APTIVUS capsules co-administered with ritonavir, and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of APTIVUS with 200 mg ritonavir on the AUC, Cmax, and Cmin of tipranavir or the co-administered drug, are summarized in Tables 7 and 8, respectively. For information regarding clinical recommendations see Drug Interactions (7.2). ## Nonclinical Toxicology - Long-term carcinogenicity studies in mice and rats have been conducted with tipranavir. Mice were administered 30, 150 or 300 mg/kg/day tipranavir, 150/40 mg/kg/day tipranavir/ritonavir in combination, or 40 mg/kg/day ritonavir. The incidences of benign hepatocellular adenomas and combined adenomas/carcinomas were increased in females of all groups except the low dose of tipranavir. These tumors were also increased in male mice at the high-dose of tipranavir and the tipranavir/ritonavir combination group. Hepatocellular carcinoma incidence was increased in female mice given the high dose of tipranavir and both sexes receiving tipranavir/ritonavir. The combination of tipranavir and ritonavir caused an exposure-related increase in this same tumor type in both sexes. The clinical relevance of the carcinogenic findings in mice is unknown. Systemic exposures in mice (based on AUC or Cmax) at all dose levels tested were below those in humans receiving the recommended dose level. Rats were administered 30, 100 or 300 mg/kg/day tipranavir, 100/26.7 mg/kg/day tipranavir/ritonavir in combination, or 10 mg/kg/day ritonavir. No drug-related findings in male rats were observed. At the highest dose of tipranavir, an increased incidence of benign follicular cell adenomas of the thyroid gland was observed in female rats. Based on AUC measurements, exposure to tipranavir at this dose level in rats is approximately equivalent to exposure in humans at the recommended therapeutic dose. This finding is probably not relevant to humans, because thyroid follicular cell adenomas are considered a rodent-specific effect secondary to enzyme induction. - Tipranavir showed no evidence of mutagenicity or clastogenicity in a battery of five in vitro and in vivo tests including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, unscheduled DNA synthesis in rat hepatocytes, induction of gene mutation in Chinese hamster ovary cells, a chromosome aberration assay in human peripheral lymphocytes, and a micronucleus assay in mice. - Tipranavir had no effect on fertility or early embryonic development in rats at dose levels up to 1000 mg/kg/day, equivalent to a Cmax of 258 μM in females. Based on Cmax levels in these rats, as well as an exposure (AUC) of 1670 μM·h in pregnant rats from another study, this exposure was approximately equivalent to the anticipated exposure in humans at the recommended dose level of 500/200 mg APTIVUS/ritonavir BID. # Clinical Studies - The following clinical data is derived from analyses of 48-week data from ongoing studies measuring effects on plasma HIV-1 RNA levels and CD4+ cell counts. At present there are no results from controlled studies evaluating the effect of APTIVUS/ritonavir on clinical progression of HIV-1. - APTIVUS/ritonavir 500/200 mg BID + optimized background regimen (OBR) vs. Comparator Protease Inhibitor/ritonavir BID + OBR - The two clinical trials 1182.12 and 1182.48 (RESIST 1 and RESIST 2) are ongoing, randomized, controlled, open-label, multicenter studies in HIV-1 positive, triple antiretroviral class experienced patients. All patients were required to have previously received at least two protease inhibitor-based antiretroviral regimens and were failing a protease inhibitor-based regimen at the time of study entry with baseline HIV-1 RNA at least 1000 copies/mL and any CD4+ cell count. At least one primary protease gene mutation from among 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than two mutations at codons 33, 82, 84 or 90. - These studies evaluated treatment response at 48 weeks in a total of 1483 patients receiving either APTIVUS co-administered with 200 mg of ritonavir plus OBR versus a control group receiving a ritonavir-boosted protease inhibitor (lopinavir, amprenavir, saquinavir or indinavir) plus OBR. Prior to randomization, OBR was individually defined for each patient based on genotypic resistance testing and patient history. The investigator had to declare OBR, comparator protease inhibitor, and use of new enfuvirtide prior to randomization. Randomization was stratified by choice of comparator protease inhibitor and use of new enfuvirtide. - After Week 8, patients in the control group who met the protocol defined criteria of initial lack of virologic response or confirmed virologic failure had the option of discontinuing treatment and switching to APTIVUS/ritonavir in a separate roll-over study. - Demographics and baseline characteristics were balanced between the APTIVUS/ritonavir arm and control arm. In both studies combined, the 1483 patients had a median age of 43 years (range 17-80), and were 86.3% male, 75.6% white, 12.9% black, and 0.9% Asian. The median baseline plasma HIV-1 RNA for both treatment groups was 4.8 (range 2.0 to 6.8) log10 copies/mL and median baseline CD4+ cell count was 162 (range 1 to 1894) cells/mm3. Overall, 38.4% of patients had a baseline HIV-1 RNA of >100,000 copies/mL, 58.6% had a baseline CD4+ cell count ≤200 cells/mm3, and 57.8% had experienced an AIDS defining Class C event at baseline. - Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. A total of 10.1% of patients had previously used enfuvirtide. In baseline patient samples (n=454), 97% of the HIV-1 isolates were resistant to at least one protease inhibitor, 95% of the isolates were resistant to at least one NRTI, and >75% of the isolates were resistant to at least one NNRTI. - The individually pre-selected protease inhibitor based on genotypic testing and the patient’s medical history was lopinavir in 48.7%, amprenavir in 26.4%, saquinavir in 21.8% and indinavir in 3.1% of patients. A total of 85.1% were possibly resistant or resistant to the pre-selected comparator protease inhibitors. Approximately 21% of patients used enfuvirtide during the study of which 16.6% in the APTIVUS/ritonavir arm and 13.2% in the comparator/ritonavir arm represented first time use of enfuvirtide (new enfuvirtide). - Treatment response and efficacy outcomes of randomized treatment through Week 48 of studies 1182.12 and 1182.48 are shown in Table 12. - Through 48 weeks of treatment, the proportion of patients in the APTIVUS/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA <400 copies/mL was 30.3% and 13.6% respectively, and with HIV-1 RNA <50 copies/mL was 22.7% and 10.2% respectively. Among all randomized and treated patients, the median change from baseline in HIV-1 RNA at the last measurement up to Week 48 was -0.64 log10 copies/mL in patients receiving APTIVUS/ritonavir versus -0.22 log10 copies/mL in the comparator PI/ritonavir arm. - Among all randomized and treated patients, the median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +23 cells/mm3 in patients receiving APTIVUS/ritonavir (N=740) versus +4 cells/mm3 in the comparator PI/ritonavir (N=727) arm. - Patients in the APTIVUS/ritonavir arm achieved a significantly better virologic outcome when APTIVUS/ritonavir was combined with enfuvirtide. Among patients with new enfuvirtide use, the proportion of patients in the APTIVUS/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA <400 copies/mL was 52.4% and 19.6% respectively, and with HIV-1 RNA <50 copies/mL was 37.3% and 14.4% respectively [see Clinical Pharmacology (12.2, 12.4)]. The median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +89 cells/mm3 in patients receiving APTIVUS/ritonavir in combination with newly introduced enfuvirtide (N=124) and +18 cells/mm3 in the comparator PI/ritonavir (N=96) arm. - The pharmacokinetic profile, safety and activity of APTIVUS/ritonavir was evaluated in a randomized, open-label, multicenter study. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment-naïve patients), with baseline HIV-1 RNA of at least 1500 copies/mL. The age ranged from 2 through 18 years and patients were stratified by age (2 to <6 years, 6 to <12 years and 12 to 18 years). One hundred and ten (110) patients were randomized to receive one of two APTIVUS/ritonavir dose regimens: 375 mg/m2/150 mg/m2 dose (N=55) or 290 mg/m2/115 mg/m2 dose (N=55), plus background therapy of at least two non-protease inhibitor antiretroviral drugs, optimized using baseline genotypic resistance testing. All patients initially received APTIVUS oral solution. Pediatric patients who were 12 years or older and received the maximum dose of 500/200 mg BID could subsequently change to APTIVUS capsules at day 28 [see Adverse Reactions (6.2), Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Microbiology (12.4)]. - Demographics and baseline characteristics were balanced between the APTIVUS/ritonavir dose groups. The 110 randomized pediatric patients had a median age of 11.7 years (range 2 to 18), and were 57.2% male, 68.1% white, 30% black, and 1.8% Asian. The median baseline plasma HIV-1 RNA was 4.7 (range 3.0 to 6.8) log10 copies/mL and median baseline CD4+ cell count was 379 (range 2 to 2578) cells/mm3. Overall, 37.4% of patients had a baseline HIV-1 RNA of >100,000 copies/mL; 28.7% had a baseline CD4+ cell count ≤200 cells/mm3, and 48% had experienced a prior AIDS defining Class C event at baseline. Patients had prior exposure to a median of 4 NRTIs, 1 NNRTI, and 2 PIs. - Eighty three (75%) completed the 48 week period while 25% discontinued prematurely. Of the patients who discontinued prematurely, 9 (8%) discontinued due to virologic failure, and 9 (8%) discontinued due to adverse reactions. - At 48 weeks, 40% of patients had viral load <400 copies/mL. The proportion of patients with viral load <400 copies/mL tended to be greater (70%) in the youngest group of patients, who had less baseline viral resistance, compared to the older groups (37% and 31%). The HIV-1 RNA results are presented in Table 13. - The dose selection for all age groups was based on the following: - A greater proportion of patients receiving APTIVUS/ritonavir 375 mg/m2/150 mg/m2 compared to 290 mg/m2/115 mg/m2 achieved HIV-1 RNA <400 and <50 copies/mL. - A greater proportion of patients 6 to 18 years of age with multiple baseline protease inhibitor resistance-associated substitutions receiving APTIVUS/ritonavir 375 mg/m2/150 mg/m2 achieved HIV-1 RNA <400 copies/mL at 48 weeks compared to patients receiving APTIVUS/ritonavir 290 mg/m2/115 mg/m2. - No clinically significant increase in adverse event rates observed with 375 mg/m2/150 mg/m2 compared to 290 mg/m2/115 mg/m2. - Overall, 6 (5%) patients ages 6 to 18 had AIDS defining illness during the treatment period and all received the 290 mg/m2/115 mg/m2 dose. - The guidance for possible dose reduction for patients who develop intolerance or toxicity and cannot continue with APTIVUS/ritonavir 14 mg/kg/6 mg/kg (or 375 mg/m2/150 mg/m2) is based on the following: - The 290 mg/m2/115 mg/m2 twice daily regimen provided tipranavir plasma concentrations similar to those obtained in adults receiving 500/200 mg twice daily. The 375 mg/m2/150 mg/m2 twice daily regimen provided tipranavir plasma concentrations 37% higher than those obtained in adults receiving 500/200 mg twice daily. - The observed response rates for APTIVUS/ritonavir dose of 290 mg/m2/115 mg/m2 as shown in Table 13. - Dose reduction is not appropriate for patients whose virus is resistant to more than one protease inhibitor. - When body surface area (BSA) dosing is converted to mg/kg dosing, the APTIVUS/ritonavir 375 mg/m2/150 mg/m2 twice daily regimen is similar to 14 mg/kg/6 mg/kg and APTIVUS/ritonavir 290 mg/m2/115 mg/m2 twice daily regimen is similar to 12 mg/kg/5 mg/kg twice daily. # How Supplied - APTIVUS capsules 250 mg are pink, oblong soft gelatin capsules imprinted in black with "TPV 250". They are packaged in HDPE unit-of-use bottles with a child resistant closure and 120 capsules. (NDC 0597-0003-02) - APTIVUS oral solution is a clear yellow viscous buttermint-butter toffee flavored liquid containing 100 mg tipranavir in each mL. The solution is supplied in a unit-of-use amber glass bottle providing 95 mL of solution with a child resistant closure. A 5 mL plastic oral dispensing syringe is also provided. (NDC 0597-0002-01). - Storage - APTIVUS capsules should be stored in a refrigerator 2°-8°C (36°-46°F) prior to opening the bottle. After opening the bottle, the capsules may be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) and must be used within 60 days after first opening the bottle. - APTIVUS oral solution should be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Do not refrigerate or freeze. The solution must be used within 60 days after first opening the bottle. - Store in a safe place out of the reach of children. ## Storage There is limited information regarding Tipranavir Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Hepatic Impairment and Toxicity - Inform patients that APTIVUS co-administered with 200 mg of ritonavir, has been associated with severe liver disease, including some deaths. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. Symptoms of hepatitis include fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Extra vigilance is needed for patients with chronic hepatitis B or C co-infection, as these patients have an increased risk of developing hepatotoxicity. - Liver function tests should be performed prior to initiating therapy with APTIVUS and 200 mg of ritonavir, and frequently throughout the duration of treatment. Patients with chronic hepatitis B or C co-infection or elevations in liver enzymes prior to treatment are at increased risk (approximately 2-fold) for developing further liver enzyme elevations or severe liver disease. Caution should be exercised when administering APTIVUS/ritonavir to patients with liver enzyme abnormalities or history of chronic liver disease. Increased liver function testing is warranted in these patients. APTIVUS should not be given to patients with moderate to severe hepatic impairment. - Intracranial Hemorrhage - Inform patients that APTIVUS co-administered with 200 mg of ritonavir has been associated with reports of both fatal and non-fatal intracranial hemorrhage. Patients should report any unusual or unexplained bleeding to their physician. - Drug Interactions - APTIVUS may interact with some drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medications or herbal products, particularly St. John’s wort. - Use of Vitamin E - Advise patients taking APTIVUS oral solution not to take supplemental vitamin E greater than a standard multivitamin as APTIVUS oral solution contains 116 IU/mL of vitamin E and when taken at the recommended maximum dose of 500 mg/200 mg tipranavir/ritonavir BID, results in a daily dose of 1160 IU. This intake is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU). - Rash - Rash, including flat or raised rashes or sensitivity to the sun, have been reported in approximately 10% of subjects receiving APTIVUS. Some patients who developed rash also had one or more of the following symptoms: joint pain or stiffness, throat tightness, generalized itching, muscle aches, fever, redness, blisters, or peeling of the skin. Women taking birth control pills may get a skin rash. Tell patients to discontinue use of APTIVUS and call their physician right away if any of these symptoms develop. - Sulfa Allergy - Tell patients to report any history of sulfonamide allergy to the physician. - Contraceptives - Women receiving estrogen-based hormonal contraceptives should be instructed that additional or alternative contraceptive measures should be used during therapy with APTIVUS/ritonavir. There may be an increased risk of rash when APTIVUS is given with hormonal contraceptives. - Fat Redistribution - Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. - Administration - Inform patients that APTIVUS must be co-administered with ritonavir to ensure its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that may be insufficient to achieve the desired antiviral effect. - APTIVUS co-administered with ritonavir capsules or solution can be taken with or without meals - APTIVUS co-administered with ritonavir tablets must only be taken with meals - Tell patients that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using APTIVUS. Advise patients to take APTIVUS and other concomitant antiretroviral therapy every day as prescribed. APTIVUS, co-administered with ritonavir, must be given in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their healthcare professional. If a dose of APTIVUS is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose. - APTIVUS 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 APTIVUS. - 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. It is not known if APTIVUS 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. # Precautions with Alcohol - Alcohol-Tipranavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - APTIVUS®[1] # Look-Alike Drug Names There is limited information regarding Tipranavir Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Tipranavir
a374f903db6807c581aba5c46993bf37c7136e8a	wikidoc	Tiratricol	Tiratricol # Overview Tiratricol (also known as TRIAC or triiodothyroacetic acid) is a thyroid hormone analogue. # Uses It is indicated in the management of thyroid hormone resistance syndrome and is used, in combination with levothyroxine, to suppress thyroid-stimulating hormone production in patients with thyroid cancer. It has been investigated for use in reducing goiter. It has also shown some effectiveness in reducing the atrophy caused when using corticosteroids. Tiratricol has also been widely marketed, under various trade names, as a weight loss aid. In 1999 and 2000, the United States Food and Drug Administration and Health Canada both issued warnings to the public regarding the use of dietary supplements containing tiratricol. # Legal status Tiratricol is not approved for sale in Canada or the United States. It was once an approved drug in Brazil, but its marketing authorization was suspended in 2003, effectively prohibiting its sale. Tiratricol is still available in France for therapy of thyroid hormone resistance and adjuvant therapy of thyroid cancer. It is available as an orphan drug to be prescribed by registered specialists in Europe.	Tiratricol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Tiratricol (also known as TRIAC or triiodothyroacetic acid) is a thyroid hormone analogue. # Uses It is indicated in the management of thyroid hormone resistance syndrome[1] and is used, in combination with levothyroxine, to suppress thyroid-stimulating hormone production in patients with thyroid cancer. It has been investigated for use in reducing goiter.[2] It has also shown some effectiveness in reducing the atrophy caused when using corticosteroids.[3] Tiratricol has also been widely marketed, under various trade names, as a weight loss aid. In 1999 and 2000, the United States Food and Drug Administration and Health Canada both issued warnings to the public regarding the use of dietary supplements containing tiratricol.[4][5] # Legal status Tiratricol is not approved for sale in Canada or the United States. It was once an approved drug in Brazil, but its marketing authorization was suspended in 2003, effectively prohibiting its sale.[6] Tiratricol is still available in France for therapy of thyroid hormone resistance and adjuvant therapy of thyroid cancer.[7] It is available as an orphan drug to be prescribed by registered specialists in Europe.	https://www.wikidoc.org/index.php/Tiratricol
7457c4c38c84490fd8e24ad017aab68c737d2ca3	wikidoc	Tizanidine	Tizanidine # 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 Tizanidine is a central alpha-2-adrenergic agonist that is FDA approved for the {{{indicationType}}} of spasticity. Common adverse reactions include dry mouth, somnolence, asthenia, dizziness, urinary tract infection, constipation, liver function tests abnormal, vomiting, speech disorder, amblyopia, urinary frequency, flu syndrome, SGPT/ALT increased, dyskinesia, nervousness, pharyngitis, and rhinitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Tizanidine hydrochloride capsules may be prescribed with or without food. Once the formulation has been selected and the decision to take with or without food has been made, this regimen should not be altered. - Food has complex effects on tizanidine pharmacokinetics, which differ with the different formulations. Tizanidine hydrochloride capsules and tizanidine hydrochloride tablets are bioequivalent to each other under fasting conditions (more than 3 hours after a meal), but not under fed conditions (within 30 minutes of a meal). These pharmacokinetic differences may result in clinically significant differences when switching administration of tablet and capsules and when switching administration between the fed or fasted state. These changes may result in increased adverse events, or delayed or more rapid onset of activity, depending upon the nature of the switch. For this reason, the prescriber should be thoroughly familiar with the changes in kinetics associated with these different conditions. - The recommended starting dose is 2 mg (base). Because the effect of tizanidine hydrochloride capsules peaks at approximately 1 to 2 hours post-dose and dissipates between 3 to 6 hours post-dose, treatment can be repeated at 6 to 8 hour intervals, as needed, to a maximum of three doses in 24 hours. - Dosage can be gradually increased by 2 mg (base) to 4 mg (base) at each dose, with 1 to 4 days between dosage increases, until a satisfactory reduction of muscle tone is achieved. The total daily dose should not exceed 36 mg (base). Single doses greater than 16 mg (base) have not been studied. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tizanidine in adult patients. ### Non–Guideline-Supported Use - Tizanidine (initial, 2 milligrams (mg) at bedtime, then titrated to a maximum of 24 mg/day given in three divided doses) for 12 weeks. - Tizanidine 2 milligrams were given twice daily for 7 days. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tizanidine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tizanidine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tizanidine in pediatric patients. # Contraindications - Tizanidine hydrochloride capsules are contraindicated in patients taking potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin. # Warnings ### Precautions - Hypotension - Tizanidine is an α2-adrenergic agonist that can produce hypotension. Syncope has been reported in the post marketing setting. The chance of significant hypotension may possibly be minimized by titration of the dose and by focusing attention on signs and symptoms of hypotension prior to dose advancement. In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects. - Monitor for hypotension when tizanidine is used in patients receiving concurrent antihypertensive therapy. It is not recommended that tizanidine be used with other α2-adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of either fluvoxamine or ciprofloxacin and single doses of 4 mg (base) of tizanidine. Therefore, concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated. - Risk of Liver Injury - Tizanidine may cause hepatocellular liver injury. Tizanidine should be used with caution in patients with any hepatic impairment. Monitoring of aminotransferase levels is recommended for baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected. - Sedation - Tizanidine can cause sedation, which may interfere with everyday activity. In the multiple dose studies, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study. The CNS depressant effects of tizanidine with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation. - Hallucinosis/Psychotic-like Symptoms - Tizanidine use has been associated with hallucinations. Formed, visual hallucinations or delusions have been reported in 5 of 170 patients (3%) in two North American controlled clinical studies. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One FDA approved labeling dated October 4, 2013 patient among these five continued to have problems for at least 2 weeks following discontinuation of tizanidine. Consider discontinuing tizanidine in patients who develop hallucinations. - Interaction with CYP1A2 Inhibitors - Because of potential drug interactions, tizanidine is contraindicated in patients taking potent CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin. Adverse reactions such as hypotension, bradycardia, or excessive drowsiness can occur when tizanidine is taken with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than ciprofloxacin (which is contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine). Concomitant use should be avoided unless the necessity for tizanidine therapy is clinically evident. In such a case, use with caution. - Hypersensitivity Reactions - Tizanidine can cause anaphylaxis. Signs and symptoms including respiratory compromise, urticaria, and angioedema of the throat and tongue have been reported. Patients should be informed of the signs and symptoms of severe allergic reactions and instructed to discontinue tizanidine and seek immediate medical care should these signs and symptoms occur. - Increased Risk of Adverse Reactions in Patients with Renal Impairment - Tizanidine should be used with caution in patients with renal insufficiency (creatinine clearance < 25 mL/min), as clearance is reduced by more than 50%. In these patients, during titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose. - Withdrawal Adverse Reactions - Withdrawal adverse reactions include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses (20 mg (base) to 28 mg (base) daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the dose should be decreased slowly (2 mg (base) to 4 mg (base) per day). # Adverse Reactions ## Clinical Trials Experience - 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 clinical practice. - Three double-blind, randomized, placebo controlled -clinical studies were conducted to evaluate the effect of tizanidine on spasticity control. Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury. Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg (base)/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies patient ages ranged from 15 to 69 years and 51.4 percent were women. The median dose during the plateau phase ranged from 20 mg (base)/day to 28 mg (base)/day. - The most frequent adverse reactions reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness) and dizziness. Three-quarters of the patients rated the events as mild to moderate and one-quarter of the patients rated the events as being severe. These events appeared to be dose related. - Table 1 lists signs and symptoms that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received tizanidine where the frequency in the tizanidine group was greater than the placebo group. For comparison purposes, the corresponding frequency of the event (per 100 patients) among placebo treated patients is also provided. - In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1), the patients were specifically asked if they had experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness) and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these reactions is summarized in Table 2. Other events were, in general, reported at a rate of 2% or less. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of tizanidine. 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. - Certain events, such as somnolence, dry mouth, hypotension, decreased blood pressure, bradycardia, dizziness, weakness or asthenia, muscle spasms, hallucinations, fatigue, liver function test abnormality and hepatotoxicity, have been observed in post marketing and clinical trials and are discussed in previous sections of this document. - The following adverse reactions have been identified as occurring in the post marketing experience of tizanidine. Based on the information provided regarding these reactions, a causal relationship with tizanidine cannot be entirely excluded. The events are listed in order of decreasing clinical significance; severity in the post marketing setting is not reported. - Stevens Johnson Syndrome - Anaphylactic Reaction - Exfoliative Dermatitis - Ventricular Tachycardia - Hepatitis - Convulsion - Depression - Arthralgia - Paresthesia - Rash - Tremor # Drug Interactions - Fluvoxamine - Concomitant use of fluvoxamine and tizanidine is contraindicated. Changes in pharmacokinetics of tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. - Ciprofloxacin - Concomitant use of ciprofloxacin and tizanidine is contraindicated. Changes in pharmacokinetics of tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. - CYP1A2 Inhibitors other than Fluvoxamine and Ciprofloxacin - Because of potential drug interactions, concomitant use of tizanidine with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than strong CYP1A2 inhibitors (which are contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided. If their use is clinically necessary, therapy should be initiated with 2 mg (base) dose and increased in 2 mg (base) to 4 mg (base) steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy. - Oral Contraceptives - Concomitant use of tizanidine with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate tizanidine with a single 2 mg (base) dose and increase in 2 mg (base) to 4 mg (base) steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy. - Alcohol - Alcohol increases the overall amount of drug in the bloodstream after a dose of tizanidine hydrochloride. This was associated with an increase in adverse reactions of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive. - Other CNS Depressants - The sedative effects of tizanidine with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation. - α2-adrenergic Agonists - Because hypotensive effects may be cumulative, it is not recommended that tizanidine be used with other α2-adrenergic agonists. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Tizanidine has not been studied in pregnant women. Tizanidine should be given to pregnant women only if the benefit outweighs the risk to the unborn fetus. Reproduction studies performed in rats at a dose of 3 mg (base)/kg, equal to the maximum recommended human dose on a mg/m2 basis, and in rabbits at 30 mg (base)/kg, 16 times the maximum recommended human dose on a mg/m2 basis, did not show evidence of teratogenicity. Tizanidine at doses that are equal to and up to 8 times the maximum recommended human dose on a mg/m2 basis increased gestation duration in rats. Prenatal and postnatal pup loss was increased and developmental retardation occurred. Post-implantation loss was increased in rabbits at doses of 1 mg (base)/kg or greater, equal to or greater than 0.5 times the maximum recommended human dose on a mg/m2 basis. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tizanidine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tizanidine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tizanidine is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Tizanidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Clinical studies of tizanidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Cross-study comparison of pharmacokinetic data following single dose administration of 6 mg (base) tizanidine showed that younger subjects cleared the drug four times faster than the elderly subjects. In elderly patients with renal insufficiency (creatinine clearance < 25 mL/min), tizanidine clearance is reduced by more than 50% compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. Monitor elderly patients because they may have an increased risk for adverse reactions associated with tizanidine. ### Gender There is no FDA guidance on the use of Tizanidine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tizanidine with respect to specific racial populations. ### Renal Impairment - Tizanidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. In patients with renal insufficiency (creatinine clearance < 25 mL/min) clearance was reduced by more than 50%. In these patients, during titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose. ### Hepatic Impairment - The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tizanidine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tizanidine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Tizanidine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tizanidine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose. ### Management - Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken. Tizanidine is a lipid-soluble drug, which is only slightly soluble in water and methanol. Therefore, dialysis is not likely to be an efficient method of removing drug from the body. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center. ## Chronic Overdose There is limited information regarding Chronic Overdose of Tizanidine in the drug label. # Pharmacology ## Mechanism of Action - Tizanidine is a central alpha-2-adrenergic receptor agonist and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons. ## Structure - Tizanidine hydrochloride is a central alpha2-adrenergic agonist. Tizanidine hydrochloride, USP is an almost white to slightly yellow crystalline powder, which is odorless or with a faint characteristic odor. Tizanidine is slightly soluble in water and methanol; solubility in water decreases as the pH increases. Its chemical name is 5-Chloro-N-(4,5-dihydro-1H-imidazol-2yl)-2,1,3-benzothiadiazol-4-amine hydrochloride. Tizanidine’s molecular formula is C9H8ClN5SHCl, its molecular weight is 290.2 and its structural formula is: - Tizanidine hydrochloride capsules are supplied as 2 mg, 4 mg, and 6 mg capsules for oral administration. Tizanidine hydrochloride capsules contain the active ingredient, tizanidine hydrochloride, USP (2.29 mg equivalent to 2 mg tizanidine base, 4.58 mg equivalent to 4 mg tizanidine base, and 6.87 mg equivalent to 6 mg tizanidine base), and the inactive ingredients anhydrous lactose, colloidal silicon dioxide, hypromellose, microcrystalline cellulose and talc. In addition, each of the empty hard gelatin capsules contain the following: gelatin, red iron oxide, titanium dioxide and yellow iron oxide. The imprinting ink contains the following: ammonia, black iron oxide, potassium hydroxide, propylene glycol and shellac. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Tizanidine in the drug label. ## Pharmacokinetics - Absorption and Distribution - Following oral administration, tizanidine is essentially completely absorbed. The absolute oral bioavailability of tizanidine is approximately 40% (CV = 24%), due to extensive first-pass hepatic metabolism. Tizanidine is extensively distributed throughout the body with a mean steady state volume of distribution of 2.4 L/kg (CV = 21%) following intravenous administration in healthy adult volunteers. Tizanidine is approximately 30% bound to plasma proteins. - Differences between Tizanidine Hydrochloride Capsules and Tizanidine Hydrochloride Tablets - Tizanidine hydrochloride capsules and tizanidine hydrochloride tablets are bioequivalent to each other under fasting conditions, but not under fed conditions. A single dose of either two 4 mg (base) tablets or two 4 mg (base) capsules was administered under fed and fasting conditions in an open label, four period, randomized crossover study in 96 human volunteers, of whom 81 were eligible for the statistical analysis. Following oral administration of either the tablet or capsule (in the fasted state), peak plasma concentrations of tizanidine occurred 1 hour after dosing with a half-life of approximately 2 hours. When two 4 mg (base) tablets were administered with food, the mean maximal plasma concentration was increased by approximately 30%, and the median time to peak plasma concentration was increased by 25 minutes, to 1 hour and 25 minutes. In contrast, when two 4 mg (base) capsules were administered with food, the mean maximal plasma concentration was decreased by 20%, the median time to peak plasma concentration was increased 2 to 3 hours. Consequently, the mean Cmax for the capsule when administered with food is approximately 66% the Cmax for the tablet when administered with food. - Food also increased the extent of absorption for both the tablets and capsules. The increase with the tablet (~30%) was significantly greater than with the capsule (~10%). Consequently when each was administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. Administration of the capsule contents sprinkled on applesauce was not bioequivalent to administration of an intact capsule under fasting conditions. Administration of the capsule contents on applesauce resulted in a 15% to 20% increase in Cmax and AUC of tizanidine and a 15 minute decrease in the median lag time and time to peak concentration compared to administration of an intact capsule while fasting. - Metabolism and Excretion - Tizanidine has linear pharmacokinetics over the doses studied in clinical development . Tizanidine has a half-life of approximately 2.5 hours (CV = 33%). Approximately 95% of an administered dose is metabolized. The primary cytochrome P450 isoenzyme involved in tizanidine metabolism is CYP1A2. Tizanidine metabolites are not known to be active; their half-lives range from 20 to 40 hours. - Following single and multiple oral dosing of 14C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively. - Special Populations - Age Effects - No specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of 6 mg (base) tizanidine showed that younger subjects cleared the drug four times faster than the elderly subjects. Tizanidine has not been evaluated in children. - Hepatic Impairment - The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine. Tizanidine is not recommended in this patient population. - Renal Impairment - Tizanidine clearance is reduced by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. Tizanidine should be used with caution in renally impaired patients. - Gender Effects - No specific pharmacokinetic study was conducted to investigate gender effects. Retrospective analysis of pharmacokinetic data, however, following single and multiple dose administration of 4 mg (base) tizanidine showed that gender had no effect on the pharmacokinetics of tizanidine. - Race Effects - Pharmacokinetic differences due to race have not been studied. - Drug Interactions - CYP1A2 Inhibitors - The interaction between tizanidine and either fluvoxamine or ciprofloxacin is most likely due to inhibition of CYP1A2 by fluvoxamine or ciprofloxacin. The effect of fluvoxamine on the pharmacokinetics of a single 4 mg (base) dose of tizanidine was studied in 10 healthy subjects. The Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively. The effect of ciprofloxacin on the pharmacokinetics of a single 4 mg (base) dose of tizanidine was studied in 10 healthy subjects. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively. - Although there have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, other CYP1A2 inhibitors, such as zileuton, other fluoroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone and verapamil), cimetidine, famotidine oral contraceptives, acyclovir and ticlopidine, may also lead to substantial increases in tizanidine blood concentrations. - In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes. - Oral Contraceptives - No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg (base) tizanidine, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives. - Acetaminophen - Tizanidine delayed the Tmax of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine. - Alcohol - Alcohol increased the AUC of tizanidine by approximately 20%, while also increasing its Cmax by approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive. ## Nonclinical Toxicology - Carcinogenesis - Tizanidine was administered to mice for 78 weeks at oral doses up to 16 mg (base)/kg/day, which is 2 times the maximum recommended human dose (MRHD) on a mg/m2 basis. Tizanidine was administered to rats for 104 weeks at oral doses up to 9 mg (base)/kg/day, which is 2.5 times the MRHD on a mg/m2 basis. There was no increase in tumors in either species. - Mutagenesis - Tizanidine was negative in in vitro (bacterial reverse mutation , mammalian gene mutation, and chromosomal aberration test in mammalian cells) and in vivo (bone marrow micronucleus, and cytogenetics) assay. - Impairment of Fertility - Oral administration of tizanidine resulted in reduced fertility in male and female rats following doses of 30 mg (base)/kg/day and 10 mg (base)/kg/day, respectively. No effect on fertility was observed at doses of 10 mg (base)/kg/day (male) and 3 mg (base)/kg/day (female), which are approximately 8 and 3 times, respectively, the MRHD on a mg/m2 basis). # Clinical Studies - Tizanidine’s capacity to reduce increased muscle tone associated with spasticity was demonstrated in two adequate and well controlled studies in patients with multiple sclerosis or spinal cord injury (Studies 1 and 2). - Single-dose Study in Patients with Multiple Sclerosis with Spasticity: In Study 1, patients with multiple sclerosis were randomized to receive single oral doses of drug or placebo. Patients and assessors were blind to treatment assignment and efforts were made to reduce the likelihood that assessors would become aware indirectly of treatment assignment (e.g., they did not provide direct care to patients and were prohibited from asking questions about side effects). In all, 140 patients received placebo, 8 mg (base) or 16 mg (base) of tizanidine. - Response was assessed by physical examination; muscle tone was rated on a 5 point scale (Ashworth score), with a score of 0 used to describe normal muscle tone. A score of 1 indicated a slight spastic catch while a score of 2 indicated more marked muscle resistance. A score of 3 was used to describe considerable increase in tone, making passive movement difficult. A muscle immobilized by spasticity was given a score of 4. Spasm counts were also collected. - Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for tizanidine compared to placebo was detected at 1, 2 and 3 hours after treatment. Figure 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 mg (base) and 16 mg (base) tizanidine groups was indistinguishable from muscle tone in placebo treated patients. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg (base) produced a larger effect, adverse events including hypotension were more common and more severe than in the 8 mg (base) group. There were no differences in the number of spasms occurring in each group. - Seven-week Study in Patients with Spinal Cord Injury with Spasticity: In a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine. Steps similar to those taken in the first study were employed to ensure the integrity of blinding. - Patients were titrated over 3 weeks up to a maximum tolerated dose or 36 mg (base) daily given in three unequal doses (e.g., 10 mg (base) given in the morning and afternoon and 16 mg (base) given at night). Patients were then maintained on their maximally tolerated dose for 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a period of 2.5 hours following either the morning or afternoon dose. The number of daytime spasms was recorded daily by patients. - At endpoint (the protocol-specified time of outcome assessment), there was a statistically significant reduction in muscle tone and frequency of spasms in the tizanidine treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine treated patients on measures of activities of daily living. Figure 3 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. # How Supplied - Tizanidine Hydrochloride Capsules - Tizanidine Hydrochloride Capsules are available containing tizanidine hydrochloride, USP equivalent to 2 mg, 4 mg, or 6 mg of tizanidine base. - The 2 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and an orange opaque body filled with light yellow to yellow granular powder. The capsule is axially printed with MYLAN over TE 2 in black ink on both the cap and the body. They are available as follows: NDC 0378-1665-19, bottles of 150 capsules - NDC 0378-1665-19, bottles of 150 capsules - The 4 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and a white opaque body filled with light yellow to yellow granular powder. The capsule is axially printed with MYLAN over TE 4 in black ink on both the cap and the body. They are available as follows: NDC 0378-1666-19, bottles of 150 capsules - NDC 0378-1666-19, bottles of 150 capsules - The 6 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and a peach opaque body filled with light yellow to yellow granular powder. The capsule is axially printed with MYLAN over TE 6 in black ink on both the cap and the body. They are available as follows: NDC 0378-1667-19, bottles of 150 capsules - NDC 0378-1667-19, bottles of 150 capsules - Store at 20° to 25°C (68° to 77°F). - Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. ## Storage There is limited information regarding Tizanidine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Serious Drug Interactions - Advise patients they should not take tizanidine hydrochloride capsules if they are taking fluvoxamine or ciprofloxacin because of the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation. Instruct patients to inform their physicians or pharmacists when they start or stop taking any medication because of the risks associated with interaction between tizanidine hydrochloride capsules and other medicines. - Tizanidine Hydrochloride Capsules Dosing - Tell patients to take tizanidine hydrochloride capsules exactly as prescribed (consistently either with or without food) and not to switch between tablets and capsules. Inform patients that they should not take more tizanidine hydrochloride capsules than prescribed because of the risk of adverse events at single doses greater than 8 mg (base) or total daily doses greater than 36 mg (base). Tell patients that they should not suddenly discontinue tizanidine hydrochloride capsules, because rebound hypertension and tachycardia may occur. - Effects of Tizanidine Hydrochloride Capsules - Warn patients that they may experience hypotension and to be careful when changing from a lying or sitting to a standing position. Tell patients that tizanidine hydrochloride capsules may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery. Tell patients that the sedation may be additive when tizanidine hydrochloride capsules is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants. Remind patients that if they depend on their spasticity to sustain posture and balance in locomotion, or whenever spasticity is utilized to obtain increased function, that tizanidine hydrochloride capsules decrease spasticity and caution should be used. # Precautions with Alcohol - Alcohol-Tizanidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TIZANIDINE HYDROCHLORIDE® # Look-Alike Drug Names - tiZANidine® — tiaGABine® - Zanaflex® — Xiaflex® # Drug Shortage Status # Price	Tizanidine 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. # Overview Tizanidine is a central alpha-2-adrenergic agonist that is FDA approved for the {{{indicationType}}} of spasticity. Common adverse reactions include dry mouth, somnolence, asthenia, dizziness, urinary tract infection, constipation, liver function tests abnormal, vomiting, speech disorder, amblyopia, urinary frequency, flu syndrome, SGPT/ALT increased, dyskinesia, nervousness, pharyngitis, and rhinitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Tizanidine hydrochloride capsules may be prescribed with or without food. Once the formulation has been selected and the decision to take with or without food has been made, this regimen should not be altered. - Food has complex effects on tizanidine pharmacokinetics, which differ with the different formulations. Tizanidine hydrochloride capsules and tizanidine hydrochloride tablets are bioequivalent to each other under fasting conditions (more than 3 hours after a meal), but not under fed conditions (within 30 minutes of a meal). These pharmacokinetic differences may result in clinically significant differences when switching administration of tablet and capsules and when switching administration between the fed or fasted state. These changes may result in increased adverse events, or delayed or more rapid onset of activity, depending upon the nature of the switch. For this reason, the prescriber should be thoroughly familiar with the changes in kinetics associated with these different conditions. - The recommended starting dose is 2 mg (base). Because the effect of tizanidine hydrochloride capsules peaks at approximately 1 to 2 hours post-dose and dissipates between 3 to 6 hours post-dose, treatment can be repeated at 6 to 8 hour intervals, as needed, to a maximum of three doses in 24 hours. - Dosage can be gradually increased by 2 mg (base) to 4 mg (base) at each dose, with 1 to 4 days between dosage increases, until a satisfactory reduction of muscle tone is achieved. The total daily dose should not exceed 36 mg (base). Single doses greater than 16 mg (base) have not been studied. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tizanidine in adult patients. ### Non–Guideline-Supported Use - Tizanidine (initial, 2 milligrams (mg) at bedtime, then titrated to a maximum of 24 mg/day given in three divided doses) for 12 weeks. - Tizanidine 2 milligrams were given twice daily for 7 days. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tizanidine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tizanidine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tizanidine in pediatric patients. # Contraindications - Tizanidine hydrochloride capsules are contraindicated in patients taking potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin. # Warnings ### Precautions - Hypotension - Tizanidine is an α2-adrenergic agonist that can produce hypotension. Syncope has been reported in the post marketing setting. The chance of significant hypotension may possibly be minimized by titration of the dose and by focusing attention on signs and symptoms of hypotension prior to dose advancement. In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects. - Monitor for hypotension when tizanidine is used in patients receiving concurrent antihypertensive therapy. It is not recommended that tizanidine be used with other α2-adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of either fluvoxamine or ciprofloxacin and single doses of 4 mg (base) of tizanidine. Therefore, concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated. - Risk of Liver Injury - Tizanidine may cause hepatocellular liver injury. Tizanidine should be used with caution in patients with any hepatic impairment. Monitoring of aminotransferase levels is recommended for baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected. - Sedation - Tizanidine can cause sedation, which may interfere with everyday activity. In the multiple dose studies, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study. The CNS depressant effects of tizanidine with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation. - Hallucinosis/Psychotic-like Symptoms - Tizanidine use has been associated with hallucinations. Formed, visual hallucinations or delusions have been reported in 5 of 170 patients (3%) in two North American controlled clinical studies. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One FDA approved labeling dated October 4, 2013 patient among these five continued to have problems for at least 2 weeks following discontinuation of tizanidine. Consider discontinuing tizanidine in patients who develop hallucinations. - Interaction with CYP1A2 Inhibitors - Because of potential drug interactions, tizanidine is contraindicated in patients taking potent CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin. Adverse reactions such as hypotension, bradycardia, or excessive drowsiness can occur when tizanidine is taken with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than ciprofloxacin (which is contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine). Concomitant use should be avoided unless the necessity for tizanidine therapy is clinically evident. In such a case, use with caution. - Hypersensitivity Reactions - Tizanidine can cause anaphylaxis. Signs and symptoms including respiratory compromise, urticaria, and angioedema of the throat and tongue have been reported. Patients should be informed of the signs and symptoms of severe allergic reactions and instructed to discontinue tizanidine and seek immediate medical care should these signs and symptoms occur. - Increased Risk of Adverse Reactions in Patients with Renal Impairment - Tizanidine should be used with caution in patients with renal insufficiency (creatinine clearance < 25 mL/min), as clearance is reduced by more than 50%. In these patients, during titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose. - Withdrawal Adverse Reactions - Withdrawal adverse reactions include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses (20 mg (base) to 28 mg (base) daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the dose should be decreased slowly (2 mg (base) to 4 mg (base) per day). # Adverse Reactions ## Clinical Trials Experience - 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 clinical practice. - Three double-blind, randomized, placebo controlled -clinical studies were conducted to evaluate the effect of tizanidine on spasticity control. Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury. Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg (base)/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies patient ages ranged from 15 to 69 years and 51.4 percent were women. The median dose during the plateau phase ranged from 20 mg (base)/day to 28 mg (base)/day. - The most frequent adverse reactions reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness) and dizziness. Three-quarters of the patients rated the events as mild to moderate and one-quarter of the patients rated the events as being severe. These events appeared to be dose related. - Table 1 lists signs and symptoms that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received tizanidine where the frequency in the tizanidine group was greater than the placebo group. For comparison purposes, the corresponding frequency of the event (per 100 patients) among placebo treated patients is also provided. - In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1), the patients were specifically asked if they had experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness) and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these reactions is summarized in Table 2. Other events were, in general, reported at a rate of 2% or less. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of tizanidine. 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. - Certain events, such as somnolence, dry mouth, hypotension, decreased blood pressure, bradycardia, dizziness, weakness or asthenia, muscle spasms, hallucinations, fatigue, liver function test abnormality and hepatotoxicity, have been observed in post marketing and clinical trials and are discussed in previous sections of this document. - The following adverse reactions have been identified as occurring in the post marketing experience of tizanidine. Based on the information provided regarding these reactions, a causal relationship with tizanidine cannot be entirely excluded. The events are listed in order of decreasing clinical significance; severity in the post marketing setting is not reported. - Stevens Johnson Syndrome - Anaphylactic Reaction - Exfoliative Dermatitis - Ventricular Tachycardia - Hepatitis - Convulsion - Depression - Arthralgia - Paresthesia - Rash - Tremor # Drug Interactions - Fluvoxamine - Concomitant use of fluvoxamine and tizanidine is contraindicated. Changes in pharmacokinetics of tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. - Ciprofloxacin - Concomitant use of ciprofloxacin and tizanidine is contraindicated. Changes in pharmacokinetics of tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. - CYP1A2 Inhibitors other than Fluvoxamine and Ciprofloxacin - Because of potential drug interactions, concomitant use of tizanidine with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than strong CYP1A2 inhibitors (which are contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided. If their use is clinically necessary, therapy should be initiated with 2 mg (base) dose and increased in 2 mg (base) to 4 mg (base) steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy. - Oral Contraceptives - Concomitant use of tizanidine with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate tizanidine with a single 2 mg (base) dose and increase in 2 mg (base) to 4 mg (base) steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy. - Alcohol - Alcohol increases the overall amount of drug in the bloodstream after a dose of tizanidine hydrochloride. This was associated with an increase in adverse reactions of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive. - Other CNS Depressants - The sedative effects of tizanidine with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation. - α2-adrenergic Agonists - Because hypotensive effects may be cumulative, it is not recommended that tizanidine be used with other α2-adrenergic agonists. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Tizanidine has not been studied in pregnant women. Tizanidine should be given to pregnant women only if the benefit outweighs the risk to the unborn fetus. Reproduction studies performed in rats at a dose of 3 mg (base)/kg, equal to the maximum recommended human dose on a mg/m2 basis, and in rabbits at 30 mg (base)/kg, 16 times the maximum recommended human dose on a mg/m2 basis, did not show evidence of teratogenicity. Tizanidine at doses that are equal to and up to 8 times the maximum recommended human dose on a mg/m2 basis increased gestation duration in rats. Prenatal and postnatal pup loss was increased and developmental retardation occurred. Post-implantation loss was increased in rabbits at doses of 1 mg (base)/kg or greater, equal to or greater than 0.5 times the maximum recommended human dose on a mg/m2 basis. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tizanidine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tizanidine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tizanidine is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Tizanidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Clinical studies of tizanidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Cross-study comparison of pharmacokinetic data following single dose administration of 6 mg (base) tizanidine showed that younger subjects cleared the drug four times faster than the elderly subjects. In elderly patients with renal insufficiency (creatinine clearance < 25 mL/min), tizanidine clearance is reduced by more than 50% compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. Monitor elderly patients because they may have an increased risk for adverse reactions associated with tizanidine. ### Gender There is no FDA guidance on the use of Tizanidine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tizanidine with respect to specific racial populations. ### Renal Impairment - Tizanidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. In patients with renal insufficiency (creatinine clearance < 25 mL/min) clearance was reduced by more than 50%. In these patients, during titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose. ### Hepatic Impairment - The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tizanidine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tizanidine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Tizanidine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tizanidine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose. ### Management - Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken. Tizanidine is a lipid-soluble drug, which is only slightly soluble in water and methanol. Therefore, dialysis is not likely to be an efficient method of removing drug from the body. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center. ## Chronic Overdose There is limited information regarding Chronic Overdose of Tizanidine in the drug label. # Pharmacology ## Mechanism of Action - Tizanidine is a central alpha-2-adrenergic receptor agonist and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons. ## Structure - Tizanidine hydrochloride is a central alpha2-adrenergic agonist. Tizanidine hydrochloride, USP is an almost white to slightly yellow crystalline powder, which is odorless or with a faint characteristic odor. Tizanidine is slightly soluble in water and methanol; solubility in water decreases as the pH increases. Its chemical name is 5-Chloro-N-(4,5-dihydro-1H-imidazol-2yl)-2,1,3-benzothiadiazol-4-amine hydrochloride. Tizanidine’s molecular formula is C9H8ClN5S•HCl, its molecular weight is 290.2 and its structural formula is: - Tizanidine hydrochloride capsules are supplied as 2 mg, 4 mg, and 6 mg capsules for oral administration. Tizanidine hydrochloride capsules contain the active ingredient, tizanidine hydrochloride, USP (2.29 mg equivalent to 2 mg tizanidine base, 4.58 mg equivalent to 4 mg tizanidine base, and 6.87 mg equivalent to 6 mg tizanidine base), and the inactive ingredients anhydrous lactose, colloidal silicon dioxide, hypromellose, microcrystalline cellulose and talc. In addition, each of the empty hard gelatin capsules contain the following: gelatin, red iron oxide, titanium dioxide and yellow iron oxide. The imprinting ink contains the following: ammonia, black iron oxide, potassium hydroxide, propylene glycol and shellac. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Tizanidine in the drug label. ## Pharmacokinetics - Absorption and Distribution - Following oral administration, tizanidine is essentially completely absorbed. The absolute oral bioavailability of tizanidine is approximately 40% (CV = 24%), due to extensive first-pass hepatic metabolism. Tizanidine is extensively distributed throughout the body with a mean steady state volume of distribution of 2.4 L/kg (CV = 21%) following intravenous administration in healthy adult volunteers. Tizanidine is approximately 30% bound to plasma proteins. - Differences between Tizanidine Hydrochloride Capsules and Tizanidine Hydrochloride Tablets - Tizanidine hydrochloride capsules and tizanidine hydrochloride tablets are bioequivalent to each other under fasting conditions, but not under fed conditions. A single dose of either two 4 mg (base) tablets or two 4 mg (base) capsules was administered under fed and fasting conditions in an open label, four period, randomized crossover study in 96 human volunteers, of whom 81 were eligible for the statistical analysis. Following oral administration of either the tablet or capsule (in the fasted state), peak plasma concentrations of tizanidine occurred 1 hour after dosing with a half-life of approximately 2 hours. When two 4 mg (base) tablets were administered with food, the mean maximal plasma concentration was increased by approximately 30%, and the median time to peak plasma concentration was increased by 25 minutes, to 1 hour and 25 minutes. In contrast, when two 4 mg (base) capsules were administered with food, the mean maximal plasma concentration was decreased by 20%, the median time to peak plasma concentration was increased 2 to 3 hours. Consequently, the mean Cmax for the capsule when administered with food is approximately 66% the Cmax for the tablet when administered with food. - Food also increased the extent of absorption for both the tablets and capsules. The increase with the tablet (~30%) was significantly greater than with the capsule (~10%). Consequently when each was administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. Administration of the capsule contents sprinkled on applesauce was not bioequivalent to administration of an intact capsule under fasting conditions. Administration of the capsule contents on applesauce resulted in a 15% to 20% increase in Cmax and AUC of tizanidine and a 15 minute decrease in the median lag time and time to peak concentration compared to administration of an intact capsule while fasting. - Metabolism and Excretion - Tizanidine has linear pharmacokinetics over the doses studied in clinical development [1 mg (base) to 20 mg (base)]. Tizanidine has a half-life of approximately 2.5 hours (CV = 33%). Approximately 95% of an administered dose is metabolized. The primary cytochrome P450 isoenzyme involved in tizanidine metabolism is CYP1A2. Tizanidine metabolites are not known to be active; their half-lives range from 20 to 40 hours. - Following single and multiple oral dosing of 14C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively. - Special Populations - Age Effects - No specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of 6 mg (base) tizanidine showed that younger subjects cleared the drug four times faster than the elderly subjects. Tizanidine has not been evaluated in children. - Hepatic Impairment - The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine. Tizanidine is not recommended in this patient population. - Renal Impairment - Tizanidine clearance is reduced by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. Tizanidine should be used with caution in renally impaired patients. - Gender Effects - No specific pharmacokinetic study was conducted to investigate gender effects. Retrospective analysis of pharmacokinetic data, however, following single and multiple dose administration of 4 mg (base) tizanidine showed that gender had no effect on the pharmacokinetics of tizanidine. - Race Effects - Pharmacokinetic differences due to race have not been studied. - Drug Interactions - CYP1A2 Inhibitors - The interaction between tizanidine and either fluvoxamine or ciprofloxacin is most likely due to inhibition of CYP1A2 by fluvoxamine or ciprofloxacin. The effect of fluvoxamine on the pharmacokinetics of a single 4 mg (base) dose of tizanidine was studied in 10 healthy subjects. The Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively. The effect of ciprofloxacin on the pharmacokinetics of a single 4 mg (base) dose of tizanidine was studied in 10 healthy subjects. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively. - Although there have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, other CYP1A2 inhibitors, such as zileuton, other fluoroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone and verapamil), cimetidine, famotidine oral contraceptives, acyclovir and ticlopidine, may also lead to substantial increases in tizanidine blood concentrations. - In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes. - Oral Contraceptives - No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg (base) tizanidine, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives. - Acetaminophen - Tizanidine delayed the Tmax of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine. - Alcohol - Alcohol increased the AUC of tizanidine by approximately 20%, while also increasing its Cmax by approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive. ## Nonclinical Toxicology - Carcinogenesis - Tizanidine was administered to mice for 78 weeks at oral doses up to 16 mg (base)/kg/day, which is 2 times the maximum recommended human dose (MRHD) on a mg/m2 basis. Tizanidine was administered to rats for 104 weeks at oral doses up to 9 mg (base)/kg/day, which is 2.5 times the MRHD on a mg/m2 basis. There was no increase in tumors in either species. - Mutagenesis - Tizanidine was negative in in vitro (bacterial reverse mutation [Ames], mammalian gene mutation, and chromosomal aberration test in mammalian cells) and in vivo (bone marrow micronucleus, and cytogenetics) assay. - Impairment of Fertility - Oral administration of tizanidine resulted in reduced fertility in male and female rats following doses of 30 mg (base)/kg/day and 10 mg (base)/kg/day, respectively. No effect on fertility was observed at doses of 10 mg (base)/kg/day (male) and 3 mg (base)/kg/day (female), which are approximately 8 and 3 times, respectively, the MRHD on a mg/m2 basis). # Clinical Studies - Tizanidine’s capacity to reduce increased muscle tone associated with spasticity was demonstrated in two adequate and well controlled studies in patients with multiple sclerosis or spinal cord injury (Studies 1 and 2). - Single-dose Study in Patients with Multiple Sclerosis with Spasticity: In Study 1, patients with multiple sclerosis were randomized to receive single oral doses of drug or placebo. Patients and assessors were blind to treatment assignment and efforts were made to reduce the likelihood that assessors would become aware indirectly of treatment assignment (e.g., they did not provide direct care to patients and were prohibited from asking questions about side effects). In all, 140 patients received placebo, 8 mg (base) or 16 mg (base) of tizanidine. - Response was assessed by physical examination; muscle tone was rated on a 5 point scale (Ashworth score), with a score of 0 used to describe normal muscle tone. A score of 1 indicated a slight spastic catch while a score of 2 indicated more marked muscle resistance. A score of 3 was used to describe considerable increase in tone, making passive movement difficult. A muscle immobilized by spasticity was given a score of 4. Spasm counts were also collected. - Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for tizanidine compared to placebo was detected at 1, 2 and 3 hours after treatment. Figure 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 mg (base) and 16 mg (base) tizanidine groups was indistinguishable from muscle tone in placebo treated patients. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg (base) produced a larger effect, adverse events including hypotension were more common and more severe than in the 8 mg (base) group. There were no differences in the number of spasms occurring in each group. - Seven-week Study in Patients with Spinal Cord Injury with Spasticity: In a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine. Steps similar to those taken in the first study were employed to ensure the integrity of blinding. - Patients were titrated over 3 weeks up to a maximum tolerated dose or 36 mg (base) daily given in three unequal doses (e.g., 10 mg (base) given in the morning and afternoon and 16 mg (base) given at night). Patients were then maintained on their maximally tolerated dose for 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a period of 2.5 hours following either the morning or afternoon dose. The number of daytime spasms was recorded daily by patients. - At endpoint (the protocol-specified time of outcome assessment), there was a statistically significant reduction in muscle tone and frequency of spasms in the tizanidine treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine treated patients on measures of activities of daily living. Figure 3 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. # How Supplied - Tizanidine Hydrochloride Capsules - Tizanidine Hydrochloride Capsules are available containing tizanidine hydrochloride, USP equivalent to 2 mg, 4 mg, or 6 mg of tizanidine base. - The 2 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and an orange opaque body filled with light yellow to yellow granular powder. The capsule is axially printed with MYLAN over TE 2 in black ink on both the cap and the body. They are available as follows: NDC 0378-1665-19, bottles of 150 capsules - NDC 0378-1665-19, bottles of 150 capsules - The 4 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and a white opaque body filled with light yellow to yellow granular powder. The capsule is axially printed with MYLAN over TE 4 in black ink on both the cap and the body. They are available as follows: NDC 0378-1666-19, bottles of 150 capsules - NDC 0378-1666-19, bottles of 150 capsules - The 6 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and a peach opaque body filled with light yellow to yellow granular powder. The capsule is axially printed with MYLAN over TE 6 in black ink on both the cap and the body. They are available as follows: NDC 0378-1667-19, bottles of 150 capsules - NDC 0378-1667-19, bottles of 150 capsules - Store at 20° to 25°C (68° to 77°F). - Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. ## Storage There is limited information regarding Tizanidine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Serious Drug Interactions - Advise patients they should not take tizanidine hydrochloride capsules if they are taking fluvoxamine or ciprofloxacin because of the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation. Instruct patients to inform their physicians or pharmacists when they start or stop taking any medication because of the risks associated with interaction between tizanidine hydrochloride capsules and other medicines. - Tizanidine Hydrochloride Capsules Dosing - Tell patients to take tizanidine hydrochloride capsules exactly as prescribed (consistently either with or without food) and not to switch between tablets and capsules. Inform patients that they should not take more tizanidine hydrochloride capsules than prescribed because of the risk of adverse events at single doses greater than 8 mg (base) or total daily doses greater than 36 mg (base). Tell patients that they should not suddenly discontinue tizanidine hydrochloride capsules, because rebound hypertension and tachycardia may occur. - Effects of Tizanidine Hydrochloride Capsules - Warn patients that they may experience hypotension and to be careful when changing from a lying or sitting to a standing position. Tell patients that tizanidine hydrochloride capsules may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery. Tell patients that the sedation may be additive when tizanidine hydrochloride capsules is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants. Remind patients that if they depend on their spasticity to sustain posture and balance in locomotion, or whenever spasticity is utilized to obtain increased function, that tizanidine hydrochloride capsules decrease spasticity and caution should be used. # Precautions with Alcohol - Alcohol-Tizanidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TIZANIDINE HYDROCHLORIDE®[1] # Look-Alike Drug Names - tiZANidine® — tiaGABine®[2] - Zanaflex® — Xiaflex®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Tizanidine
2d9224827d924d1fd48f0e25fc36a0223967107c	wikidoc	Tolazamide	Tolazamide # 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 Tolazamide is an oral hypoglycemic that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia, nausea, epigastric fullness, heartburn, pruritus, erythema, urticaria, leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Tolazamide tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. - There is no fixed dosage regimen for the management of diabetes mellitus with tolazamide tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose-lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. - Short-term administration of tolazamide may be sufficient during periods of transient loss of control in patients usually controlled well on diet. - The usual starting dose of tolazamide tablets for the mild to moderately severe type II diabetic patient is 100 mg to 250 mg daily administered with breakfast or the first main meal. Generally, if the fasting blood glucose is less than 200 mg/dL the starting dose is 100 mg/day as a single daily dose. If the fasting blood glucose value is greater than 200 mg/dL, the starting dose is 250 mg/day as a single dose. If the patient is malnourished, underweight, elderly, or not eating properly, the initial therapy should be 100 mg once a day. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary regimen are more prone to exhibit unsatisfactory response to drug therapy. - Transfer of patients from other oral antidiabetes regimens to tolazamide should be done conservatively. When transferring patients from oral hypoglycemic agents other than chlorpropamide to tolazamide, no transition period or initial or priming dose is necessary. When transferring from chlorpropamide, particular care should be exercised to avoid hypoglycemia. - If receiving less than 1 gm/day, begin at 100 mg of tolazamide per day. If receiving 1 gm or more per day, initiate at 250 mg of tolazamide per day as a single dose. - 250 mg of chlorpropamide may be considered to provide approximately the same degree of blood glucose control as 250 mg of tolazamide. The patient should be observed carefully for hypoglycemia during the transition period from chlorpropamide to tolazamide (1 to 2 weeks) due to the prolonged retention of chlorpropamide in the body and the possibility of a subsequent overlapping drug effect. - 100 mg of tolazamide may be considered to provide approximately the same degree of blood glucose control as 250 mg of acetohexamide. - Some type II diabetic patients who have been treated only with insulin may respond satisfactorily to therapy with tolazamide. If the patient’s previous insulin dosage has been less than 20 units, substitution of 100 mg of tolazamide per day as a single daily dose may be tried. If the previous insulin dosage was less than 40 units, but more than 20 units, the patient should be placed directly on 250 mg of tolazamide per day as a single dose. If the previous insulin dosage was greater than 40 units, the insulin dosage should be decreased by 50% and 250 mg of tolazamide per day started. The dosage of tolazamide should be adjusted weekly (or more often in the group previously requiring more than 40 units of insulin). - During this conversion period when both insulin and tolazamide are being used, hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least 3 times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is a type I diabetic who requires insulin therapy. - Daily doses of greater than 1000 mg are not recommended. Patients will generally have no further response to doses larger than this. - The usual maintenance dose is in the range of 100 to 1000 mg/day with the average maintenance dose being 250 to 500 mg/day. Following initiation of therapy, dosage adjustment is made in increments of 100 mg to 250 mg at weekly intervals based on the patient’s blood glucose response. - Once a day therapy is usually satisfactory. Doses up to 500 mg/day should be given as a single dose in the morning. 500 mg once daily is as effective as 250 mg twice daily. When a dose of more than 500 mg/day is required, the dose may be divided and given twice daily. - In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tolazamide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolazamide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tolazamide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tolazamide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolazamide in pediatric patients. # Contraindications - Tolazamide is contraindicated in patients with: - Known hypersensitivity or allergy to the drug. - Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. - Type I diabetes, as sole therapy. # Warnings - SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY - The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups. (Diabetes, 19 (supp. 2): 747-830, 1970.) - UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2 1/2 times that of patients treated with diet alone. - A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of tolazamide and of alternative modes of therapy. - Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Tolazamide in the drug label. ## Postmarketing Experience - Tolazamide tablets have generally been well tolerated. In clinical studies in which more than 1,784 diabetic patients were specifically evaluated for incidence of side effects only 2.1% were discontinued from therapy because of side effects. - Cholestatic jaundice may occur rarely; tolazamide tablets should be discontinued if this occurs. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and occurred in 1% of patients treated during clinical trials. They tend to be dose related and may disappear when dosage is reduced. - Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in 0.4% of patients treated during clinical trials. These may be transient and may disappear despite continued use of tolazamide; if skin reactions persist, the drug should be discontinued. - Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas. - Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas. - Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas; however, disulfiram-like reactions with tolazamide have been reported very rarely. - Cases of hyponatremia have been reported with tolazamide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH. - Weakness, fatigue, dizziness, vertigo, malaise and headache were reported infrequently in patients treated during clinical trials. The relationship to therapy with tolazamide is difficult to assess. # Drug Interactions There is limited information regarding Tolazamide Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Tolazamide, administered to pregnant rats at 10 times the human dose, decreased litter size but did not produce teratogenic effects in the offspring. In rats treated at a daily dose of 14 mg/kg no reproductive aberrations or drug related fetal anomalies were noted. At an elevated dose of 100 mg/kg per day there was a reduction in the number of pups born and an increased perinatal mortality. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, tolazamide is not recommended for the treatment of the pregnant diabetic patient. Serious consideration should also be given to the possible hazards of the use of tolazamide in women of child bearing age and in those who might become pregnant while using the drug. - Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. - Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If tolazamide is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolazamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tolazamide during labor and delivery. ### Nursing Mothers - Although it is not known whether tolazamide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, 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. If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. ### Pediatric Use There is no FDA guidance on the use of Tolazamide with respect to pediatric patients. ### Geriatic Use - Elderly patients are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly. The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions. - Elderly patients are prone to develop renal insufficiency, which may put them at risk of hypoglycemia. Dose selection should include assessment of renal function. ### Gender There is no FDA guidance on the use of Tolazamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tolazamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tolazamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tolazamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tolazamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tolazamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring - In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose-lowering response after an initial period of effectiveness. # IV Compatibility There is limited information regarding IV Compatibility of Tolazamide in the drug label. # Overdosage - Overdosage of sulfonylureas, including tolazamide tablets, can produce hypoglycemia. - Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustment in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is suspected or diagnosed, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate which will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. # Pharmacology ## Mechanism of Action - Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in type II diabetic patients, the blood glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. - Some patients who are initially responsive to oral hypoglycemic drugs, including tolazamide tablets, may become unresponsive or poorly responsive over time. Alternatively, tolazamide tablets may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. - In addition to its blood glucose-lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance. ## Structure - Tolazamide is an oral blood-glucose-lowering drug of the sulfonylurea class. Tolazamide is a white or creamy-white powder very slightly soluble in water and slightly soluble in alcohol. The chemical name is 1-(Hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea. Tolazamide has the following structural formula: Each tablet for oral administration contains 250 mg or 500 mg of tolazamide, USP and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Tolazamide in the drug label. ## Pharmacokinetics - Tolazamide is rapidly and well absorbed from the gastrointestinal tract. Peak serum concentrations occur at 3 to 4 hours following a single oral dose of the drug. The average biological half-life of the drug is 7 hours. The drug does not continue to accumulate in the blood after the first four to six doses are administered. A steady or equilibrium state is reached during which the peak and nadir values do not change from day to day after the fourth to sixth dose. - Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0% to 70%. They are excreted principally in the urine. Following a single oral dose of tritiated tolazamide, 85% of the dose was excreted in the urine and 7% in the feces over a five day period. Most of the urinary excretion of the drug occurred within the first 24 hours postadministration. - When normal fasting non-diabetic subjects are given a single 500 mg dose of tolazamide orally, a hypoglycemic effect can be noted within 20 minutes after ingestion with a peak hypoglycemic effect occurring in 2 to 4 hours. Following a single oral dose of 500 mg tolazamide, a statistically significant hypoglycemic effect was demonstrated in fasted nondiabetic subjects 20 hours after administration. With fasting diabetic patients, the peak hypoglycemic effect occurs at 4 to 6 hours. The duration of maximal hypoglycemic effect in fed diabetic patients is about 10 hours, with the onset occurring at 4 to 6 hours and with the blood glucose levels beginning to rise at 14 to 16 hours. Single dose potency of tolazamide in normal subjects has been shown to be 6.7 times that of tolbutamide on a milligram basis. Clinical experience in diabetic patients has demonstrated tolazamide to be approximately 5 times more potent than tolbutamide on a milligram basis, and approximately equivalent in milligram potency to chlorpropamide. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Tolazamide in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Tolazamide in the drug label. # How Supplied - Tolazamide Tablets, USP are available containing either 250 mg or 500 mg of tolazamide, USP. - The 250 mg tablets are white to off-white, round, scored tablets debossed with MYLAN above the score and 217 below the score on one side of the tablet and 250 on the other side. They are available as follows: - NDC 0378-0217-01 - bottles of 100 tablets - The 500 mg tablets are white to off-white, round, scored tablets debossed with MYLAN above the score and 551 below the score on one side of the tablet and blank on the other side. They are available as follows: - NDC 0378-0551-01 - bottles of 100 tablets ## Storage - Store at 20° to 25°C (68° to 77°F). - Protect from light. - Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Tolazamide in the drug label. # Precautions with Alcohol - Alcohol-Tolazamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TOLAZAMIDE ® # Look-Alike Drug Names There is limited information regarding Tolazamide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Tolazamide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, 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 Tolazamide is an oral hypoglycemic that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia, nausea, epigastric fullness, heartburn, pruritus, erythema, urticaria, leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Tolazamide tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. - There is no fixed dosage regimen for the management of diabetes mellitus with tolazamide tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose-lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient’s response to therapy. - Short-term administration of tolazamide may be sufficient during periods of transient loss of control in patients usually controlled well on diet. - The usual starting dose of tolazamide tablets for the mild to moderately severe type II diabetic patient is 100 mg to 250 mg daily administered with breakfast or the first main meal. Generally, if the fasting blood glucose is less than 200 mg/dL the starting dose is 100 mg/day as a single daily dose. If the fasting blood glucose value is greater than 200 mg/dL, the starting dose is 250 mg/day as a single dose. If the patient is malnourished, underweight, elderly, or not eating properly, the initial therapy should be 100 mg once a day. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary regimen are more prone to exhibit unsatisfactory response to drug therapy. - Transfer of patients from other oral antidiabetes regimens to tolazamide should be done conservatively. When transferring patients from oral hypoglycemic agents other than chlorpropamide to tolazamide, no transition period or initial or priming dose is necessary. When transferring from chlorpropamide, particular care should be exercised to avoid hypoglycemia. - If receiving less than 1 gm/day, begin at 100 mg of tolazamide per day. If receiving 1 gm or more per day, initiate at 250 mg of tolazamide per day as a single dose. - 250 mg of chlorpropamide may be considered to provide approximately the same degree of blood glucose control as 250 mg of tolazamide. The patient should be observed carefully for hypoglycemia during the transition period from chlorpropamide to tolazamide (1 to 2 weeks) due to the prolonged retention of chlorpropamide in the body and the possibility of a subsequent overlapping drug effect. - 100 mg of tolazamide may be considered to provide approximately the same degree of blood glucose control as 250 mg of acetohexamide. - Some type II diabetic patients who have been treated only with insulin may respond satisfactorily to therapy with tolazamide. If the patient’s previous insulin dosage has been less than 20 units, substitution of 100 mg of tolazamide per day as a single daily dose may be tried. If the previous insulin dosage was less than 40 units, but more than 20 units, the patient should be placed directly on 250 mg of tolazamide per day as a single dose. If the previous insulin dosage was greater than 40 units, the insulin dosage should be decreased by 50% and 250 mg of tolazamide per day started. The dosage of tolazamide should be adjusted weekly (or more often in the group previously requiring more than 40 units of insulin). - During this conversion period when both insulin and tolazamide are being used, hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least 3 times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is a type I diabetic who requires insulin therapy. - Daily doses of greater than 1000 mg are not recommended. Patients will generally have no further response to doses larger than this. - The usual maintenance dose is in the range of 100 to 1000 mg/day with the average maintenance dose being 250 to 500 mg/day. Following initiation of therapy, dosage adjustment is made in increments of 100 mg to 250 mg at weekly intervals based on the patient’s blood glucose response. - Once a day therapy is usually satisfactory. Doses up to 500 mg/day should be given as a single dose in the morning. 500 mg once daily is as effective as 250 mg twice daily. When a dose of more than 500 mg/day is required, the dose may be divided and given twice daily. - In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tolazamide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolazamide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tolazamide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tolazamide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolazamide in pediatric patients. # Contraindications - Tolazamide is contraindicated in patients with: - Known hypersensitivity or allergy to the drug. - Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. - Type I diabetes, as sole therapy. # Warnings - SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY - The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups. (Diabetes, 19 (supp. 2): 747-830, 1970.) - UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2 1/2 times that of patients treated with diet alone. * A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of tolazamide and of alternative modes of therapy. - Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Tolazamide in the drug label. ## Postmarketing Experience - Tolazamide tablets have generally been well tolerated. In clinical studies in which more than 1,784 diabetic patients were specifically evaluated for incidence of side effects only 2.1% were discontinued from therapy because of side effects. - Cholestatic jaundice may occur rarely; tolazamide tablets should be discontinued if this occurs. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and occurred in 1% of patients treated during clinical trials. They tend to be dose related and may disappear when dosage is reduced. - Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in 0.4% of patients treated during clinical trials. These may be transient and may disappear despite continued use of tolazamide; if skin reactions persist, the drug should be discontinued. - Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas. - Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas. - Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas; however, disulfiram-like reactions with tolazamide have been reported very rarely. - Cases of hyponatremia have been reported with tolazamide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH. - Weakness, fatigue, dizziness, vertigo, malaise and headache were reported infrequently in patients treated during clinical trials. The relationship to therapy with tolazamide is difficult to assess. # Drug Interactions There is limited information regarding Tolazamide Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Tolazamide, administered to pregnant rats at 10 times the human dose, decreased litter size but did not produce teratogenic effects in the offspring. In rats treated at a daily dose of 14 mg/kg no reproductive aberrations or drug related fetal anomalies were noted. At an elevated dose of 100 mg/kg per day there was a reduction in the number of pups born and an increased perinatal mortality. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, tolazamide is not recommended for the treatment of the pregnant diabetic patient. Serious consideration should also be given to the possible hazards of the use of tolazamide in women of child bearing age and in those who might become pregnant while using the drug. - Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. - Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If tolazamide is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolazamide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tolazamide during labor and delivery. ### Nursing Mothers - Although it is not known whether tolazamide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, 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. If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. ### Pediatric Use There is no FDA guidance on the use of Tolazamide with respect to pediatric patients. ### Geriatic Use - Elderly patients are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly. The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions. - Elderly patients are prone to develop renal insufficiency, which may put them at risk of hypoglycemia. Dose selection should include assessment of renal function. ### Gender There is no FDA guidance on the use of Tolazamide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tolazamide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tolazamide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tolazamide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tolazamide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tolazamide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring - In addition to the usual monitoring of urinary glucose, the patient’s blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose-lowering response after an initial period of effectiveness. # IV Compatibility There is limited information regarding IV Compatibility of Tolazamide in the drug label. # Overdosage - Overdosage of sulfonylureas, including tolazamide tablets, can produce hypoglycemia. - Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustment in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is suspected or diagnosed, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate which will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. # Pharmacology ## Mechanism of Action - Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in type II diabetic patients, the blood glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. - Some patients who are initially responsive to oral hypoglycemic drugs, including tolazamide tablets, may become unresponsive or poorly responsive over time. Alternatively, tolazamide tablets may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. - In addition to its blood glucose-lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance. ## Structure - Tolazamide is an oral blood-glucose-lowering drug of the sulfonylurea class. Tolazamide is a white or creamy-white powder very slightly soluble in water and slightly soluble in alcohol. The chemical name is 1-(Hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea. Tolazamide has the following structural formula: Each tablet for oral administration contains 250 mg or 500 mg of tolazamide, USP and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Tolazamide in the drug label. ## Pharmacokinetics - Tolazamide is rapidly and well absorbed from the gastrointestinal tract. Peak serum concentrations occur at 3 to 4 hours following a single oral dose of the drug. The average biological half-life of the drug is 7 hours. The drug does not continue to accumulate in the blood after the first four to six doses are administered. A steady or equilibrium state is reached during which the peak and nadir values do not change from day to day after the fourth to sixth dose. - Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0% to 70%. They are excreted principally in the urine. Following a single oral dose of tritiated tolazamide, 85% of the dose was excreted in the urine and 7% in the feces over a five day period. Most of the urinary excretion of the drug occurred within the first 24 hours postadministration. - When normal fasting non-diabetic subjects are given a single 500 mg dose of tolazamide orally, a hypoglycemic effect can be noted within 20 minutes after ingestion with a peak hypoglycemic effect occurring in 2 to 4 hours. Following a single oral dose of 500 mg tolazamide, a statistically significant hypoglycemic effect was demonstrated in fasted nondiabetic subjects 20 hours after administration. With fasting diabetic patients, the peak hypoglycemic effect occurs at 4 to 6 hours. The duration of maximal hypoglycemic effect in fed diabetic patients is about 10 hours, with the onset occurring at 4 to 6 hours and with the blood glucose levels beginning to rise at 14 to 16 hours. Single dose potency of tolazamide in normal subjects has been shown to be 6.7 times that of tolbutamide on a milligram basis. Clinical experience in diabetic patients has demonstrated tolazamide to be approximately 5 times more potent than tolbutamide on a milligram basis, and approximately equivalent in milligram potency to chlorpropamide. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Tolazamide in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Tolazamide in the drug label. # How Supplied - Tolazamide Tablets, USP are available containing either 250 mg or 500 mg of tolazamide, USP. - The 250 mg tablets are white to off-white, round, scored tablets debossed with MYLAN above the score and 217 below the score on one side of the tablet and 250 on the other side. They are available as follows: - NDC 0378-0217-01 - bottles of 100 tablets - The 500 mg tablets are white to off-white, round, scored tablets debossed with MYLAN above the score and 551 below the score on one side of the tablet and blank on the other side. They are available as follows: - NDC 0378-0551-01 - bottles of 100 tablets ## Storage - Store at 20° to 25°C (68° to 77°F). - Protect from light. - Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Tolazamide in the drug label. # Precautions with Alcohol - Alcohol-Tolazamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TOLAZAMIDE ®[1] # Look-Alike Drug Names There is limited information regarding Tolazamide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Tolazamide
7f4aaeed28405fb659937094740bf7f130949071	wikidoc	Tolazoline	Tolazoline # Overview Tolazoline is a non-selective competitive α-adrenergic receptor antagonist. It is a vasodilator that is used to treat spasms of peripheral blood vessels (as in acrocyanosis). It has also been used successfully as an antidote to reverse the severe peripheral vasoconstriction which can occur as a result of overdose with certain 5-HT2A agonist drugs such as 25I-NBOMe, DOB and Bromodragonfly (prolonged severe vasoconstriction can lead to gangrene if untreated). It is however most commonly used in veterinary medicine, to reverse xylazine-induced sedation. # Chemistry Tolazoline can be synthesized by the heterocyclation of the ethyl ester of iminophenzylacetic acid with ethylene diamine, which forms the desired product. The structure of tolazoline is strikingly similar to α-adrenergic agonists, which are antiedema sympathomimetics.	Tolazoline Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Tolazoline is a non-selective competitive α-adrenergic receptor antagonist. It is a vasodilator that is used to treat spasms of peripheral blood vessels (as in acrocyanosis). It has also been used successfully as an antidote to reverse the severe peripheral vasoconstriction which can occur as a result of overdose with certain 5-HT2A agonist drugs such as 25I-NBOMe,[citation needed] DOB and Bromodragonfly (prolonged severe vasoconstriction can lead to gangrene if untreated).[1][2] It is however most commonly used in veterinary medicine, to reverse xylazine-induced sedation.[3][4] # Chemistry Tolazoline can be synthesized by the heterocyclation of the ethyl ester of iminophenzylacetic acid with ethylene diamine, which forms the desired product.[5][6][7][8] The structure of tolazoline is strikingly similar to α-adrenergic agonists, which are antiedema sympathomimetics.	https://www.wikidoc.org/index.php/Tolazoline
0b9c3d502ae71a324c152e4363d2ffa07589df64	wikidoc	Tolnaftate	Tolnaftate # 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. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Tolnaftate is a OTC antifungal that is FDA approved for the treatment of athlete’s foot (tinea pedis), ringworm (tinea corporis). Common adverse reactions include irritation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - athlete’s foot (tinea pedis) - ringworm (tinea corporis) - for effective relief of itching, burning, cracking ### Directions - wash affected area and dry thoroughly - apply a thin layer over affected area twice daily (morning and night) - supervise children in the use of this product - for athlete’s foot: pay special attention to spaces between the toes. Wear well-fitting, ventilated shoes, and change shoes and socks at least once daily. - use daily for 4 weeks. If condition lasts longer, ask a doctor. - to prevent athlete’s foot, apply once or twice daily (morning and/or night) - this product is not effective on the scalp or nails ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tolnaftate in adult patients. ### Non–Guideline-Supported Use - Onychomycosis due to dermatophyte # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tolnaftate in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tolnaftate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolnaftate in pediatric patients. # Contraindications There is limited information regarding Tolnaftate Contraindications in the drug label. # Warnings - For external use only - avoid contact with the eyes - irritation occurs - there is no improvement within 4 weeks - children under 2 years of age unless directed by a doctor - If swallowed, get medical help or contact a Poison Control Center right away. (1-800-222-1222) # Adverse Reactions ## Clinical Trials Experience - irritation ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Tolnaftate in the drug label. # Drug Interactions There is limited information regarding Tolnaftate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolnaftate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tolnaftate during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Tolnaftate with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Tolnaftate with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Tolnaftate with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Tolnaftate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tolnaftate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tolnaftate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tolnaftate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tolnaftate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tolnaftate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical cream ### Monitoring There is limited information regarding Monitoring of Tolnaftate in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tolnaftate in the drug label. # Overdosage There is limited information regarding Overdose of Tolnaftate in the drug label. # Pharmacology ## Mechanism of Action There is limited information regarding Tolnaftate Mechanism of Action in the drug label. ## Structure There is limited information regarding Tolnaftate Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Tolnaftate in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Tolnaftate in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Tolnaftate in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Tolnaftate in the drug label. # How Supplied There is limited information regarding Tolnaftate How Supplied in the drug label. ## Storage - store at 68°-77°F (20°-25°C) # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL Cures Most Athlete’s Foot Relieves Itching & Burning Compare to Tinactin® active ingredient Tolnaftate Cream USP, 1% Antifungal ### Ingredients and Appearance # Patient Counseling Information There is limited information regarding Patient Counseling Information of Tolnaftate in the drug label. # Precautions with Alcohol - Alcohol-Tolnaftate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tinactin® # Look-Alike Drug Names There is limited information regarding Tolnaftate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Tolnaftate 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. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Tolnaftate is a OTC antifungal that is FDA approved for the treatment of athlete’s foot (tinea pedis), ringworm (tinea corporis). Common adverse reactions include irritation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - athlete’s foot (tinea pedis) - ringworm (tinea corporis) - for effective relief of itching, burning, cracking ### Directions - wash affected area and dry thoroughly - apply a thin layer over affected area twice daily (morning and night) - supervise children in the use of this product - for athlete’s foot: pay special attention to spaces between the toes. Wear well-fitting, ventilated shoes, and change shoes and socks at least once daily. - use daily for 4 weeks. If condition lasts longer, ask a doctor. - to prevent athlete’s foot, apply once or twice daily (morning and/or night) - this product is not effective on the scalp or nails ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tolnaftate in adult patients. ### Non–Guideline-Supported Use - Onychomycosis due to dermatophyte[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Tolnaftate in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tolnaftate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolnaftate in pediatric patients. # Contraindications There is limited information regarding Tolnaftate Contraindications in the drug label. # Warnings - For external use only - avoid contact with the eyes - irritation occurs - there is no improvement within 4 weeks - children under 2 years of age unless directed by a doctor - If swallowed, get medical help or contact a Poison Control Center right away. (1-800-222-1222) # Adverse Reactions ## Clinical Trials Experience - irritation ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Tolnaftate in the drug label. # Drug Interactions There is limited information regarding Tolnaftate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolnaftate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tolnaftate during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Tolnaftate with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Tolnaftate with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Tolnaftate with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Tolnaftate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tolnaftate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tolnaftate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tolnaftate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tolnaftate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tolnaftate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical cream ### Monitoring There is limited information regarding Monitoring of Tolnaftate in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tolnaftate in the drug label. # Overdosage There is limited information regarding Overdose of Tolnaftate in the drug label. # Pharmacology ## Mechanism of Action There is limited information regarding Tolnaftate Mechanism of Action in the drug label. ## Structure There is limited information regarding Tolnaftate Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Tolnaftate in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Tolnaftate in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Tolnaftate in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Tolnaftate in the drug label. # How Supplied There is limited information regarding Tolnaftate How Supplied in the drug label. ## Storage - store at 68°-77°F (20°-25°C) # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL Cures Most Athlete’s Foot Relieves Itching & Burning Compare to Tinactin® active ingredient Tolnaftate Cream USP, 1% Antifungal ### Ingredients and Appearance # Patient Counseling Information There is limited information regarding Patient Counseling Information of Tolnaftate in the drug label. # Precautions with Alcohol - Alcohol-Tolnaftate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tinactin®[2] # Look-Alike Drug Names There is limited information regarding Tolnaftate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Tolnaftate
3a311aef5079041674caa1b7aee83c32c523af2b	wikidoc	Toothbrush	Toothbrush The toothbrush is an instrument consisting of a small brush on a handle used to clean teeth through tooth brushing. Toothpaste, often containing fluoride, is commonly added to a toothbrush to aid in cleaning. Toothbrushes are offered with varying textures of bristles, and come in many different sizes and forms. Most dentists recommend using a toothbrush labelled "Soft", since firmer bristled toothbrushes can damage tooth enamel and irritate gums as indicated by the American Dental Association. Toothbrushes are often made from synthetic fibers, although natural toothbrushes are also known in many parts of the world. The first commercial toothbrush was invented by Goldstein and Hautman in 1875. # History A variety of oral hygiene measures have been used since before recorded history. This has been verified by various excavations done all over the world, in which chewsticks, tree twigs, bird feathers, animal bones and porcupine quills were recovered. The first modern idea of a toothbrush is believed to have been invented in China in the late 1400's by the Chinese, which used the stiff hairs from a hog's neck, attached to a bamboo stick. However, many other peoples used different forms of toothbrushes. Ancient Indian medicine has used the neem tree and its products to create toothbrushes and similar products for millennia. In the Muslim world, the miswak, or siwak, made from a twig or root with antiseptic properties is widely used. Rubbing baking soda or chalk against the teeth was also common. William Addis of England is credited with creating the first mass-produced toothbrush in 1780. In 1770 he had been placed in jail for causing a riot. While in prison, he decided that the method for teeth brushing of the time – rubbing a rag on one's teeth with soot and salt – could be improved. So he took a small animal bone, drilled small holes in it, obtained some bristles from a guard, tied them in tufts, then passed the bristles through the holes on the bone and glued them. He soon became very wealthy. He died in the year 1808 and left the business to his eldest son, William II. The first patent for a toothbrush was by H. N. Wadsworth in 1857 (US Patent No. 18,653) in the United States, but mass production of the product in America only started in 1885. The rather advanced design had a bone handle with holes bored into it for the Siberian Boar hair bristles. Boar wasn't an ideal material; it retained bacteria, it didn't dry well, and the bristles would often fall out of the brush. It wasn't until World War II, however, that the concept of brushing teeth really caught on in the U.S., in part because it was part of American soldiers' regular daily duty to clean their teeth. It was a practice that they brought back to their home life after the conclusion of the war. Natural bristles (from animal hair) were replaced by synthetic fibers, usually nylon, by DuPont in 1938. The first nylon bristle toothbrush, made with nylon yarn, went on sale on February 24, 1938. The first electric toothbrush, the Broxodent, was introduced by the Bristol-Myers Company (now Bristol-Myers Squibb) at the centennial of the American Dental Association in 1959. In January 2003, the toothbrush was selected as the number one invention Americans could not live without, beating out the automobile, computer, cell phone, and microwave oven, according to the Lemelson-MIT Invention Index. # Electric toothbrushes The first electric toothbrush was developed in 1939 in Scotland, but did not appear on the open market until the 1960s, when it was marketed as the Broxodent in the United States by Squibb. In 1961, General Electric introduced a rechargeable cordless toothbrush that moved up and down when activated. In 1987, the first rotary action toothbrush for home use, the Interplak, appeared in shops for the general public. There are currently many different varieties of model that use this mechanism.	Toothbrush Template:Nr The toothbrush is an instrument consisting of a small brush on a handle used to clean teeth through tooth brushing. Toothpaste, often containing fluoride, is commonly added to a toothbrush to aid in cleaning. Toothbrushes are offered with varying textures of bristles, and come in many different sizes and forms. Most dentists recommend using a toothbrush labelled "Soft", since firmer bristled toothbrushes can damage tooth enamel and irritate gums as indicated by the American Dental Association.[citation needed] Toothbrushes are often made from synthetic fibers, although natural toothbrushes are also known in many parts of the world. The first commercial toothbrush was invented by Goldstein and Hautman in 1875. # History A variety of oral hygiene measures have been used since before recorded history. This has been verified by various excavations done all over the world, in which chewsticks, tree twigs, bird feathers, animal bones and porcupine quills were recovered. The first modern idea of a toothbrush is believed to have been invented in China in the late 1400's by the Chinese,[1] which used the stiff hairs from a hog's neck, attached to a bamboo stick. However, many other peoples used different forms of toothbrushes. Ancient Indian medicine has used the neem tree and its products to create toothbrushes and similar products for millennia. In the Muslim world, the miswak, or siwak, made from a twig or root with antiseptic properties is widely used. Rubbing baking soda or chalk against the teeth was also common. William Addis of England is credited with creating the first mass-produced toothbrush in 1780. In 1770 he had been placed in jail for causing a riot. While in prison, he decided that the method for teeth brushing of the time – rubbing a rag on one's teeth with soot and salt – could be improved. So he took a small animal bone, drilled small holes in it, obtained some bristles from a guard, tied them in tufts, then passed the bristles through the holes on the bone and glued them. He soon became very wealthy. He died in the year 1808 and left the business to his eldest son, William II. The first patent for a toothbrush was by H. N. Wadsworth in 1857 (US Patent No. 18,653) in the United States, but mass production of the product in America only started in 1885. The rather advanced design had a bone handle with holes bored into it for the Siberian Boar hair bristles. Boar wasn't an ideal material; it retained bacteria, it didn't dry well, and the bristles would often fall out of the brush. It wasn't until World War II, however, that the concept of brushing teeth really caught on in the U.S., in part because it was part of American soldiers' regular daily duty to clean their teeth. It was a practice that they brought back to their home life after the conclusion of the war.[citation needed] Natural bristles (from animal hair) were replaced by synthetic fibers, usually nylon, by DuPont in 1938. The first nylon bristle toothbrush, made with nylon yarn, went on sale on February 24, 1938. The first electric toothbrush, the Broxodent, was introduced by the Bristol-Myers Company (now Bristol-Myers Squibb) at the centennial of the American Dental Association in 1959. In January 2003, the toothbrush was selected as the number one invention Americans could not live without, beating out the automobile, computer, cell phone, and microwave oven, according to the Lemelson-MIT Invention Index.[1] # Electric toothbrushes The first electric toothbrush was developed in 1939 in Scotland, but did not appear on the open market until the 1960s, when it was marketed as the Broxodent in the United States by Squibb.[citation needed] In 1961, General Electric introduced a rechargeable cordless toothbrush that moved up and down when activated.[citation needed] In 1987, the first rotary action toothbrush for home use, the Interplak, appeared in shops for the general public.[citation needed] There are currently many different varieties of model that use this mechanism.	https://www.wikidoc.org/index.php/Toothbrush

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